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Abstract Background Beta-lactam therapeutic drug monitoring (BL TDM; drug level testing) can facilitate improved outcomes in critically ill patients. Yet less than 20% of hospitals have implemented BL TDM. The purpose of this study was to characterize provider perceptions and key considerations for successful implementation of BL TDM. Methods This was a sequential mixed methods study from 2020 to 2021 of stakeholders at three academic medical centers with varying degrees of BL TDM implementation - Mayo Clinic (BL TDM not implemented), University of Florida Health Shands (partially implemented), and Royal Brisbane and Women’s Hospital (fully implemented). Stakeholders completed a survey to characterize their knowledge, perceptions, and experience with BL TDM. A diverse group of 30 respondents were then purposively sampled for semi-structured interviews. Results from the two strands were integrated, themes were identified, and findings were situated within implementation science frameworks. Results Among the 138 survey respondents (22% response rate), the majority were physicians (38%) and pharmacists (33%). 71% practiced in critical care and 21% in infectious diseases. The majority of respondents felt BL TDM was relevant to their practice and improved medication effectiveness and safety (Figure 1). Two implementation themes were identified: individual internalization and organizational features. Individuals needed to internalize, make sense of, and agree to BL TDM implementation which was positively influenced by repeated exposure to evidence and expertise. The process of internalization seemed more complex with BL TDM than with other antibiotics (i.e., vancomycin). Organizational considerations relevant to BL TDM implementation included adequate physical and informational infrastructure, access to trained personnel, supportive governance/leadership, and robust process and workflow development. Conclusion We found broad enthusiasm about the relevance and potential benefits of BL TDM among stakeholders. Prior literature suggested the primary barrier to implementation was assay availability, but we identified many more individual and organizational attributes which impacted the scale and spread of BL TDM. Disclosures Sara Ausman, PharmD, Gilead: Honoraria Christina G. Rivera, PharmD, Gilead: Grant/Research Support|Gilead: Honoraria|Insmed: Honoraria Jason Roberts, BPharm(Hons), PhD, FSHP, FISAC, British Society of Chemotherapy: Grant/Research Support|Cipla: Honoraria|Gilead: Advisor/Consultant|MSD: Advisor/Consultant|MSD: Honoraria|Pfizer: Board Member|Pfizer: Honoraria|Qpex: Grant/Research Support|Sandoz: Board Member|Summit: Advisor/Consultant|Wolters Kluwer: Advisor/Consultant Marc H. Scheetz, PharmD, MSc, Abbvie: Advisor/Consultant|Allecra: Grant/Research Support|Merck: Advisor/Consultant|Nevakar: Advisor/Consultant|Nevakar: Grant/Research Support|Premier Healthcare Solutions: Honoraria|Spero: Advisor/Consultant|SuperTrans Medical: Advisor/Consultant|SuperTrans Medical: Grant/Research Support|Takeda: Advisor/Consultant|Third Pole Therapeutics: Advisor/Consultant.

Blood cultures have been the gold standard for identifying pathogens in infective endocarditis (IE). Blood culture-negative endocarditis (BCNE), however, occurs in 40% or more of IE cases with the bulk of them due to recent antibiotic exposure prior to obtaining blood cultures. Increasingly, molecular techniques are being used for pathogen identification in cases of BCNE and more recently has included metagenomic next-generation sequencing (mNGS). We therefore performed a literature search on August 31, 2022, that assessed the mNGS in IE and 13 publications were identified and included in a systematic review. Eight (61.5%) of them focused only on IE with mNGS performed on cardiac valve tissue in four studies, plasma in three studies and cardiac implantable electronic devices (CIED) in one study. Gram-positive cocci, including Staphylococcus aureus (n = 31, 8.9%), coagulase-negative staphylococci (n = 61, 17.6%), streptococci (n = 130, 37.5%), and Enterococcus faecalis (n = 23, 6.6%) were the predominant organisms identified by mNGS. Subsequent investigations are needed to further define the utility of mNGS in BCNE and its impact on patient outcomes. Despite some pitfalls, mNGS seems to be of value in pathogen identification in IE cases, particularly in those with BCNE. This study was registered and on the Open Science Framework platform.

ImportanceLate-onset meningitis (LOM) has been associated with adverse neurodevelopmental outcomes in children born extremely preterm.ObjectiveTo report the incidence of LOM during birth hospitalization and neurodevelopmental outcomes at 18 to 26 months’ corrected age.Design, Setting, and ParticipantsThis cohort study is a secondary analysis of a multicenter prospective cohort of children born at 22 to 26 weeks’ gestation between 2003 and 2017 with follow-up from 2004 to 2021. The study was conducted at 25 Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network centers.ExposuresCulture-confirmed LOM.Main Outcomes and MeasuresIncidence and microbiology of LOM (2003-2017); lumbar puncture (LP) performance in late-onset sepsis (LOS) evaluations (2011-2017); composite outcome of death or neurodevelopmental impairment (NDI; 2004-2021).ResultsAmong 13 372 infants (median [IQR] gestational age, 25.4 [24.4-26.1] weeks; 6864 [51%] boys), LOM was diagnosed in 167 (1%); LOS without LOM in 4564 (34%); and neither LOS nor LOM in 8641 (65%). The observed incidence of LOM decreased from 2% (95% CI, 1%-3%) in 2003 to 0.4% (95% CI, 0.7%-1.0%) in 2017 (P < .001). LP performance in LOS evaluations decreased from 36% (95% CI, 33%-40%) in 2011 to 24% (95% CI, 21%-27%) in 2017 (P < .001). Among infants with culture-confirmed LOS, LP performance decreased from 58% (95% CI, 51%-65%) to 45% (95% CI, 38%-51%; P = .008). LP performance varied by center among all LOS evaluations (10%-59%, P < .001) and among those with culture-confirmed LOS (23%-79%, P < .001). LOM occurred in the absence of concurrent LOS in 27 of 167 cases (16%). The most common LOM isolates were coagulase-negative Staphylococcus (98 [59%]), Candida albicans (38 [23%]), and Escherichia coli (27 [16%]). Death or NDI occurred in 22 of 46 children (48%) with LOM due to coagulase-negative Staphylococcus, 43 of 67 (64%) due to all other bacterial pathogens, and 26 of 33 (79%) due to fungal pathogens. The adjusted relative risk of death or NDI was increased among children with LOM (aOR, 1.53; 95% CI, 1.04-2.25) and among those with LOS without LOM (aOR, 1.41; 95% CI, 1.29-1.54) compared with children with neither infection.Conclusions and RelevanceIn this cohort study, LP was performed with decreasing frequency, and the observed incidence of LOM also decreased. Both LOM and LOS were associated with increased risk of death or NDI; risk varied by LOM pathogen. The full association of LOM with outcomes of children born extremely preterm may be underestimated by current diagnostic practices.

AbstractBackgroundRisk factors for intervention in terminal ileal (TI) stricturing Crohn's disease (CD) are poorly defined. Novel and rigorous definitions for TI strictures recently became available.ObjectiveWe aimed to describe the rates of symptoms or need for endoscopic balloon dilation (EBD) or surgery as well as risk factors of progression in a well‐defined stricturing CD cohort.MethodsConsecutive adult patients with non‐penetrating stricturing TI CD, as defined by centrally‐read magnetic resonance enterography CONSTRICT criteria, were separated into a derivation and validation cohort. Clinical and imaging characteristics were collected following prespecified scoring conventions. Primary outcome was a composite endpoint of EBD or surgery (“intervention”). Multivariable analysis was performed.ResultsEighty‐six patients (48.8% female, median age 36 years) met selection criteria, 17.4% had prior EBD, 59.3% previously received biologics and 58.1% of strictures were anastomotic. Median follow‐up was 63.4 [95% CI: 57, 68.9] months. In the derivation cohort, at 12 and 48 months, 26% and 45% of patients had intervention, respectively. Multivariable analysis showed obstructive symptoms (Hazard ratio [HR] 1.444; 95% CI 1.126–1.852), stricture duration (HR 0.974; 95% CI, 0.954–0.995) and length (HR 1.039; 95% CI, 1.011–1.069) predicted intervention. The concordance index for split‐sample validation was 0.74 and 0.67, respectively. Biologics were not associated with intervention. An online risk calculator was constructed.ConclusionIn patients with TI stricturing CD, 26% and 45% required intervention at 1 and 4 years. Obstructive symptoms, stricture duration and length were independent and validated predictors of the need for intervention. These findings are important for clinical practice and aid in the design of future trials for CD strictures.

Abstract Intestinal failure (IF) is a rare disease that requires ongoing intravenous supplementation to sustain growth and health. Advancements in parenteral nutrition (PN) and central venous access in the 1960s and 1970s transformed a life‐limiting disease to a chronic one in which patients are able to administer hydration, electrolytes, micronutrients, and macronutrients in the comfort of their home. However, despite ongoing advancements in the field of home PN (HPN), complications—whether related to central venous catheters or PN itself—remain common and can be associated with significant morbidity and mortality. Central venous access can be associated with thrombosis, central line–associated bloodstream infection, or damage and can result in loss of access over time. PN can be associated with IF‐associated liver disease or hyperglycemia. The key to preserving central venous access and quality of life and maintaining health for patients with chronic IF (CIF) is education focused on prevention and prompt management of CIF complications as they arise. This education typically takes place at the time of initiation of HPN, either in the hospital setting or in the patient's home. The present manuscript describes the historical progression of HPN, prevalence and characteristics of CIF, and an in‐depth discussion of the most common catheter‐related and PN‐related complications and their management, along with a discussion of our education and training process.

Abstract Background Idiopathic pulmonary fibrosis (IPF) is characterized by pathological accumulation of scar tissue in the lung parenchyma. Many of the processes that are implicated in fibrosis, such as matrix deposition also occur following pneumonectomy (PNX). However, fibrosis does not occur. Since fibroblasts are the major cell type responsible for extracellular matrix production, we hypothesized that comparing their responses to PNX and bleomycin (BLM) would unveil key differences in the role they play during regulated and fibrotic lung growth. Methods RNA-sequencing was performed on flow cytometry-sorted fibroblasts from mouse lungs 14 days after bleomycin challenge, PNX, or sham. Pathway and transcription factor binding motif enrichment analysis were performed to characterize RNA-sequencing data. Normal human lung fibroblasts (NHLFs) were used as a cell culture model to validate targets. Results RNA-sequencing analysis revealed similar biological processes to be involved in both responses, including signaling by transforming growth factor-β (TGF-β1) and tumor necrosis factor-α. Transcription factor binding motif enrichment predicted erythroid transformation specific (ETS) superfamily members to play a key role in the response to BLM, whereas nuclear factor-κB (NF-κB) and activator protein-1 (AP-1) were predicted to orchestrate much of the response to PNX. Itpkc, encoding inositol triphosphate kinase C, was a gene uniquely up-regulated by PNX and a likely AP-1 target. ITPKC overexpression in NHLFs antagonized the fibrotic effect of TGF-β1. RNA-sequencing analysis of primary NHLFs overexpressing ITPKC further supported its role in repressing collagen production and predicted it as an activator of canonical NF-κB signaling. ITPKC overexpression showed considerable overlap with the innate immune signaling seen following PNX. Conclusion Taken together, our RNA-sequencing analysis suggests that during post-PNX lung growth, AP-1 activates ITPKC to promote canonical NF-κB signaling to prevent fibrogenesis. Future studies to understand this lack of ITPKC induction during fibrotic injury may identify attractive therapeutic targets.

Background: Biomechanical studies support the use of suture tape reinforcement for limiting graft elongation and increasing strength in knee ligament reconstructions. Purpose: To compare posterior cruciate ligament (PCL) laxity, complication and reoperation rates, and patient-reported outcomes (PROs) after all-inside single-bundle PCL reconstruction (PCLR) with versus without independent suture tape reinforcement. Study Design: Cohort study; Level of evidence, 3. Methods: A retrospective cohort study of consecutive patients who underwent primary, all-inside allograft single-bundle PCLR with and without independent suture tape reinforcement at a single academic institution from 2012 to 2019. Medical records were reviewed for patient characteristics, additional injuries, and concomitant procedures. PRO scores (including the International Knee Documentation Committee [IKDC], Tegner activity scale, and Lysholm scores), bilateral comparison kneeling radiographs, and physical examination findings were collected at a minimum of 2 years postoperatively. Results: Included were 50 patients: 19 with suture tape reinforcement (mean age 30.6 ± 2.9 years) and 31 without suture tape reinforcement (control group; mean age 26.2 ± 1.6 years). One PCLR graft in the suture tape group failed. Posterior drawer examination revealed grade 1+ laxity in 4 of 19 (21%) of the suture tape cohort versus 6 of 31 (19%) of the control cohort ( P > .999). Bilateral kneeling radiographs showed similar side-to-side differences in laxity between the groups (suture tape vs control: mean, 1.9 ± 0.4 vs 2.6 ± 0.6 mm; P = .361). There were no statistically significant differences between the groups in postoperative IKDC (suture tape vs control: 79.3 vs 79.6; P = .779), Lysholm (87.5 vs 84.3; P = .828), or Tegner activity (5.6 vs 5.7; P = .562) scores. Conclusion: All-inside single-bundle PCLR with and without independent suture tape reinforcement demonstrated low rates of graft failure, complications, and reoperations, with satisfactory PROs at a minimum 2-year follow-up. Radiographic posterior tibial translation was comparable between the 2 groups.