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Background: There is limited information describing pharmacist participation in prophylactic enoxaparin monitoring in the surgical intensive care unit (SICU). Objective: Our study sought to: 1) characterize pharmacist recommendations for enoxaparin monitoring in trauma patients admitted to the SICU, 2) describe the frequency that medical providers accept pharmacist recommendations for enoxaparin monitoring in trauma patients admitted to the SICU, and 3) illustrate the frequency that trauma patients admitted to our SICU service achieve anti-factor Xa trough concentrations (AFXa-TRs) of 0.11 - 0.20 IU/mL following pharmacist recommendation to adjust prophylactic enoxaparin dosing. Methods: Adult patients who had an AFXa-TR drawn after at least three consecutive prophylactic enoxaparin doses between June 1, 2017 and March 1, 2018 were identified through chart review and included in this study. Patients were excluded based on the following criteria: 1) age less than 18 years, 2) anti-factor Xa (AFXa) level not representative of a trough concentration, 3) AFXa-TR not representative of steady state concentration, and 4) non-trauma based prophylactic enoxaparin dosing. This study was exempt from IRB review. Results: The final analysis consisted of 42 patients. A pharmacist provided at least one recommendation in 97.6% (41/42) of trauma patients with enoxaparin monitoring during their SICU stay. In total, a pharmacist made 170 recommendations, mean of 4.2 (SD 1.8) recommendations per patient. Recommendations were: 1) obtain an AFXa-TR, n=90; 2) adjust enoxaparin dose based on AFXa-TR, n=58; and 3) maintain enoxaparin dose based on AFXa-TR, n=22. Medical providers accepted 89.4% (152/170) of pharmacist recommendations for enoxaparin monitoring. Dose adjustments were made in 33 patients following pharmacist recommendation; of these, 27 had a repeat AFXa-TR following at least one dose adjustment. Target AFXa-TRs were achieved in 19/27 patients, indicating 70.4% had recommended AFXa concentrations. Conclusions: Pharmacists provided recommendations for prophylactic enoxaparin monitoring and dose adjustment in trauma patients admitted to the SICU. Medical providers regularly accepted pharmacist recommendations and trauma patients commonly achieved target AFXa-TR following pharmacist recommendation for dose adjustment. Further research is required to identify the optimal enoxaparin dose for VTE prophylaxis in trauma patients.

Nimish Patel1, Christopher D Miller1,21Albany College of Pharmacy and Health Sciences, 2Albany Medical Center Division of HIV Medicine, Albany, NYAbstract: Fixed-dose combination tablets have become an important therapy option for patients infected with the human immunodeficiency virus. Fixed-dose combination rilpivirine-tenofovir-emtricitabine is a recently approved therapy option that has been extensively studied within the treatment-naïve population. When compared with efavirenz-based therapy, improved tolerability with rilpivirine-based therapy was balanced by higher rates of virologic failure to provide similar overall efficacy rates within the intention-to-treat analysis. As a result, providers will need to balance the potential for improved tolerability with fixed-dose combination rilpivirine-tenofovir-emtricitabine against a higher potential for virologic failure, particularly among patients with baseline viral loads above 100,000 copies/mL. Current treatment guidelines have recommended that fixed-dose combination rilpivirine-tenofovir-emtricitabine be an alternative therapy option for treatment-naïve patients and advise caution in those patients with high viral loads at baseline. Similar to other non-nucleoside reverse transcriptase inhibitor-based regimens, there are a number of drug interaction concerns with fixed-dose combination rilpivirine-tenofovir-emtricitabine that will necessitate monitoring and, in some cases, appropriate management. Additionally, the emergence of drug resistance to fixed-dose combination rilpivirine-tenofovir-emtricitabine has been well documented in clinical studies and close attention will be necessary in order to protect current and future therapy options. Overall, fixed-dose combination rilpivirine-tenofovir-emtricitabine is poised to provide an important therapy option for patients when appropriately applied.Keywords: rilpivirine, human immunodeficiency virus, antiretroviral, tenofovir, emtricitabine

Most major U.S. professional sports and the National Collegiate Athletic Association (NCAA) have adopted concussion policies. Current National Football League and NCAA guidelines do not permit an athlete with a concussion to return to play on the same day as the injury. No adolescent or high-school athletes with a concussion should be allowed to return to play on the same day regardless of severity.Loss of consciousness is uncommon with concussion.Acute concussion symptoms are generally self-limited, and most symptoms typically resolve within two weeks. Concussion risk and severity may be affected by age, sex, and genetic predisposition.Athletes with a concussion should rest physically and cognitively until symptoms have resolved at rest and with exertion. Rehabilitation following concussion progresses through a stepwise graded fashion.Neuropsychological testing can provide objective data on an athlete after a concussion. However, it alone cannot be used to diagnose a concussion or determine when an athlete is allowed to return to play.Retirement from contact or collision sports may be necessary for an athlete who has sustained multiple concussions or has a history of prolonged symptoms after concussions.Long-term effects of concussions are still relatively unknown, and further research is required to offer guidance for athletes of all levels. [ABSTRACT FROM AUTHOR]

Rationale: Pulmonary embolism (PE) decreases the exhaled end-tidal ratio of carbon dioxide to oxygen (etCO(2)/O(2)).Objectives: To test if the etCO(2)/O(2) can produce clinically important changes in the probability of segmental or larger PE on computerized tomography multidetector-row pulmonary angiography (MDCTPA) in a moderate-risk population with a positive D-dimer.Methods: Emergency department and hospitalized patients with one or more predefined symptoms or signs, one or more risk factors for PE, and 64-slice MDCTPA enrolled from four hospitals. D-dimer greater than 499 ng/ml was test(+), and D-dimer less than 500 ng/ml was test(-). The median etCO(2)/O(2) less than 0.28 from seven or more breaths was test(+) and etCO(2)/O(2) greater than 0.45 was test(-). MDCTPA images were read by two independent radiologists and the criterion standard was the interpretation of acute PE by either reader. PE size was then graded.Measurements and Main Results: We enrolled 495 patients, including 60 (12%) with segmental or larger, and 29 (6%) with subsegmental PE. A total of 367 (74%) patients were D-dimer(+), including all 60 with segmental or larger PE (posterior probability 16%). The combination of D-dimer(+) and etCO(2)/O(2)(+) increased the posterior probability of segmental or larger PE to 28% (95% confidence interval [CI] for difference of 12%, 3.0-22%). The combination of D-dimer(+) and etCO(2)/O(2)(-) was observed in 40 patients (8%; 95% CI, 6-11%), and none (0/40; 95% CI, 0-9%) had segmental or larger PE on MDCTPA. No strategy changed the prevalence of subsegmental PE.Conclusions: In moderate-risk patients with a positive D-dimer, the et etCO(2)/O(2) less than 0.28 significantly increases the probability of segmental or larger PE and the etCO(2)/O(2) greater than 0.45 predicts the absence of segmental or larger PE on MDCTPA. [ABSTRACT FROM AUTHOR]

PURPOSE: The purpose of this study was to determine whether an algorithm that recommended individualized changes in therapy would help providers to change therapy appropriately and improve glycemic control in their patients. METHODS: The algorithm recommended specific doses of oral agents and insulin based on a patient's medications and glucose or A1C levels at the time of the visit. The prospective observational study analyzed the effect of the algorithm on treatment decisions and A1C levels in patients with type 2 diabetes. RESULTS: The study included 1250 patients seen in pairs of initial and follow-up visits during a 7-month baseline and/or a subsequent 7-month algorithm period. The patients had a mean age of 62 years, body mass index of 33 kg/m(2), duration of diabetes of 10 years, were 94% African American and 71% female, and had average initial A1C level of 7.7%. When the algorithm was available, providers were 45% more likely to intensify therapy when indicated (P = .005) and increased therapy by a 20% greater amount (P < .001). A1C level at follow-up was 90% more likelyto be <7% in the algorithm group, even after adjusting for differences in age, sex, body mass index, race, duration of diabetes and therapy, glucose, and A1C level at the initial visit (P < .001). CONCLUSIONS: Use of an algorithm that recommends patient-specific changes in diabetes medications improves both provider behavior and patient A1C levels and should allow quantitative evaluation of provider actions for that provider's patients. [ABSTRACT FROM AUTHOR]

Objective: Management of diabetes is frequently suboptimal in primary care settings, where providers often fail to intensify therapy when glucose levels are high, a problem known as clinical inertia. We asked whether interventions targeting clinical inertia can improve outcomes.Research Design and Methods: A controlled trial over a 3-year period was conducted in a municipal hospital primary care clinic in a large academic medical center. We studied all patients (4,138) with type 2 diabetes who were seen in continuity clinics by 345 internal medicine residents and were randomized to be control subjects or to receive one of three interventions. Instead of consultative advice, the interventions were hard copy computerized reminders that provided patient-specific recommendations for management at the time of each patient's visit, individual face-to-face feedback on performance for 5 min every 2 weeks, or both.Results: Over an average patient follow-up of 15 months within the intervention site, improvements in and final HbA1c (A1C) with feedback + reminders (deltaA1C 0.6%, final A1C 7.46%) were significantly better than control (deltaA1C 0.2%, final A1C 7.84%, P < 0.02); changes were smaller with feedback only and reminders only (P = NS vs. control). Trends were similar but not significant with systolic blood pressure (sBP) and LDL cholesterol. Multivariable analysis showed that the feedback intervention independently facilitated attainment of American Diabetes Association goals for both A1C and sBP. Over a 2-year period, overall glycemic control improved in the intervention site but did not change in other primary care sites (final A1C 7.5 vs. 8.2%, P < 0.001).Conclusions: Feedback on performance aimed at overcoming clinical inertia and given to internal medicine resident primary care providers improves glycemic control. Partnering generalists with diabetes specialists may be important to enhance diabetes management in other primary care settings. [ABSTRACT FROM AUTHOR]

PURPOSE: The purpose of this study was to determine whether 'clinical inertia'-inadequate intensification of therapy by the provider-could contribute to high A1C levels in patients with type 2 diabetes managed in a primary care site. METHODS: In a prospective observational study, management was compared in the Medical Clinic, a primary care site supervised by general internal medicine faculty, and the Diabetes Clinic, a specialty site supervised by endocrinologists. These municipal hospital clinics serve a common population that is largely African American, poor, and uninsured. RESULTS: Four hundred thirty-eight African American patients in the Medical Clinic and 2157 in the Diabetes Clinic were similar in average age, diabetes duration, body mass index, and gender, but A1C averaged 8.6% in the Medical Clinic versus 7.7% in the Diabetes Clinic (P < .0001). Use of pharmacotherapy was less intensive in the Medical Clinic (less use of insulin), and when patients had elevated glucose levels during clinic visits, therapy was less than half as likely to be advanced in the Medical Clinic compared to the Diabetes Clinic (P < .0001). Intensification rates were lower in the Medical Clinic regardless of type of therapy (P < .0001), and intensification of therapy was independently associated with improvement in A1C (P < .001). CONCLUSIONS: Medical Clinic patients had worse glycemic control, were less likely to be treated with insulin, and were less likely to have their therapy intensified if glucose levels were elevated. To improve diabetes management and glycemic control nationwide, physicians in training and generalists must learn to overcome clinical inertia, to intensify therapy when appropriate, and to use insulin when clinically indicated. [ABSTRACT FROM AUTHOR]

PURPOSE: This study was conducted to determine how time is allocated to diabetes care. METHODS: Patients with type 2 diabetes who were receiving care from the internal medicine residents were shadowed by research nurses to observe the process of management. The amount of time spent with patients and the care provided were observed and documented. RESULTS: The total time patients spent in the clinic averaged 2 hours and 26 minutes: 1 to 9 minutes waiting, 25 minutes with the resident, and 12 minutes with medical assistants and nurses. The residents spent an average of only 5 minutes on diabetes. Glucose monitoring was addressed in 70% of visits; a history of hypoglycemia was sought in only 30%. Blood pressure values were mentioned in 75% of visits; hemoglobin A1c (A1C) values were addressed in only 40%. The need for proper foot care was discussed in 55% of visits; feet were examined in only 40%. Although 65% of patients had capillary glucose levels greater than 150 mg/dL during the visit and their A1C averaged 8.9%, therapy was intensified for only 15% of patients. CONCLUSIONS: During a routine office visit in a resident-staffed general medicine clinic, little time is devoted to diabetes management. Given the time pressures on the primary care practitioner and the need for better diabetes care, it is essential to teach an efficient but systematic approach to diabetes care. [ABSTRACT FROM AUTHOR]

Dural sinus thrombosis (DST) is a life threatening illness and is often overlooked but it must be considered in the differential diagnosis of a patient presenting with a significant headache. DST presents similarly to benign intracranial hypertension (BIH) with intracranial hypertension and headache. A case of a 23 year old woman with DST is described that was initially diagnosed as BIH. A Medline search to determine the examination of a patient with suspected BIH or DST yielded several articles on this topic but only two brief case reports in the emergency medicine literature. Any patient with suspected DST or BIH must have a confirmatory magnetic resonance imaging and magnetic resonance venography study. Treatment of DST seems to be effective, considerably different from BIH, and lack of treatment may lead to increased morbidity and mortality. [ABSTRACT FROM AUTHOR]

Objectives: The aim of this study was to compare outcomes in patients receiving consistent unfractionated heparin (UFH)/enoxaparin (ENOX) therapy and in those switched at randomization to bivalirudin monotherapy.Background: Crossover between UFH and ENOX has been associated with increased adverse outcomes in patients with acute coronary syndromes. The ACUITY (Acute Catheterization and Urgent Intervention Triage strategY) trial demonstrated superior net clinical outcomes with similar rates of ischemia and significantly less major bleeding with bivalirudin monotherapy compared with UFH/ENOX plus a glycoprotein (GP) IIb/IIIa inhibitor. It is unknown if these results would be preserved in patients switched from UFH/ENOX to bivalirudin monotherapy.Methods: We compared composite ischemia, major bleeding, and net clinical outcomes at 30 days in patients receiving consistent UFH/ENOX therapy and in those switched at randomization from pre-treatment with UFH/ENOX to bivalirudin monotherapy. We also compared outcomes in patients naive to antithrombin therapy who were randomized to UFH/ENOX or bivalirudin monotherapy.Results: Two thousand one hundred thirty-seven patients received consistent UFH/ENOX (UFH n = 1,294, ENOX n = 843), and 2,078 patients pre-treated with UFH/ENOX were switched to bivalirudin. Patients switching to bivalirudin had similar rates of ischemia (6.9% vs. 7.4%, p = 0.52), less major bleeding (2.8% vs. 5.8%, p < 0.01), and improved net clinical outcomes (9.2% vs. 11.9%, p < 0.01) than those on consistent UFH/ENOX plus a GP IIb/IIIa inhibitor. Patients naive to antithrombin therapy who were administered bivalirudin (n = 1,427) had similar rates of ischemia (6.2% vs. 5.5%, p = 0.47), less major bleeding (2.5% vs. 4.9%, p < 0.001), and similar net clinical outcomes (8.0% vs. 9.4%, p = 0.17) compared with naive patients administered UFH/ENOX plus a GP IIb/IIIa inhibitor (n = 1,462).Conclusions: Switching from UFH/ENOX to bivalirudin monotherapy results in comparable ischemic outcomes and an approximately 50% reduction in major bleeding compared with consistent UFH/ENOX plus a GP IIb/IIIa inhibitor. Patients naive to antithrombin therapy administered bivalirudin monotherapy had a significant reduction in bleeding and similar rates of ischemia compared with naive patients initiated with UFH or ENOX plus a GP IIb/IIIa inhibitor. [ABSTRACT FROM AUTHOR]

Objectives: This study aimed to identify the prevalence of and factors associated with diagnostic uncertainty when critically ill children are admitted to the PICU. Understanding diagnostic uncertainty is necessary to develop effective strategies to reduce diagnostic errors in the PICU., Design: Multicenter retrospective cohort study with structured medical record review by trained clinicians using a standardized instrument to identify diagnostic uncertainty in narrative clinical notes. Diagnoses and diagnostic uncertainty were compared across time from PICU admission to hospital discharge. Generalized linear mixed models were used to determine patient, clinician, and encounter characteristics associated with diagnostic uncertainty at PICU admission., Setting: Four academic tertiary-referral PICUs., Patients: Eight hundred eighty-two randomly selected patients 0-18 years old who were nonelectively admitted to participating PICUs., Interventions: None., Measurements and Main Results: PICU admission notes for 228 of 882 patients (25.9%) indicated diagnostic uncertainty. Patients with uncertainty decreased over time but 58 (6.6%) had remaining diagnostic uncertainty at hospital discharge. Multivariable analysis showed that diagnostic uncertainty was significantly associated with off hours admission (odds ratio [OR], 1.52; p = 0.037), greater severity of illness (OR, 1.04; p = 0.025), an atypical presentation (OR, 2.14; p = 0.046), diagnostic discordance at admission between attending intensivists and resident physicians/advanced practice providers (OR, 3.62; p < 0.001), and having a neurologic primary diagnosis (OR, 1.87; p = 0.03). Older patients (OR, 0.96; p = 0.014) and those with a respiratory (OR, 0.58; p = 0.009) or trauma primary diagnosis (OR, 0.08; p < 0.001) were less likely to have diagnostic uncertainty. There were no significant associations between diagnostic uncertainty and attending intensivists' characteristics., Conclusions: Diagnostic uncertainty at PICU admission was common and was associated with off hours admission, severe illness, atypical presentation, diagnostic discordance between clinicians, and a neurologic primary diagnosis. Further study on the recognition and management of diagnostic uncertainty is needed to inform interventions to improve diagnosis among critically ill children., Competing Interests: Dr. Landrigan has consulted with and holds equity in the I-PASS (Handoff elements mnemonic: I-illness severity, P-patient summary, A-action items, S-situation awareness, S-synthesis) Institute, which seeks to train institutions in best handoff practices and aid in their implementation. In addition, Dr. Landrigan has received monetary awards, honoraria, and travel reimbursement from multiple academic and professional organizations for teaching and consulting on sleep deprivation, physician performance, handoffs, and safety; he has served as an expert witness in cases regarding patient safety and sleep deprivation; and he received funding from the Agency for Healthcare Research and Quality (AHRQ). Drs. Cifra’s, K. A. Smith’s, Bloxham’s, Hoppe’s, Miller’s, Riffe’s, Robb’s, Simone’s, Tumulty’s, Dawson’s, and Herwaldt’s institutions received funding from the Eunice Kennedy Shriver National Institute of Child Health and Human Development, the AHRQ, and the National Center for Advancing Translational Sciences. Drs. Cifra, Bloxham, Miller, and Tumulty received funding from the AHRQ, MedStar Research Institute, and De Gruyter. Drs. Cifra, C. M. Smith, K. A. Smith, Bagdure, Bloxham, Goldhar, Hoppe, Miller, Pizzo, Riffe, Robb, Tumulty, Wolfe, Wendt, Eyck, Dawson, Reisingerr, Singh, and Herwaldt received support for article research from the National Institutes of Health. Dr. Gorga disclosed institutional grant funding. Dr. Ten Eyck disclosed work for hire. Dr. Dawson received funding from Neurosurgery, the University of Nebraska Medical Center, and IotaSoft. Dr. Singh is supported in part by the AHRQ (R01HS028595 and R18HS029347), the Houston Veterans Administration (VA) Health Services Research and Development Center for Innovations in Quality, Effectiveness and Safety (CIN 13–413), and the VA National Center for Patient Safety; he disclosed government work. The views expressed in this article are those of the authors and do not necessarily reflect the position or policy of the Department of the VA or the U.S. government. Dr. Herwaldt’s institution received funding from the Centers for Disease Control and Prevention. The remaining authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2024 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.)

Introduction: Prostate cancer continues to be a major cause of morbidity and mortality for men worldwide. Enzalutamide, a second-generation non-steroidal antiandrogen that blocks androgen receptor (AR) transcriptional activity, is a treatment for biochemically recurrent, metastatic, castration-sensitive, and castration-resistant tumors. Unfortunately, most patients ultimately develop resistance to enzalutamide, making long-term treatment with this agent challenging., Areas Covered: We performed a literature search of PubMed without date restrictions to investigate the literature surrounding enzalutamide and discuss the current uses of enzalutamide, proposed mechanisms driving resistance, and summarize current efforts to mitigate this resistance., Expert Opinion: Enzalutamide is an effective prostate cancer therapy that is currently used in biochemically recurrent and metastatic disease and for both castration-sensitive and castration-resistant tumors. Unfortunately, resistance to enzalutamide occurs in each of these scenarios. In the clinical setting, enzalutamide-resistant tumors are either AR-driven or AR-indifferent. AR-dependent resistance mechanisms include genomic or epigenomic events that result in enhanced AR signaling. Tumors that do not require AR signaling instead may depend on alternative oncogenic pathways. There are numerous strategies to mitigate enzalutamide resistance, including concurrent use of PARP inhibitors or immune therapies. Additional work is required to uncover novel approaches to treat patients in the enzalutamide-resistant setting.

Introduction: This study sought to assess the cardiorespiratory safety of parenteral olanzapine and benzodiazepine combination treatment compared to parenteral droperidol or haloperidol and benzodiazepine combination treatment., Materials and Methods: This was a retrospective chart review conducted in adult emergency department patients who received intramuscular (IM) or intravenous (IV) droperidol, haloperidol, or olanzapine within one hour of IM or IV benzodiazepine. Patients were stratified into groups based on whether they received either olanzapine in combination with a benzodiazepine (n = 48) or droperidol or haloperidol in combination with a benzodiazepine (n = 48)., Results: Patients in each group had a decrease in their systolic blood pressure (SBP) after IM/IV olanzapine and IM/IV droperidol or haloperidol when used in combination with an IM/IV benzodiazepine ((Olanzapine + benzodiazepine (mmHg), median (IQR): Pre-SBP: 132 (117-151) vs. Post-SBP: 117 (99-131), p < 0.01) (Droperidol or haloperidol + benzodiazepine (mmHg), median (IQR): Pre-SBP: 138 (122-149) vs. Post-SBP: 106 (98-127), p < 0.01)). Both groups had similar percent SBP decreases post-combination treatment (Olanzapine + benzodiazepine (15.6 %) vs. Droperidol or haloperidol + benzodiazepine (15.2 %); p = 0.55). We did not observe any statistically significant between group differences for hypotension (Olanzapine + benzodiazepine: 1/48, 2.1 % vs. Droperidol or haloperidol + benzodiazepine: 3/48, 6.3 %; p = 0.62)), escalation in oxygen requirements (Olanzapine + benzodiazepine: 7/48, 14.6 %) vs. Droperidol or haloperidol + benzodiazepine: 5/48, 10.4 %; p = 0.76)), or intubation due to cardiorespiratory depression (Olanzapine + benzodiazepine: 0/0, 0 % vs. Droperidol or haloperidol + benzodiazepine: 0/0, 0 %; p = 1.00))., Conclusion: This study found decreases in SBP after administering parenteral olanzapine and parenteral droperidol or haloperidol in combination with a parenteral benzodiazepine. The percent change in SBP and the frequency of hypotensive episodes post-combination treatment were not different between groups. There were also no differences between groups in need of increased oxygen requirements post-combination treatment or need for intubation due to cardiorespiratory depression. This study suggests parenteral olanzapine in combination with a parenteral benzodiazepine may have comparable cardiorespiratory safety versus parenteral droperidol or haloperidol in combination with a parenteral benzodiazepine when treating agitation in the adult ED., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Antibody-oligonucleotide conjugates are a promising class of therapeutics for extrahepatic delivery of small interfering ribonucleic acids (siRNAs). These conjugates can be optimized for improved delivery and mRNA knockdown (KD) through understanding of structure-activity relationships. In this study, we systematically examined factors including antibody isotype, siRNA chemistry, linkers, conjugation chemistry, PEGylation, and drug-to-antibody ratios (DARs) for their impact on bioconjugation, pharmacokinetics (PK), siRNA delivery, and bioactivity. Conjugation site (cysteine, lysine, and Asn297 glycan) and DAR proved critical for optimal conjugate PK and siRNA delivery. SiRNA chemistry including 2' sugar modifications and positioning of phosphorothioates were found to be critical for delivery and duration of action. By utilizing cleavable and noncleavable linkers, we demonstrated the impact of linkers on PK and mRNA KD. To achieve optimal properties of antibody-siRNA conjugates, a careful selection of siRNA chemistry, DAR, conjugation sites, linkers, and antibody isotype is necessary.

Background: Many Postgraduate Year One (PGY1) Pharmacy residencies provide research training however, details of this training are not well described. Publication rates have been utilized to assess residency research learning experiences. Higher publication rates have been reported by programs that have implemented a structured research learning experience. Objective: The primary objective was to identify differences in the research learning experiences for American Society of Health-System Pharmacists (ASHP) accredited PGY1 Pharmacy residencies with reported resident publication rates of ≥20% vs <20%. Methods: This survey was distributed to PGY1 Pharmacy residency program directors (RPDs). Seven sections were analyzed to identify research learning experience differences between programs with reported publication rates of ≥20% vs <20%: (1) program characteristics/research outcomes; (2) involved individuals; (3) requirements; (4) learning experience structure; (5) educational methods; (6) formal education; (7) barriers/RPD perceptions. Variables with P < 0.05 on logistic regression were considered statistically significant. Results: The survey response rate was 31.3% (308/984). Significant positive predictors for reported publication rates of ≥20% were: involved individuals: research director/coordinator, individuals trained in statistics, non-pharmacy medical staff; requirements: Collaborative Institutional Training Initiative training, research seminars/training courses, research manuscript; learning experience structure: research committee; educational methods: didactic residency-led lectures/courses, formal workshops, self-taught online modules; and formal education: manuscript preparation. Conclusion: This study suggests there are differences in the research learning experiences at PGY1 Pharmacy residencies with reported resident publications rates of ≥20% vs <20%. We encourage PGY1 Pharmacy residency programs to consider implementing elements associated with reported resident publication rates of ≥20%., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

B7-H3 (CD276) is a transmembrane glycoprotein of the B7 immune checkpoint superfamily that has emerged as a promising therapeutic target. To better understand the applicability of B7-H3-directed therapies, we analyzed 156,791 samples comprising 50 cancer types to interrogate the clinical, genomic, transcriptomic, and immunologic correlates of B7-H3 mRNA expression. DNA (592-gene/whole-exome) and RNA (whole-transcriptome) sequencing was performed from samples submitted to Caris Life Sciences. B7-H3 high versus low expression was based on top and bottom quartiles for each cancer type. Patients' overall survival was determined from insurance claims data. Pathway analysis was performed using gene set enrichment analyses. Immune cell fractions were inferred using quanTIseq. B7-H3 is expressed across several human malignancies including prostate, pancreatic, ovarian, and lung cancers. High B7-H3 expression is associated with differences in overall survival, possibly indicating a prognostic role of B7-H3 for some cancers. When examining molecular features across all cancer types, we did not identify recurrent associations between B7-H3 expression and genetic alterations in TP53, RB1, and KRAS. However, we find consistent enrichment of epithelial-to-mesenchymal transition, Wnt, TGFβ, and Notch signaling pathways. In addition, tumors with high B7-H3 expression are associated with greater proportions of M1 macrophages, but lower fractions of CD8+ T cells. We have begun to define the genomic, transcriptomic, clinical, and immunologic features associated with B7-H3 expression in 50 cancer types. We report novel clinical and molecular features of B7-H3-high tumors which may inform how current B7-H3 therapeutics should be deployed and prioritized., Significance: B7-H3-targeting therapeutics have shown promising results in initial clinical trials. In this pan-cancer analysis of B7-H3 mRNA expression, we found that B7-H3 exhibits robust expression in many common cancer types. These results may inform further development of B7-H3-targeting therapeutics and may guide clinical decisions for patients with limited treatment options., (© 2024 The Authors; Published by the American Association for Cancer Research.)

Some researchers have speculated that the prostatic microbiome is involved in the development of prostate cancer (PCa) but there is no consensus on certain microbiota in the prostatic tissue of PCa vs. healthy controls. This systematic review aims to investigate and compare the microbiome of PCa and healthy tissue to determine the microbial association with the pathogenesis of PCa. We searched MEDLINE, Embase, and Scopus databases. Articles were screened by two independent and blinded reviewers. Literature that compared the prostatic tissue microbiome of patients with PCa with benign controls was included. We found that PCa may be associated with increased Propionibacterium acnes , the herpesviridae and papillomaviridae families, and Mycoplasma genitalium , but definitive conclusions cannot be drawn from the existing data. Challenges include the difficulty of obtaining uncontaminated tissue samples and securing tissue from healthy controls. As a result, methods are varied with many studies using cancerous and "healthy" tissue from the same prostate. The organisms chosen for each study were also highly variable, making it difficult to compare studies. These issues have led to lower confidence in our results. Overall, further work is warranted to better understand the implications of the prostatic microbiome in the pathogenesis of PCa.

Introduction: Immune checkpoint inhibitor-induced inflammatory arthritis (ICI-IA) poses a major clinical challenge to ICI therapy for cancer, with 13% of cases halting ICI therapy and ICI-IA being difficult to identify for timely referral to a rheumatologist. The objective of this study was to rapidly identify ICI-IA patients in clinical data and assess associated immune-related adverse events (irAEs) and risk factors., Methods: We conducted a retrospective study of the electronic health records (EHRs) of 89 patients who developed ICI-IA out of 2451 cancer patients who received ICI therapy at Northwestern University between March 2011 to January 2021. Logistic regression and random forest machine learning models were trained on all EHR diagnoses, labs, medications, and procedures to identify ICI-IA patients and EHR codes indicating ICI-IA. Multivariate logistic regression was then used to test associations between ICI-IA and cancer type, ICI regimen, and comorbid irAEs., Results: Logistic regression and random forest models identified ICI-IA patients with accuracies of 0.79 and 0.80, respectively. Key EHR features from the random forest model included ICI-IA relevant features (joint pain, steroid prescription, rheumatoid factor tests) and features suggesting comorbid irAEs (thyroid function tests, pruritus, triamcinolone prescription). Compared to 871 adjudicated ICI patients who did not develop arthritis, ICI-IA patients had higher odds of developing cutaneous (odds ratio [OR]=2.66; 95% Confidence Interval [CI] 1.63-4.35), endocrine (OR=2.09; 95% CI 1.15-3.80), or gastrointestinal (OR=2.88; 95% CI 1.76-4.72) irAEs adjusting for demographics, cancer type, and ICI regimen. Melanoma (OR=1.99; 95% CI 1.08-3.65) and renal cell carcinoma (OR=2.03; 95% CI 1.06-3.84) patients were more likely to develop ICI-IA compared to lung cancer patients. Patients on nivolumab+ipilimumab were more likely to develop ICI-IA compared to patients on pembrolizumab (OR=1.86; 95% CI 1.01-3.43)., Discussion: Our machine learning models rapidly identified patients with ICI-IA in EHR data and elucidated clinical features indicative of comorbid irAEs. Patients with ICI-IA were significantly more likely to also develop cutaneous, endocrine, and gastrointestinal irAEs during their clinical course compared to ICI therapy patients without ICI-IA., Competing Interests: TLW receives unrelated research funding from Gilead Sciences. AK is a strategic advisor for Datavant, Inc. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.​, (Copyright © 2024 Tran, Lin, Galvez, Rasmussen, Pacheco, Perottino, Rahbari, Miller, John, Theros, Vogel, Dinh, Malik, Ramzan, Tegtmeyer, Mohindra, Johnson, Luo, Kho, Sosman and Walunas.)

In a cross-sectional analysis of 354 Ugandan children (age 12-48 months) infected with Schistosoma mansoni, we assessed relationships between infection intensity and nutritional morbidities. Higher intensity was associated with an increased risk for anemia (RR = 1.05, 95% confidence interval [CI] 1.01-1.10) yet not associated with risk for underweight, stunting, or wasting., Competing Interests: Potential conflicts of interest. A. L. B. reports grants from UKRI Future Leaders Fellowship in Global Health (grant number MR/T041900/1) and Wellcome Trust Biomedical Facilities Grant (Schistosomiasis Snail Resource Facilities—SSR). S. C. reports receipt of the Thrasher Early Career Award. J. F. F. reports a Midcareer Investigator Award in Patient Oriented Research from US National Institutes of Health/NIAID (award number K24 AI112964-06). E. L. W. reports grants from UK Medical Research Council (MRC), UK National Institute for Health and Care Research (NIHR), and European and Developing Countries Clinical Trial Partnership—European Union (EDCTP). All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Patients with prostate cancer (PC) generally do not respond favorably to immune checkpoint inhibitors, which may be due to a low abundance of tumor-infiltrating lymphocytes even when mutational load is high. Here, we identified a patient who presented with high-grade primary prostate cancer with two adjacent tumor nodules. While both nodules were mismatch repair-deficient (MMRd), exhibited pathogenic MSH2 and MSH6 alterations, had a high tumor mutational burden (TMB), and demonstrated high microsatellite instability (MSI), they had markedly distinct immune phenotypes. The first displayed a dense infiltrate of lymphocytes ("hot nodule"), while the second displayed significantly fewer infiltrating lymphocytes ("cold nodule"). Whole-exome DNA analysis found that both nodules shared many identical mutations, indicating that they were derived from a single clone. However, the cold nodule appeared to be sub-clonal relative to the hot nodule, suggesting divergent evolution of the cold nodule from the hot nodule. Whole-transcriptome RNA analysis found that the cold nodule demonstrated lower expression of genes related to antigen presentation (HLA) and, paradoxically, classical tumor immune tolerance markers such as PD-L1 (CD274) and CTLA-4. Immune cell deconvolution suggested that the hot nodule was enriched not only in CD8+ and CD4 + T lymphocytes, but also in M1 macrophages, activated NK cells, and γδ T cells compared to the cold nodule. This case highlights that MMRd/TMB-high PC can evolve to minimize an anti-tumor immune response, and nominates downregulation of antigen presentation machinery (HLA loss) as a potential mechanism of adaptive immune evasion in PC., (© 2024. The Author(s).)

Background: The objective of this study is to identify patient and EMS agency factors associated with timely reperfusion of patients with ST-elevation myocardial infarction (STEMI)., Methods: We conducted a cohort study of adult patients (≥18 years old) with STEMI activations from 2016 to 2020. Data was obtained from a regional STEMI registry, which included eight rural county EMS agencies and three North Carolina percutaneous coronary intervention (PCI) centers. On each patient, prehospital and in-hospital time intervals were abstracted. The primary outcome was the ability to achieve the 90-minute EMS FMC to PCI time goal (yes vs. no). We used generalized estimating equations accounting for within-agency clustering to evaluate the association between patient and agency factors and meeting first medical contact (FMC) to PCI time goal while accounting for clustering within the agency., Results: Among 365 rural STEMI patients 30.1% were female (110/365) with a mean age of 62.5 ± 12.7 years. PCI was performed within the time goal in 60.5% (221/365) of encounters. The FMC to PCI time goal was met in 45.5% (50/110) of women vs 69.8% (178/255) of men ( p  < 0.001). The median PCI center activation time was 12 min (IQR 7-19) in the group that received PCI within the time goal compared to 21 min (IQR 10-37) in the cohort that did not. After adjusting for loaded mileage and other clinical variables (e.g., pulse rate, hypertension etc.), the male sex was associated with an improved chance of meeting the goal of FMC to PCI (aOR: 2.94; 95% CI 2.11-4.10) compared to the female sex., Conclusion: Nearly 40% of rural STEMI patients transported by EMS failed to receive FMC to PCI within 90 min. Women were less likely than men to receive reperfusion within the time goal, which represents an important health care disparity.

Background: Those experiencing houselessness rely on obtaining food from community organizers and donations. Simultaneously, the houseless face disproportionally high rates of medical conditions that may be affected by diet including diabetes, hypertension, and hyperlipidemia. There is limited literature on the resources and barriers of the houseless community regarding optimal nutrition from an actionable perspective. Further, less data is available on how street medicine organizations may best impact the nutrition of the unhoused they serve. Elucidating this information will inform how organizational efforts may best support the nutrition of the houseless community., Methods: In partnership with the medical student-run organization, Chicago Street Medicine, at Northwestern University Feinberg School of Medicine, twenty adults experiencing houselessness in Chicago, Illinois participated in the cross-sectional study. A 10-item survey was verbally administered to characterize the participants' daily food intake, food sources, barriers, resources, and nutritional preferences and needs. All data was directly transcribed into REDCap. Descriptive statistics were generated., Results: Individuals consumed a median of 2 snacks and meals per day (IQR: 1-3). No participant consumed adequate servings of every food group, with only one participant meeting the dietary intake requirements for one food group. Participants most often received their food from donations (n = 15), purchasing themselves (n = 11), food pantries (n = 4), and shelters (n = 3). Eleven of nineteen participants endorsed dental concerns as a major barrier to consuming certain foods. Twelve participants had access to a can opener and twelve could heat their meals on a stove or microwave. Seven had access to kitchen facilities where they may prepare a meal. Approximately half of participants had been counseled by a physician to maintain a particular diet, with most related to reducing sugar intake., Conclusion: Most houseless participants were unable to acquire a balanced diet and often relied on organizational efforts to eat. Organizations should consider the chronic health conditions, dentition needs, and physical resources and barriers to optimal nutrition when obtaining food to distribute to the unhoused., (© 2023. The Author(s).)

Background: ST-elevation myocardial infarction (STEMI) guidelines recommend an emergency medical services (EMS) first medical contact (FMC) to percutaneous coronary intervention (PCI) time of ≤90 min. The primary objective of this study was to evaluate the association between FMC to PCI time and mortality in rural STEMI patients., Methods: We conducted a cohort study of patients ≥18 years old with STEMI activations from January 2016 to March 2020. Data were obtained from a rural North Carolina Regional STEMI Data Registry, which included eight rural EMS agencies and three PCI centers, the National Cardiovascular Data Registry, and the EMS electronic health record. Prehospital and in-hospital time intervals were digitally abstracted. The outcome of index hospitalization mortality was compared between patients who did and did not meet FMC to PCI time goal using Fisher's exact tests. Negative predictive value (NPV) for index hospitalization death was calculated with 95% confidence intervals (CIs). A receiver operating characteristic curve was constructed and an optimal FMC to PCI time goal was identified by maximizing NPV to prevent index hospitalization death., Results: Among 365 rural EMS STEMI patients, 30.1% (110/365) were female with a mean ± SD age of 62.5 ± 12.7 years. PCI was performed within the 90-min time goal in 60.5% (221/365) of patients. Among these patients, 3% (11/365) died during initial STEMI hospitalization, with 1.4% (3/221) mortality in the group that met the 90-minute time goal compared to 5.6% (8/144) in patients exceeding the time goal (p = 0.03). Meeting the 90-min time goal yielded a 98.6% (95% CI 96.1%-99.7%) NPV for index death. A 78-min FMC to PCI time was the optimal cut point, yielding a NPV for index mortality of 99.3% (95% CI 96.1%-100%)., Conclusions: Death among rural patients with STEMI was four times more likely when they did not receive PCI within 90 min., (© 2023 The Authors. Academic Emergency Medicine published by Wiley Periodicals LLC on behalf of Society for Academic Emergency Medicine.)

Objectives: Effective interventions to prevent diagnostic error among critically ill children should be informed by diagnostic error prevalence and etiologies. We aimed to determine the prevalence and characteristics of diagnostic errors and identify factors associated with error in patients admitted to the PICU., Design: Multicenter retrospective cohort study using structured medical record review by trained clinicians using the Revised Safer Dx instrument to identify diagnostic error (defined as missed opportunities in diagnosis). Cases with potential errors were further reviewed by four pediatric intensivists who made final consensus determinations of diagnostic error occurrence. Demographic, clinical, clinician, and encounter data were also collected., Setting: Four academic tertiary-referral PICUs., Patients: Eight hundred eighty-two randomly selected patients 0-18 years old who were nonelectively admitted to participating PICUs., Interventions: None., Measurements and Main Results: Of 882 patient admissions, 13 (1.5%) had a diagnostic error up to 7 days after PICU admission. Infections (46%) and respiratory conditions (23%) were the most common missed diagnoses. One diagnostic error caused harm with a prolonged hospital stay. Common missed diagnostic opportunities included failure to consider the diagnosis despite a suggestive history (69%) and failure to broaden diagnostic testing (69%). Unadjusted analysis identified more diagnostic errors in patients with atypical presentations (23.1% vs 3.6%, p = 0.011), neurologic chief complaints (46.2% vs 18.8%, p = 0.024), admitting intensivists greater than or equal to 45 years old (92.3% vs 65.1%, p = 0.042), admitting intensivists with more service weeks/year (mean 12.8 vs 10.9 wk, p = 0.031), and diagnostic uncertainty on admission (77% vs 25.1%, p < 0.001). Generalized linear mixed models determined that atypical presentation (odds ratio [OR] 4.58; 95% CI, 0.94-17.1) and diagnostic uncertainty on admission (OR 9.67; 95% CI, 2.86-44.0) were significantly associated with diagnostic error., Conclusions: Among critically ill children, 1.5% had a diagnostic error up to 7 days after PICU admission. Diagnostic errors were associated with atypical presentations and diagnostic uncertainty on admission, suggesting possible targets for intervention., Competing Interests: Drs. Cifra, Smith, Riffe, Landrigan, and Dawson’s institutions received funding from the Eunice Kennedy Shriver National Institute of Child Health and Human Development through a K12 grant to the University of Iowa Stead Family Department of Pediatrics (no. HD027748-28) and the National Center for Advancing Translational Sciences. Drs. Cifra, KA Smith, Riffe, Landrigan, Dawson, and Herwaldt’s institutions received funding from the Agency for Healthcare Research and Quality (AHRQ) through a K08 grant (no. HS026965). This work was further supported by the National Center for Advancing Translational Sciences of the National Institutes of Health (no. UL1TR002537) through the University of Iowa’s Institute for Clinical and Translational Science. Dr. Cifra received funding from the AHRQ, MedStar Research Institute, and De Gruyter. Drs. Cifra, CM Smith, KA Smith, Riffe, Ten Eyck, Landrigan, and Dawson received support for article research from the National Institutes of Health. Drs. Custer and Tumulty’s institution received funding from University of Iowa. Dr. Miller’s institution received funding from the University of Iowa Department of Pediatrics. Dr. Landrigan received funding from I-PASS Institute and Missouri Hospital Association Executive Speakers Bureau. Dr. Singh is funded in part by the Houston Veterans Administration (VA) Health Services Research and Development (HSR&D) Center for Innovations in Quality, Effectiveness, and Safety (CIN13–413), the VA HSR&D Service (IIR17–127 and the Presidential Early Career Award for Scientists and Engineers USA 14–274), the VA National Center for Patient Safety, the Agency for Healthcare Research and Quality (R01HS27363), and the Gordon and Betty Moore Foundation. He disclosed government work. Dr. Herwaldt’s institution received funding from the Centers for Disease Control and Prevention; she disclosed that Professional Disposables International, Inc. (PDI) is providing a product for a clinical trial. The remaining authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2023 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.)

Although targeting TfR1 to deliver oligonucleotides to skeletal muscle has been demonstrated in rodents, effectiveness and pharmacokinetic/pharmacodynamic (PKPD) properties remained unknown in higher species. We developed antibody-oligonucleotide conjugates (AOCs) towards mice or monkeys utilizing anti-TfR1 monoclonal antibodies (αTfR1) conjugated to various classes of oligonucleotides (siRNA, ASOs and PMOs). αTfR1 AOCs delivered oligonucleotides to muscle tissue in both species. In mice, αTfR1 AOCs achieved a > 15-fold higher concentration to muscle tissue than unconjugated siRNA. A single dose of an αTfR1 conjugated to an siRNA against Ssb mRNA produced > 75% Ssb mRNA reduction in mice and monkeys, and mRNA silencing was greatest in skeletal and cardiac (striated) muscle with minimal to no activity in other major organs. In mice the EC50 for Ssb mRNA reduction in skeletal muscle was >75-fold less than in systemic tissues. Oligonucleotides conjugated to control antibodies or cholesterol produced no mRNA reduction or were 10-fold less potent, respectively. Tissue PKPD of AOCs demonstrated mRNA silencing activity primarily driven by receptor-mediated delivery in striated muscle for siRNA oligonucleotides. In mice, we show that AOC-mediated delivery is operable across various oligonucleotide modalities. AOC PKPD properties translated to higher species, providing promise for a new class of oligonucleotide therapeutics., (© The Author(s) 2023. Published by Oxford University Press on behalf of Nucleic Acids Research.)

Background: The optimal diagnostic strategy for patients with chest pain and detectable to mildly elevated serum troponin is not known. The objective was to compare clinical outcomes among an early decision for a noninvasive versus an invasive-based care pathway., Methods: The CMR-IMPACT trial (Cardiac Magnetic Resonance Imaging Strategy for the Management of Patients with Acute Chest Pain and Detectable to Elevated Troponin) was conducted at 4 United States tertiary care hospitals from September 2013 to July 2018. A convenience sample of 312 participants with acute chest pain symptoms and a contemporary troponin between detectable and 1.0 ng/mL were randomized early in their care to 1 of 2 care pathways: invasive-based (n=156) or cardiac magnetic resonance (CMR)-based (n=156) with modification allowed as the patient condition evolved. The primary outcome was a composite including death, myocardial infarction, and cardiac-related hospital readmission or emergency visits., Results: Participants (N=312, mean age, 60.6 years, SD 11.3; 125 women [59.9%]), were followed over a median of 2.6 years (95% CI, 2.4-2.9). Early assigned testing was initiated in 102 out of 156 (65.3%) CMR-based and 110 out of 156 (70.5%) invasive-based participants. The primary outcome (CMR-based versus invasive-based) occurred in 59% versus 52% (hazard ratio, 1.17 [95% CI, 0.86-1.57]), acute coronary syndrome after discharge 23% versus 22% (hazard ratio, 1.07 [95% CI, 0.67-1.71]), and invasive angiography at any time 52% versus 74% (hazard ratio, 0.66 [95% CI, 0.49-0.87]). Among patients completing CMR imaging, 55 out of 95 (58%) were safely identified for discharge based on a negative CMR and did not have angiography or revascularization within 90 days. Therapeutic yield of angiography was higher in the CMR-based arm (52 interventions in 81 angiographies [64.2%] versus 46 interventions in 115 angiographies [40.0%] in the invasive-based arm [ P =0.001])., Conclusions: Initial management with CMR or invasive-based care pathways resulted in no detectable difference in clinical and safety event rates. The CMR-based pathway facilitated safe discharge, enriched the therapeutic yield of angiography, and reduced invasive angiography utilization over long-term follow-up., Registration: URL: https://www., Clinicaltrials: gov; Unique identifier: NCT01931852., Competing Interests: Disclosures Dr Miller received research funding from Abbott, Research Triangle Institute (RTI) International (COVID-related), and Gifols Therapeutics (COVID-related). Dr Mahler receives funding/support from Roche Diagnostics, Abbott Laboratories, QuidelOrtho, Siemens, Grifols, Pathfast, Genetesis, Cytovale, National Heart, Lung, and Blood Institute (NHLBI; 1 R01 HL118263-01), and Health Resources and Services Administration (HRSA; 1H2ARH399760100). He is a consultant for Roche, Quidel, Abbott, Genetesis, Inflammatix, Radiometer, and Amgen and the Chief Medical Officer for Impathiq Inc. Dr Stopyra receives research funding from National Center for Advancing Translational Sciences (NCATS)/National Institutes of Health (NIH) (KL2TR001421), HRSA (H2ARH39976-01-00), NHLBI (U01HL123027), Roche Diagnostics, and Abbott Point of Care. He has provided paid consulting to Roche Diagnostics. Dr Hiestand receives research funding from Siemens. Dr Caterino receives research funding from National Institute on Aging (NIA)/NIH. Dr Snavely receives research funding from Abbott Laboratories, NHLBI (1 R01 HL118263-01), and HRSA (1 H2ARH399760100).

Background: Skin and soft tissue infections (SSTIs) are often caused by gram-positive bacteria that colonize the skin. Given the overuse of antibiotics, SSTIs are increasingly caused by resistant bacteria, including methicillin-resistant Staphylococcus aureus (MRSA). Guidance on the utility of MRSA nasal screening for MRSA SSTI is limited., Objective: To determine whether MRSA nasal screening predicts the risk of MRSA SSTIs., Methods: This was a single-center, retrospective cohort study of adult patients with an SSTI diagnosis that had MRSA nasal screening and wound cultures obtained within 48 hours of starting antibiotics. Sensitivity, specificity, positive and negative predictive value, and positive and negative likelihood ratios were calculated using VassarStats. Pretest and posttest probabilities were estimated with Microsoft Excel., Results: A total of 884 patient encounters were reviewed between December 1, 2018, and October 31, 2021, and 300 patient encounters were included. The prevalence of MRSA SSTI was 18.3%. The MRSA nasal colonization had a sensitivity of 63.6%, specificity of 93.9%, positive predictive value of 70.0% (95% CI = 55.2%-81.7%), negative predictive value of 92.0% (95% CI = 87.7%-94.9%), positive likelihood ratio of 10.39 (95% CI = 6.12-17.65), negative likelihood ratio of 0.39 (95% CI = 0.27-0.55), positive posttest probability of 70.0%, and negative posttest probability of 8.0%., Conclusions: Given the high positive likelihood ratio, a positive MRSA nasal screen was associated with a large increase in the probability of MRSA SSTI at our institution, and a negative MRSA nasal screen was associated with a small but potentially significant decrease in the probability of MRSA SSTI.

Background: Free online adaptive vancomycin dosing calculators are available to estimate area under the concentration-time curve (AUC), but the accuracy of predicting vancomycin AUC using these calculators compared with using a 2-point pharmacokinetic approach has not been described., Objective: To evaluate the accuracy of calculator-predicted AUC (cpAUC) using 4 free online calculators compared with reference AUC (rAUC), and to assess pharmacists' impressions of the ease of use., Methods: Vancomycin AUC was estimated using (1) the reference method via the Sawchuk-Zaske method and linear-logarithmic trapezoidal rule using 2 steady-state postdistributional vancomycin serum concentrations and (2) 4 free online vancomycin dosing calculators including ClinCalc, VancoPK, TDMx, and DMC. Accuracy was calculated by dividing cpAUC by rAUC. Ease of cpAUC estimation was determined by using a 10-point Likert scale., Results: All 4 calculators had a median cpAUC accuracy ranging from 89% to 110%. Concordance between cpAUC and rAUC determinations of AUC <400 and > 600 mg·h/L occurred 63.3% to 71.4% and 74.5% to 78.6% of the time, respectively. Pharmacist investigators agreed that ClinCalc and VancoPK calculators were easiest to use., Conclusion and Relevance: cpAUC accuracy varied among the 4 calculators, but all consistently identified patients with an rAUC <400 mg·h/L and an rAUC > 600 mg·h/L at comparable frequencies. All 4 calculators demonstrated some imprecision based on their wide 95% CIs and potential inaccuracies in predicting an rAUC <400 mg·h/L or an rAUC > 600 mg·h/L. Clin Calc and VancoPK were most user friendly based on our pharmacists' impressions.

Background: Compliance with guideline recommendations for surgical antibiotic prophylaxis (SAP) in colorectal surgery, particularly redosing, has been suboptimal at many institutions including ours. This study aimed to evaluate if single-dose antibiotic prophylaxis with ertapenem improves compliance with guideline recommendations for SAP versus multiple-dose antibiotic prophylaxis in elective colorectal surgery. Methods: A retrospective, cohort study of the use of ertapenem compared with standard of care antibiotic agents was performed in adult patients undergoing elective colorectal surgery at an academic medical center between January 2020 and February 2022. The primary outcome was compliance with guideline-recommended SAP for colorectal surgery. The secondary outcome was surgical site infections (SSIs) within 30 days after surgery. Results: A total of 135 patients were included in this study. Fifty-eight patients received single-dose antibiotic prophylaxis with ertapenem and 77 patients received multiple-dose antibiotic prophylaxis. Cefazolin plus metronidazole was the most common multiple-dose regimen (65 of 77). Single-dose antibiotic prophylaxis with ertapenem increased overall SAP compliance (96.6% vs. 64.9%; p < 0.001) as well as compliance with antibiotic administration within the recommended time period before incision (96.6% vs. 84.4%; p = 0.022), compliance with intra-operative antibiotic redosing when warranted (100% vs. 83.1%; p < 0.001), and compliance with guideline-recommended dosing (100% vs. 92.2%; p = 0.037). Surgical site infection rates were not statistically different between the groups (12.1% vs. 19.4%; p = 0.248). Conclusions: Single-dose antibiotic prophylaxis with ertapenem increased compliance with guideline-recommended SAP for elective colorectal surgeries. No statistically significant difference was observed in SSI rates regardless of the antibiotic regimen used.

Background: Intravenous fluids and vasopressor agents are commonly used in early resuscitation of patients with sepsis, but comparative data for prioritizing their delivery are limited., Methods: In an unblinded superiority trial conducted at 60 U.S. centers, we randomly assigned patients to either a restrictive fluid strategy (prioritizing vasopressors and lower intravenous fluid volumes) or a liberal fluid strategy (prioritizing higher volumes of intravenous fluids before vasopressor use) for a 24-hour period. Randomization occurred within 4 hours after a patient met the criteria for sepsis-induced hypotension refractory to initial treatment with 1 to 3 liters of intravenous fluid. We hypothesized that all-cause mortality before discharge home by day 90 (primary outcome) would be lower with a restrictive fluid strategy than with a liberal fluid strategy. Safety was also assessed., Results: A total of 1563 patients were enrolled, with 782 assigned to the restrictive fluid group and 781 to the liberal fluid group. Resuscitation therapies that were administered during the 24-hour protocol period differed between the two groups; less intravenous fluid was administered in the restrictive fluid group than in the liberal fluid group (difference of medians, -2134 ml; 95% confidence interval [CI], -2318 to -1949), whereas the restrictive fluid group had earlier, more prevalent, and longer duration of vasopressor use. Death from any cause before discharge home by day 90 occurred in 109 patients (14.0%) in the restrictive fluid group and in 116 patients (14.9%) in the liberal fluid group (estimated difference, -0.9 percentage points; 95% CI, -4.4 to 2.6; P = 0.61); 5 patients in the restrictive fluid group and 4 patients in the liberal fluid group had their data censored (lost to follow-up). The number of reported serious adverse events was similar in the two groups., Conclusions: Among patients with sepsis-induced hypotension, the restrictive fluid strategy that was used in this trial did not result in significantly lower (or higher) mortality before discharge home by day 90 than the liberal fluid strategy. (Funded by the National Heart, Lung, and Blood Institute; CLOVERS ClinicalTrials.gov number, NCT03434028.)., (Copyright © 2023 Massachusetts Medical Society.)

Introduction: Patients with lower urinary tract symptoms (LUTS) can be subcategorized into polyuria, normal or oliguria groups. Polyuria may be caused by pathologies including diabetes mellitus (DM), chronic kidney disease (CKD), diabetes insipidus (DI), or primary polydipsia (PPD). While fluid restriction is appropriate for some, doing so in all may result in serious complications. This study investigates the prevalence of these pathologies in LUTS patients with polyuria., Materials and Methods: Two databases were retrospectively queried for men and women who filled out a lower urinary tract symptom score (LUTSS) questionnaire, 24-h bladder diary (24HBD) and were polyuric (>2.5 L/day). Patients were divided into four groups: poorly controlled DM, DI, an CKD grade 3 and PPD. One-way analysis of variance compared 24HBD and LUTSS questionnaires. Pearson correlation examined LUTSS and bother with 24-h voided volume (24 HVV), maximum voided volume (MVV) and total voids., Results: Among 814 patients who completed a 24HBD, 176 had polyuria (22%). Of the patients with complete data, 7.8% had poorly-controlled DM, 3.1% had DI, 4.7% had CKD grade 3% and 84.4% had PPD. Amongst the four different sub-groups, significant differences were seen in 24 HVV (p < 0.001), nocturnal urine volume (NUV) (p < 0.001), MVV (p = 0.003), daytime voids (p = 0.05), nocturnal polyuria index (NPi) (p < 0.001) and nocturia index (Ni) (p = 0.002). Significance was also seen between LUTSS and bother subscore (r = 0.68, p < 0.001), LUTSS and total voids (r = 0.29, p = 0.001) and bother sub-score and total voids (r = 0.21, p = 0.019)., Conclusions: 22% of patients with LUTS were found to have polyuria based on a 24HBD. Within this cohort, four sub-populations were identified as being demonstrating statistically significant differences in 24 HVV, NUV, MVV, daytime voids, NPi and Ni. Identifying the underlying etiology of polyuria should be carried out to safely treat patients with LUTS., (© 2022 The Authors. Neurourology and Urodynamics published by Wiley Periodicals LLC.)

Background: Rural patients with ST-elevation myocardial infarction (STEMI) may be less likely to receive prompt reperfusion therapy. This study's primary objective was to compare rural versus urban time intervals among a national cohort of prehospital patients with STEMI., Methods: The ESO Data Collaborative (Austin, TX), containing records from 1,366 emergency medical services agencies, was queried for adult 9-1-1 responses with suspected STEMI from 1/1/2018-12/31/2019. The scene address for each encounter was classified as either urban or rural using the 2010 US Census Urban Area Zip Code Tabulation Area relationship. The primary outcome was total EMS interval (9-1-1 call to hospital arrival); a key secondary outcome was the proportion of responses that had EMS intervals under 60 minutes. Generalized estimating equations were used to determine whether rural versus urban differences in interval outcomes occurred when adjusting for loaded mileage (distance from scene to hospital) and patient and clinical encounter characteristics., Results: Of 15,915,027 adult 9-1-1 transports, 23,655 records with suspected STEMI were included in the analysis. Most responses (91.6%, n = 21,661) occurred in urban settings. Median EMS interval was 37.6 minutes (IQR 30.0-48.0) in urban settings compared to 57.0 minutes (IQR 46.5-70.7) in rural settings (p < 0.01). Urban responses more frequently had EMS intervals <60 minutes (89.5%, n = 19,130), compared to rural responses (55.5%, n = 1,100, p < 0.01). After adjusting for loaded mileage, age, sex, race/ethnicity, abnormal vital signs, pain assessment, aspirin administration, and IV/IO attempt, rural location was associated with a 5.8 (95%CI 4.2-7.4) minute longer EMS interval than urban, and rural location was associated with a reduced chance of achieving EMS interval < 60 minutes (OR 0.40; 95%CI 0.33-0.49) as compared to urban location., Conclusion: In this large national sample, rural location was associated with significantly longer EMS interval for patients with suspected STEMI, even after accounting for loaded mileage.

Background: Emergency medical services (EMS) assesses millions of patients with chest pain each year. However, tools validated to risk stratify patients for acute coronary syndrome (ACS) and pulmonary embolism (PE) have not been translated to the prehospital setting. The objective of this study is to assess the prehospital performance of risk stratification scores for 30-day major adverse cardiac events (MACE) and PE., Methods: A prospective observational cohort study of patients ≥21 years of age with acute chest pain who were transported by EMS in two North Carolina (NC) counties was conducted from 18 April 2018-2 January 2019. In this convenience sample, paramedics completed HEAR (history, electrocardiogram, age, risk factor), ED Assessment of Chest Pain Score (EDACS), Revised Geneva Score (RGS), and pulmonary embolism rule-out criteria (PERC) assessments on each patient. MACE (all-cause death, myocardial infarction, and revascularization) and PE at 30 days were determined by hospital records and NC Death Index. The positive (+LR) and negative likelihood ratios (-LR) of the risk scores for 30-day MACE and PE were calculated., Results: During the study period, 82.1% (687/837) patients had all four risk score assessments. The cohort was 51.1% (351/687) female, 49.5% (340/687) African American, and had a mean age of 55.0 years (SD 16.0). At 30 days, MACE occurred in 7.4% (51/687), PE occurred in 0.9% (6/687), and the combined outcome occurred in 8.2% (56/687). The HEAR score had a - LR of 0.46 (95% CI 0.27-0.78) and + LR of 1.48 (95% CI 1.26-1.74) for 30-day MACE. EDACS had a - LR of 0.61 (95% CI 0.46-0.81) and + LR of 2.53 (95% CI 1.86-3.46) for 30-day MACE. The PERC score had a - LR of 0 (95% CI 0.0-1.4) and a + LR of 1.38 (95% CI 1.32-1.45) for 30-day PE. The RGS score had a - LR of 0 (95% CI 0.0-0.65) and a + LR of 2.36 (95% CI 2.16-2.57) for 30-day PE. The combination of a low-risk HEAR score and negative PERC evaluation had a - LR of 0.25 (95% CI 0.08-0.76) and a + LR of 1.21 (95% CI 1.21-1.30) for 30-day MACE or PE., Conclusion: The combination of a paramedic-obtained HEAR score and PERC evaluation performed best to exclude 30-day MACE and PE but was not sufficient for directing prehospital decision making.

What Is Known and Objective: Current vancomycin monitoring guidelines recommend the use of area under the concentration-time curve (AUC 24 ) monitoring in patients with serious Methicillin-Resistant Staphylococcus aureus (MRSA) infections by utilizing either a Bayesian approach or first-order analytic equations. Several open-access websites exist that allow estimation of vancomycin AUC 24 with the use of a single steady-state concentration. It is uncertain how these open-access calculators perform against guideline-recommended methods. The objective was to compare AUC 24 estimates from two online, open-access, single-concentration vancomycin calculators compared with the two-point pharmacokinetic (2PK) method., Methods: AUC 24 estimates were made using the 2PK reference method and the single-concentration vancomycin calculators, ClinCalc and VancoPK. The AUC 24 estimates from the 2PK reference method were compared to the online calculators by assessing bias (median AUC 24 difference) and precision (AUC 24 difference ± 100 mg*h/L). Clinical precision was also assessed by characterizing the frequency that the 2PK reference method and the online calculators showed clinical disagreement based on the following AUC 24 categories: (1) AUC 24  < 400 mg*h/L; (2) AUC 24 400-600 mg*h/L and (3) AUC 24  > 600 mg*h/L., Results and Discussion: A total of 253 patients were included in the study. The AUC 24 estimates from the ClinCalc and VancoPK single-concentration vancomycin calculators showed some bias and imprecision, though VancoPK appeared to have less. Clinical disagreement versus the 2PK reference method occurred in 31.2% and 19.4% of AUC 24 estimates from the ClinCalc and VancoPK single-concentration vancomycin calculators, suggesting clinical imprecision., What Is New and Conclusion: The AUC 24 estimates from single-concentration, online vancomycin calculators showed some bias and imprecision in comparison to the 2PK method. Institutions should validate these online, trough-only calculators relative to a 2PK method in their patient populations prior to adoption as standard-of-care., (© 2022 John Wiley & Sons Ltd.)

Background: Trauma patients are at increased risk of developing venous thromboembolism given alterations in the coagulation cascade. Chemoprophylaxis with standard dosing of enoxaparin 30 mg subcutaneously twice daily has evolved to incorporate the use of anti-factor Xa (AFXa) trough level monitoring given concerns for decreased enoxaparin bioavailability in this patient population. Current available evidence suggests low rates of goal AFXa trough level achievement with standard enoxaparin dosing. Our study aims to identify the incidence of critically ill trauma patients that did not achieve goal AFXa trough levels and attempts to identify predictors that may influence the lack of achievement of goal levels. Methods: This was a retrospective, cohort analysis performed at a single academic medical center. Adult patients 18 years or older admitted to the surgical intensive care unit secondary to trauma who were initiated on standard prophylactic enoxaparin and had at least 1 AFXa trough level representative of steady state were included. Patient demographics and clinical data were collected, and descriptive statistics were utilized. All statistical tests were 2-tailed and a P  < .05 was considered significant. Variables with a P  < .10 on univariable analysis were included in a multivariable logistic regression analysis. Results: A majority of our patient population did not achieve goal AFXa trough levels while receiving standard doses of prophylactic enoxaparin (82.4% [108/131]). Sub-target AFXa levels were associated with higher creatinine clearance values. Positive predictors of obtaining target AFXa levels included automobile versus pedestrian mechanism of injury and requiring an enoxaparin dose escalation to at least 40 mg twice daily. Conclusions: Our study found low rates of achievement of goal AFXa trough levels in critically ill trauma patients receiving standard prophylactic enoxaparin dosing. Certain variables were identified as negative and positive predictors for achievement of goal AFXa trough levels, although the biologic plausibility of these predictors is questionable and requires further investigation., Competing Interests: Declaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2021.)

Background: Approximately 30% of antimicrobials prescribed in the outpatient setting are unnecessary and up to 50% are inappropriate. Despite this, antimicrobial stewardship (AS) efforts mostly focus on the inpatient setting, and limited data describe AS interventions at hospital discharge. Acknowledging the potential value of discharge AS, we used our existing resources to review discharge oral antimicrobial prescriptions., Objective: The primary objective of this retrospective, single-center study was to evaluate the impact of an AS program on discharge oral antimicrobial prescriptions., Methods: Discharge oral antimicrobial prescriptions sent to our hospital-operated outpatient pharmacy, reviewed by an infectious diseases (ID) pharmacist, and recorded into our data collection tool from September 1, 2020, to February 28, 2021, were evaluated retrospectively. The primary outcome was to identify the frequency a drug-related problem (DRP) was identified by an ID pharmacist. Secondary outcomes included DRP characterization, percentage of prescriptions with interventions, intervention acceptance rate, and reduction in antimicrobial days dispensed at discharge when interventions to limit treatment duration were accepted., Results: Of the 803 discharge oral antimicrobial prescriptions reviewed, at least 1 DRP was identified in 43.1% (346/803). The most frequently identified DRPs pertained to treatment duration, drug selection, and dose selection. At least 1 intervention was recommended in 42.8% (344/803) of prescriptions. In total, 438 interventions were made and the acceptance rate was 75.6% (331/438). The most common types of interventions included recommendations for a different duration, a different dose or frequency, and antimicrobial discontinuation. When interventions to reduce treatment duration were accepted, the median (interquartile range) number of antimicrobial days decreased from 8 (5-10) days to 4 (0-5.5) days ( P < 0.001)., Conclusion and Relevance: An ID pharmacist's review of discharge oral antimicrobial prescriptions sent to our hospital-operated outpatient pharmacy resulted in identification of DRPs and subsequent interventions in a substantial number of prescriptions.

Purpose: While some guidelines recognize the need for β-lactam therapeutic drug monitoring (TDM), there is still a paucity of data regarding the prevalence of and barriers to performing β-lactam TDM in the United States. We sought to estimate the prevalence of β-lactam TDM, describe monitoring practices, and identify actual and perceived barriers to implementation among health systems in the US., Methods: A multicenter, cross-sectional, 40-item electronic survey was distributed to all postgraduate year 2 (PGY2) infectious diseases (ID) pharmacy residency program directors (RPDs) listed in the American Society of Health-System Pharmacists pharmacy residency directory. The primary outcome was the percentage of institutions with established β-lactam TDM. Secondary outcomes included assessing β-lactam TDM methods and identifying potential barriers to implementation., Results: The survey was distributed to 126 PGY2 ID RPDs, with a response rate of 31.7% (40 of 126). Only 8% of respondents (3 of 39) performed β-lactam TDM. Patient populations, therapeutic targets, and frequency and timing of obtaining repeat β-lactam concentration measurements varied among institutions. The greatest barrier to implementation was lack of access to testing with a rapid turnaround time. Institutions were unlikely to implement β-lactam TDM within the next year but were significantly more inclined to do so within 5 years (P < 0.001)., Conclusion: β-lactam TDM was infrequently performed at the surveyed US health systems. Lack of access to serum concentration testing with rapid turnaround and lack of US-specific guidelines appear to be considerable barriers to implementing β-lactam TDM. Among institutions that have implemented β-lactam TDM, there is considerable variation in monitoring approaches., (© American Society of Health-System Pharmacists 2022. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Syntrophic anaerobic consortia comprised of fatty acid-degrading bacteria and hydrogen/formate-scavenging methanogenic archaea are of central importance for balanced and resilient natural and manufactured ecosystems: anoxic sediments, soils, and wastewater treatment bioreactors. Previously published studies investigated interaction between the syntrophic bi-cultures, but little information is available on the influence of fermentative bacteria on syntrophic fatty acid oxidation, even though fermentative organisms are always present together with syntrophic partners in the above-mentioned ecosystems. Here, we present experimental observations of stimulated butyrate oxidation and methane generation by a coculture of Syntrophomonas wolfei with any of the following methanogens: Methanospirillum hungatei, Methanobrevibacter arboriphilus, or Methanobacterium formicicum due to the addition of a fermentative Trichococcus flocculiformis strain ES5. The addition of T. flocculiformis ES5 to the syntrophic cocultures led to an increase in the rates of butyrate consumption (120%) and volumetric methane production (150%). Scanning electron microscopy of the most positively affected coculture (S. wolfei, M. hungatei , and T. flocculiformis ES5) revealed a tendency of T. flocculiformis ES5 to aggregate with the syntrophic partners. Analysis of coculture's proteome with or without addition of the fermentative bacterium points to a potential link with signal transducing systems of M. hungatei , as well as activation of additional butyryl coenzyme A dehydrogenase and an electron transfer flavoprotein in S. wolfei. IMPORTANCE Results from the present study open doors to fascinating research on complex microbial cultures in anaerobic environments (of biotechnological and ecological relevance). Such studies of defined mixed populations are critical to understanding the highly intertwined natural and engineered microbial systems and to developing more reliable and trustable metabolic models. By investigating the existing cultured microbial consortia, like the ones described here, we can acquire knowledge on microbial interactions that go beyond "who feeds whom" relations but yet benefit the parties involved. Transfer of signaling compounds and stimulation of gene expression are examples of indirect influence that members of mixed communities can exert on each other. Understanding such microbial relationships will enable development of new sustainable biotechnologies with mixed microbial cocultures and contribute to the general understanding of the complex natural microbial interactions.