Penicillin allergy reassessment for treatment improvement: A dental office tool to support appropriate penicillin allergy labeling.

BACKGROUND: Dental appointments offer an opportunity to evaluate a documented penicillin (PCN) allergy and determine whether the patient might be a candidate for medical reassessment of their allergy. The authors gathered feedback on the Penicillin Allergy Reassessment for Treatment Improvement (PARTI) tool, designed to enhance dentist-patient communications regarding PCN allergies. METHODS: From January 2022 through May 2023, the authors conducted a mixed-methods study, collecting focus group data from patients with PCN allergies and surveying health care workers (HCWs) regarding the PARTI tool. Feedback focused on reassessment procedures, patient-centered allergy information, and medical records updates. Thematic analysis was used for focus group data. RESULTS: The study included 15 patients in focus groups and 50 HCW survey respondents representing diverse US regions. Patient demographic characteristics included varied races, the mean age was 52 years, and most of the patients were female (53.3%). Most patients had health care interactions within the preceding year, at which 86.6% of patients were asked about drug allergies. HCW respondents primarily consisted of pharmacists (30%) and dentists, dental hygienists, and dental assistants (28%). Feedback on the PARTI tool was constructive, with both patients and HCWs recognizing its potential benefits and providing insights for improvement. Many HCWs (68%) highlighted the importance of step 3 of the PARTI tool, that is, the section on PCN allergy testing. Feedback from participants was incorporated into the final PARTI tool. CONCLUSIONS: Patient and HCW feedback on the PARTI tool was used to finalize a tool for the dental office to provide to patients who are candidates for PCN allergy reassessment. The feedback will also be used to inform an upcoming pilot study in US dental offices, focused on the process for PCN allergy reassessment and health record documentation. PRACTICAL IMPLICATIONS: Deploying the PARTI tool in dental offices is pivotal, as mislabeling patients with PCN allergies could have severe consequences, such as hindering the prescription of lifesaving antibiotics for conditions like endocarditis, in the future. This implementation not only enhances communication between dentists and patients, but it is also crucial for ensuring improved patient safety and maintaining accurate medical records among health care settings.

Factor Xa Inhibitors versus warfarin in patients with morbid obesity and atrial fibrillation.

PURPOSE: Factor Xa Inhibitors have emerged as a first-line agent in the management of non-valvular atrial fibrillation (NVAF), but there is a need for additional data surrounding their use in the morbidly obese population. The purpose of this study was to evaluate whether Factor Xa Inhibitors are as safe and effective as warfarin for the treatment of NVAF in individuals with a BMI ≥ 40 kg/m2 and/or weight ≥ 120 kg. METHODS: This was a multi-center retrospective cohort study comparing the use of Factor Xa Inhibitors (apixaban and rivaroxaban) to warfarin for the management of NVAF in adult patients with a BMI ≥ 40 kg/m2 and/or weight ≥ 120 kg. The primary outcomes were stroke or systemic embolism and major bleeding within 12 months. RESULTS: A total of 3,156 patients were included in the final analysis; 1,396 in the warfarin group and 1760 in the Factor Xa Inhibitor group. The mean weight and BMI of the overall cohort was 134.1 kg and 44.7 kg/m2, respectively. There was no difference in stroke or systemic embolism (OR 1.21, 95% CI 0.78-1.85) or major bleeding (OR 0.99, 95% CI 0.65 - 1.53) with Factor Xa Inhibitors compared to warfarin after controlling for covariates. CONCLUSION: This analysis of real-world data suggests no difference in bleeding or thrombotic outcomes for severely obese patients with NVAF taking Factor Xa Inhibitors compared to warfarin. Overall, our study adds further data to support the use of Factor Xa Inhibitors as an alternative to warfarin in severely obese patients with NVAF.

Efficacy and safety of factor Xa inhibitors in low body weight patients.

STUDY OBJECTIVE: The purpose of this study is to provide evidence for the safety and efficacy of factor Xa inhibitors in patients with a weight ≤60 kg or BMI < 18.5 kg/m2 . DESIGN: Multicenter, retrospective, cohort study. SETTING: Twenty-two Ascension Health hospitals. PATIENTS: Low-body-weight adult patients (weight ≤ 60 kg or BMI < 18.5 kg/m2 ) receiving treatment for atrial fibrillation or venous thromboembolism. INTERVENTION: Factor Xa inhibitors (apixaban or rivaroxaban) or warfarin. MEASUREMENTS AND MAIN RESULTS: This study included 2538 patients between the factor Xa inhibitors (n = 1695) and warfarin (n = 843) groups with a mean weight of 53.5 ± 5.5 kg and BMI of 20.7 ± 3.1 kg/m2 . No significant difference in time to major bleeding was noted after controlling for potential confounders (HR 1.03, 95% CI 0.70-1.53, p = 0.87); similar results were seen following propensity score matching. Thromboembolism (5.3% vs. 6.2%, p = 0.38), composite major + clinically relevant nonmajor bleeding (9.8% vs. 11.5%, p = 0.18), and all-cause mortality (10.7% vs. 12.8%, p = 0.12) were similar between patients receiving factor Xa inhibitors versus warfarin. CONCLUSION: No differences in safety or effectiveness were noted between factor Xa inhibitors versus warfarin. These findings provide encouraging evidence to support the use of factor Xa inhibitors in low-body-weight patients.

Venous Thromboembolism Prophylaxis in Low Body Weight Critically Ill Patients.

OBJECTIVE: To compare bleeding and thromboembolic events in low body weight patients receiving reduced-dose venous thromboembolism (VTE) prophylaxis versus standard-dose VTE prophylaxis. DESIGN: Multicenter, retrospective, cohort study. SETTING: Five Ascension Health Hospitals. PATIENTS: Adult, critically ill, low body weight (≤50 kg) patients who received either reduced-dose VTE prophylaxis (n = 140) or standard-dose VTE prophylaxis (n = 279) for at least 48 h. INTERVENTION: Reduced-dose prophylaxis (enoxaparin 30 mg daily or heparin 5000 units every 12 h subcutaneously) or standard-dose prophylaxis (enoxaparin 40 mg daily, enoxaparin 30 mg every 12 h, or heparin 5000 units every 8 h subcutaneously). MEASUREMENTS AND MAIN RESULTS: A total of 419 patients were included with a mean weight of 45.1 ± 4.2 kg in the standard-dose group and 44.0 ± 5.1 kg in the reduced-dose prophylaxis group (P = .02). The primary endpoint, composite bleeding, was significantly lower in patients receiving reduced-dose prophylaxis (5% vs 12.5%, P = .02). After adjusting for confounding factors, results remained consistent demonstrating reduced composite bleeding with reduced-dose prophylaxis (odds ratio: 0.36, 95% confidence interval: 0.14-0.96). Major bleeding events occurred in 3.6% of reduced-dose patients compared with 8.6% in standard-dose patients (P = .056). Clinically relevant nonmajor bleeding (5.4% vs 2.9%, P = .24) and VTE (2.2% vs 0%, P = .08) events were similar between groups. CONCLUSIONS: A reduced-dose VTE prophylaxis strategy in low body weight, critically ill patients was associated with a lower risk of composite bleeding and similar rate of thromboembolism.

Does Melatonin Decrease the Use of As-Needed Antipsychotics or Benzodiazepines in Noncritically Ill Hospitalized Patients? A Multicenter Retrospective Cohort Study.

Background: Delirium is a common neuropsychiatric syndrome without an FDA-approved treatment. Commonly used modalities show little improvement in outcomes; therefore, prevention efforts are imperative. Abnormalities in the sleep/wake cycle have been linked to delirium, and melatonin has been proposed to replace the hypothesized low levels of endogenous melatonin and restore sleep/wake cycle synchronization. Objectives: The primary objective of this study was to evaluate the association between melatonin, benzodiazepines (BZDs) or zolpidem (ZLP), and the use of as-needed antipsychotics and BZDs for delirium in noncritically ill adult patients. Methods: This was a multicenter retrospective cohort study of noncritically ill adult patients admitted to two separate health systems from August 2012 to December 2018 receiving either melatonin or nonmelatonin medications (ZLP or BZDs) for sleep. The coprimary endpoint was the proportion of patients receiving a pro re nata (PRN) antipsychotic or BZD 5 days from the patient's first dose of melatonin, BZD, or ZLP. Secondary outcomes included evaluation of the coprimary outcome in patients 65 years of age or older, total number of PRN antipsychotic and BZD doses, and length of stay. Results: Two hundred and twenty-five patients were included in the final analysis. Administration of BZD or ZLP was associated with a higher risk of subsequent BZD administration as compared with melatonin (OR 2.78, 95% CI 1.2-1.87) and ZLP (OR 2.78, 95% CI 1.25-6.17). BZD or ZLP had no impact on PRN antipsychotic use compared with melatonin (OR 1.09, 95% CI 0.51-2.35) and ZLP (OR 1.16, 95% CI 0.56-2.4). Conclusion: Melatonin use was found to be associated with a significant decrease in PRN BZD use in noncritically ill patients hospitalized on general floors; however, there was no observed association with overall PRN antipsychotic use. These results suggest that using melatonin may help decrease utilization of medications commonly used to manage delirium.

Cost, Utilization, and Patient and Family Experience With ACO-Based Pediatric Care Management.

BACKGROUND AND OBJECTIVES: Children and Youth with Special Health Care Needs have high healthcare utilization, fragmented care, and unmet health needs. Accountable Care Organizations (ACOs) increasingly use pediatric care management to improve quality and reduce unnecessary utilization. We evaluated effects of pediatric care management on total medical expense (TME) and utilization; perceived quality of care coordination, unmet needs, and patient and family experience; and differential impact by payor, risk score, care manager discipline, and behavioral health diagnosis. METHODS: Mixed-methods analysis including claims using quasi-stepped-wedge design pre and postenrollment to estimate difference-in-differences, participant survey, and semistructured interviews. Participants included 1321 patients with medical, behavioral, or social needs, high utilization, in Medicaid or commercial ACOs, and enrolled in multidisciplinary, primary care-embedded care management. RESULTS: TME significantly declined 1 to 6 months postenrollment and continued through 19 to 24 months (-$645.48 per member per month, P < .001). Emergency department and inpatient utilization significantly decreased 7 to 12 months post-enrollment and persisted through 19 to 24 months (-29% emergency department, P = .012; -82% inpatient, P < .001). Of respondents, 87.2% of survey respondents were somewhat or very satisfied with care coordination, 56.1% received education coordination when needed, and 81.5% had no unmet health needs. Emergency department or inpatient utilization decreases were consistent across payors and care manager disciplines, occurred sooner with behavioral health diagnoses, and were significant among children with above-median risk scores. Satisfaction and experience were equivalent across groups, with more unmet needs and frustration with above-median risk scores. CONCLUSIONS: Pediatric care management in multipayor ACOs may effectively reduce TME and utilization and clinically provide high-quality care coordination, including education and family stress, with high participant satisfaction.

Zavegepant Intranasal Spray for Migraines.

OBJECTIVE: The objective is to review the pharmacology, efficacy, and safety of intranasal zavegepant in the acute treatment of migraine with or without aura. DATA SOURCE: PubMed, Embase database, and ClinicalTrials.gov were searched using the following terms: Zavzpret, Zavegepant, BHV-3500, and migraine. STUDY SELECTION AND DATA EXTRACTION: Articles published in English from January 2013 to September 2023 related to pharmacology, safety, efficacy, and clinical trials were assessed. DATA SYNTHESIS: In a phase 2/3 trial, zavegepant 10 and 20 mg were more effective than placebo on primary endpoints of freedom of pain (22.5%, 23.1%, and 15.5%, respectively), and freedom from most bothersome symptoms (MBSs) (41.9%, 47.9%, and 33.7%, respectively) 2 hours after treatment. The incidence of adverse effects for both doses was similar to placebo. In a phase 3 trial, zavegepant 10 mg was compared with placebo. Two hours after treatment, more patients in the zavegepant group achieved pain freedom (24% vs 15%) and relief from MBSs (40% vs 31%) compared with placebo. Common adverse events included dysgeusia (21% zavegepant vs 5% placebo) and nasal discomfort (5% zavegepant vs 1% placebo). RELEVANCE TO PATIENT CARE AND CLINICAL PRACTICE IN COMPARISON WITH EXISTING DRUGS: Zavegepant is indicated for acute treatment of migraine with or without aura in adults. Zavegepant method of administration and prompt relief of migraine symptoms may be an attractive alternative to triptans for those in need of relief. CONCLUSION: Zavegepant may be a convenient and useful acute treatment option for migraines with and without aura.

Comparing Post-operative Opioid Consumption before and after a Patient-Controlled Analgesia Shortage: A Re-evaluation of Safety and Effectiveness.

This retrospective cohort study aimed to compare post-surgical opioid consumption before and after a PCA (patient-controlled analgesia) shortage. The study evaluated patients who received PCA vs. nurse-administered opioid analgesia (non-PCA). Two hundred and twenty-four patients ≥18 years who were initiated on analgesia within 24 h of surgery were included. The primary outcome was opioid consumption in average daily oral morphine milliequivalents (MME). The results showed that patients in the PCA group had increased MME consumption (162 ± 100.4 vs. 70.7 ± 52.8, p < 0.01), increased length of hospital stay (4.2 vs. 3.2 days, p < 0.01), and increased frequency of nausea (33 vs. 17.9%, p < 0.01). After controlling for confounding factors, the PCA group utilized significantly more opioids (84.6 MME/day, p < 0.01) than the non-PCA group. There was no difference in pain AUC/T (0.19 ± 0.07 vs. 0.21 ± 0.08, p = 0.07) and average opioid prescribing upon discharge (150 [77.5-360] vs. 90 [77.5-400], p = 0.64) between the PCA group and non-PCA group, respectively. These results question the routine use of PCA in post-operative patients due to the increased risk of opioid consumption, longer length of hospital stay, and higher incidence of nausea.

Evaluation of standard versus prolonged magnesium infusion rates in hospitalized patients: a retrospective cohort study.

BACKGROUND: Hypomagnesemia is a common electrolyte abnormality in hospitalized patients. Prolonging the infusion rate of magnesium has been hypothesized to increase retention of magnesium, however, there is limited evidence to support prolonging the rate of infusion. AIM: To compare the absolute change in serum magnesium levels from baseline to levels drawn within 24 hours after the end of infusion between two groups receiving standard or prolonged infusion. METHODS: This was a retrospective, observational cohort study comparing patients receiving magnesium infusion at a standard rate of 0.5 gm/h to those receiving magnesium infusion at a prolonged rate of 0.17 gm/h. RESULTS: Of a total of 276 patients, 138 were included in each group. No differences existed between the groups for any demographic variables (all p>0.05). The absolute change in serum magnesium level was 0.41 mg/dL versus 0.31 mg/dL in the standard and the prolonged infusion groups, respectively (p = 0.001). The length of stay after the initial magnesium dose was slightly longer with the prolonged infusion compared to the standard infusion, with a median of 2.9 days versus 3.6 days, respectively (p = 0.02). No differences existed between the groups for any secondary or safety outcomes (all p>0.05). CONCLUSION: Hospitalized general patients did not benefit from the prolonged infusion of magnesium compared to standard infusion.

Evaluation of High-dose versus Standard-dose of Dexamethasone on Mortality among the Mechanically Ventilated COVID-19 Patients.

INTRODUCTION: Anti-inflammatory agents like dexamethasone (DEX) are a mainstay of treatment for COVID-19. Despite randomized trials demonstrating that a 6 mg daily dose of DEX improved patient outcomes in hospitalized COVID-19 patients receiving oxygen, clinicians often prescribe higher doses of corticosteroids without evidence to support this practice. The purpose of this study was to compare outcomes of ventilated COVID-19 patients who received standard dose (SD) versus high dose (HD) DEX. METHOD: This was a multi-site, retrospective, observational study on ventilated COVID-19-positive patients who received DEX for at least three days between June 1, 2020, and January 31, 2022. The primary outcome of this study was the association between mortality and SD (<6mg daily) versus HD (>10mg daily) DEX in ventilated COVID-19 patients. Secondary outcomes included average blood glucose (BG), number of BG readings above 200, incidence of bacterial nosocomial infection, ventilator-free days, length of stay (LOS), and ICU LOS. RESULTS: Of the 212 included patients, 53 (25%) received SD DEX, and 159 (75%) received HD DEX. There was no significant effect of DEX dose on mortality, number of BG readings >200, incidence of nosocomial infections, LOS, or ventilator-free days (p >0.05). After controlling for confounding factors, no difference in mortality persisted (OR 1.34 95% CI 0.62- 2.90). Average daily BG and ICU LOS were significantly greater in the HD group compared to the SD group (p = 0.003, p = 0.019, respectively). CONCLUSION: There was no association between HD DEX and mortality among ventilated COVID-19 patients compared to SD DEX. Moreover, HD DEX is associated with detrimental effects such as prolonged ICU LOS and higher average daily BG. This study supports the use of SD DEX in ventilated COVID-19 patients.

Biomarkers in the intensive care setting: A focus on using procalcitonin and C-reactive protein to optimize antimicrobial duration of therapy.

Managing the critically ill patient with infection is complex, requiring clinicians to synthesize considerable information relating to antimicrobial efficacy and treatment duration. The use of biomarkers may play an important role in identifying variation in treatment response and providing information about treatment efficacy. Though a vast number of biomarkers for clinical application have been described, procalcitonin and C-reactive protein (CRP) are the most thoroughly investigated in the critically ill. However, the presence of heterogeneous populations, variable end points, and incongruent methodology in the literature complicates the use of such biomarkers to guide antimicrobial therapy. This review focuses on an appraisal of evidence for use of procalcitonin and CRP to optimize antimicrobial duration of therapy (DOT) in critically ill patients. Procalcitonin-guided antimicrobial therapy in mixed critically ill populations with varying degrees of sepsis appears to be safe and might assist in reducing antimicrobial DOT. Compared to procalcitonin, fewer studies exist examining the impact of CRP on antimicrobial DOT and clinical outcomes in the critically ill. Procalcitonin and CRP have been insufficiently studied in many key intensive care unit populations, including surgical patients with concomitant trauma, renally insufficient populations, the immunocompromised, and patients with septic shock. We believe the available evidence is not strong enough to warrant routine use of procalcitonin or CRP to guide antimicrobial DOT in critically ill patients with infection. So long as its limitations are recognized, procalcitonin could be considered to tailor antimicrobial DOT on a case-by-case basis in the critically ill patient.

B-cell-specific checkpoint molecules that regulate anti-tumour immunity.

The role of B cells in anti-tumour immunity is still debated and, accordingly, immunotherapies have focused on targeting T and natural killer cells to inhibit tumour growth1,2. Here, using high-throughput flow cytometry as well as bulk and single-cell RNA-sequencing and B-cell-receptor-sequencing analysis of B cells temporally during B16F10 melanoma growth, we identified a subset of B cells that expands specifically in the draining lymph node over time in tumour-bearing mice. The expanding B cell subset expresses the cell surface molecule T cell immunoglobulin and mucin domain 1 (TIM-1, encoded by Havcr1) and a unique transcriptional signature, including multiple co-inhibitory molecules such as PD-1, TIM-3, TIGIT and LAG-3. Although conditional deletion of these co-inhibitory molecules on B cells had little or no effect on tumour burden, selective deletion of Havcr1 in B cells both substantially inhibited tumour growth and enhanced effector T cell responses. Loss of TIM-1 enhanced the type 1 interferon response in B cells, which augmented B cell activation and increased antigen presentation and co-stimulation, resulting in increased expansion of tumour-specific effector T cells. Our results demonstrate that manipulation of TIM-1-expressing B cells enables engagement of the second arm of adaptive immunity to promote anti-tumour immunity and inhibit tumour growth.

Enteral Sedation in Patients Requiring Mechanical Ventilation During an Intravenous Analgesic and Sedative Shortage.

Background: There is a paucity of data evaluating the use of enteral sedation in mechanical ventilation. A sedative shortage resulted in the use of this approach. Purpose: To evaluate the feasibility of using enteral sedatives to decrease intravenous (IV) analgesia and sedative requirements. Materials/Methods: This single-center, retrospective, observational study compared two groups of patients admitted to the ICU who were mechanically ventilated. One group received a combination of enteral and IV sedatives and the second group received IV monotherapy. Linear mixed model (LMM) analyses were performed to assess the impact of enteral sedatives on IV fentanyl equivalents, IV midazolam equivalents, and propofol. Mann-Whitney U tests were performed on percent of days at goal for Richmond Agitation and Sedation Scale (RASS) and critical care pain observation tool (CPOT) scores. Results: One hundred and four patients were included. The average cohort age was 62 years and 58.7% were male. The median length of mechanical ventilation was 7.1 days and the median length of stay was 11.9 days. The LMM estimated that enteral sedatives reduced IV fentanyl equivalents received per patient by an average of 305.6 mcg/day (P = .04), although did not significantly decrease midazolam equivalents or propofol. There was no statistically significant difference in CPOT scores (P = .57 and P = .46 respectively), however RASS scores in the enteral sedation group were more often at goal (P = .03); oversedation occurred more in the non-enteral sedation group (P = .018). Conclusion: Enteral sedation may be a possible way to decrease IV analgesia requirements during periods of shortage.

Hydrocortisone versus vasopressin for the management of adult patients with septic shock refractory to norepinephrine: A multicenter retrospective study.

STUDY OBJECTIVE: Significant practice variation exists when selecting between hydrocortisone and vasopressin as second line agents in patients with septic shock in need of escalating doses of norepinephrine. The goal of this study was to assess differences in clinical outcomes between these two agents. DESIGN: Multicenter, retrospective, observational study. SETTING: Ten Ascension Health hospitals. PATIENTS: Adult patients with presumed septic shock receiving norepinephrine prior to study drug initiation between December 2015 and August 2021. INTERVENTION: Vasopressin (0.03-0.04 units/min) or hydrocortisone (200-300 mg/day). MEASUREMENTS AND MAIN RESULTS: A total of 768 patients were included with a median (interquartile range) SOFA score of 10 (8-13), norepinephrine dose of 0.3 mcg/kg/min (0.1-0.5 mcg/kg/min), and lactate of 3.8 mmol/L (2.4-7.0 mmol/L) at initiation of the study drug. A significant difference in 28-day mortality was noted favoring hydrocortisone as an adjunct to norepinephrine after controlling for potential confounding factors (OR 0.46 [95% CI, 0.32-0.66]); similar results were seen following propensity score matching. Compared to vasopressin, hydrocortisone initiation was also associated with a higher rate of hemodynamic responsiveness (91.9% vs. 68.2%, p < 0.01), improved resolution of shock (68.8% vs. 31.5%, p < 0.01), and reduced recurrence of shock within 72 h (8.7% vs. 20.7%, p < 0.01). CONCLUSIONS: Addition of hydrocortisone to norepinephrine was associated with a lower 28-day mortality in patients with septic shock, compared to the addition of vasopressin.

A positive feedback loop controls Toxoplasma chronic differentiation.

Successful infection strategies must balance pathogen amplification and persistence. In the obligate intracellular parasite Toxoplasma gondii this is accomplished through differentiation into dedicated cyst-forming chronic stages that avoid clearance by the host immune system. The transcription factor BFD1 is both necessary and sufficient for stage conversion; however, its regulation is not understood. In this study we examine five factors that are transcriptionally activated by BFD1. One of these is a cytosolic RNA-binding protein of the CCCH-type zinc-finger family, which we name bradyzoite formation deficient 2 (BFD2). Parasites lacking BFD2 fail to induce BFD1 and are consequently unable to fully differentiate in culture or in mice. BFD2 interacts with the BFD1 transcript under stress, and deletion of BFD2 reduces BFD1 protein levels but not messenger RNA abundance. The reciprocal effects on BFD2 transcription and BFD1 translation outline a positive feedback loop that enforces the chronic-stage gene-expression programme. Thus, our findings help explain how parasites both initiate and commit to chronic differentiation. This work provides new mechanistic insight into the regulation of T. gondii persistence, and can be exploited in the design of strategies to prevent and treat these key reservoirs of human infection.

Evaluation of References Supporting Hospital Pharmacy Policies.

There is a lack of research evaluating the role of references in hospital policies. The goal of this study was to describe the type of literature used as a reference in medication policies and evaluate the agreement of the policy with evidence-based guidelines. One hundred forty-seven pharmacy owned policies met inclusion criteria; 27.2% of the policies contained references, in which tertiary literature was the most frequently cited source (90%), followed by primary (47.5%), and lastly secondary (27.5%). When references were used, all policies agreed with current guidelines. For policies without references, 3.7% disagreed with published guidelines. Disagreement with guidelines may negatively impact patient care, therefore health systems should incorporate librarians into clinical policy development and review to ensure the best available evidence is incorporated into polices.

Functional profiling of the Toxoplasma genome during acute mouse infection.

Within a host, pathogens encounter a diverse and changing landscape of cell types, nutrients, and immune responses. Examining host-pathogen interactions in animal models can therefore reveal aspects of infection absent from cell culture. We use CRISPR-based screens to functionally profile the entire genome of the model apicomplexan parasite Toxoplasma gondii during mouse infection. Barcoded gRNAs were used to track mutant parasite lineages, enabling detection of bottlenecks and mapping of population structures. We uncovered over 300 genes that modulate parasite fitness in mice with previously unknown roles in infection. These candidates span multiple axes of host-parasite interaction, including determinants of tropism, host organelle remodeling, and metabolic rewiring. We mechanistically characterized three novel candidates, including GTP cyclohydrolase I, against which a small-molecule inhibitor could be repurposed as an antiparasitic compound. This compound exhibited antiparasitic activity against T. gondii and Plasmodium falciparum, the most lethal agent of malaria. Taken together, we present the first complete survey of an apicomplexan genome during infection of an animal host, and point to novel interfaces of host-parasite interaction that may offer new avenues for treatment.

Risk of bleeding with factor Xa inhibitors versus unfractionated heparin in patients with acute kidney injury.

STUDY OBJECTIVE: To compare bleeding and thromboembolic events in patients receiving therapeutic doses of apixaban or rivaroxaban versus unfractionated heparin (UFH) in patients with acute kidney injury (AKI). DESIGN: Single-center, retrospective, observational study. SETTING: Ascension St. John Hospital in Detroit, Michigan. PATIENTS: Hospitalized adult patients who received therapeutic doses of factor Xa inhibitors (n = 250) or UFH (n = 250) for at least 24 h in the setting of AKI. MEASUREMENTS AND MAIN RESULTS: After adjusting for confounding factors, patients who received a factor Xa inhibitor experienced a lower risk of composite major and clinically relevant nonmajor bleeding (CRNMB) events compared with UFH (OR: 0.57, 95% CI: 0.34-0.94; p = 0.03). There was a significantly decreased risk of CRNMB events in the factor Xa inhibitor group (OR: 0.55, 95% CI: 0.33-0.91, p = 0.02); however, no significant differences in major bleeding or venous thromboembolism (VTE) were noted. CONCLUSIONS: Our results suggest that it may be preferable to continue patients in AKI on factor Xa inhibitors versus transitioning to UFH due to the lower risk of bleeding events.