Features of the TCR repertoire associate with patients' clinical and molecular characteristics in acute myeloid leukemia.

Background: Allogeneic hematopoietic stem cell transplant remains the most effective strategy for patients with high-risk acute myeloid leukemia (AML). Leukemia-specific neoantigens presented by the major histocompatibility complexes (MHCs) are recognized by the T cell receptors (TCR) triggering the graft-versus-leukemia effect. A unique TCR signature is generated by a complex V(D)J rearrangement process to form TCR capable of binding to the peptide-MHC. The generated TCR repertoire undergoes dynamic changes with disease progression and treatment. Method: Here we applied two different computational tools (TRUST4 and MIXCR) to extract the TCR sequences from RNA-seq data from The Cancer Genome Atlas (TCGA) and examine the association between features of the TCR repertoire in adult patients with AML and their clinical and molecular characteristics. Results: We found that only ~30% of identified TCR CDR3s were shared by the two computational tools. Yet, patterns of TCR associations with patients' clinical and molecular characteristics based on data obtained from either tool were similar. The numbers of unique TCR clones were highly correlated with patients' white blood cell counts, bone marrow blast percentage, and peripheral blood blast percentage. Multivariable regressions of TCRA and TCRB median normalized number of unique clones with mutational status of AML patients using TRUST4 showed significant association of TCRA or TCRB with WT1 mutations, WBC count, %BM blast, and sex (adjusted in TCRB model). We observed a correlation between TCRA/B number of unique clones and the expression of T cells inhibitory signal genes (TIGIT, LAG3, CTLA-4) and foxp3, but not IL2RA, CD69 and TNFRSF9 suggestive of exhausted T cell phenotypes in AML. Conclusion: Benchmarking of computational tools is needed to increase the accuracy of the identified clones. The utilization of RNA-seq data enables identification of highly abundant TCRs and correlating these clones with patients' clinical and molecular characteristics. This study further supports the value of high-resolution TCR-Seq analyses to characterize the TCR repertoire in patients.

Risk factors and outcome associated with coinfection with carbapenem-resistant Klebsiella pneumoniae and carbapenem-resistant Pseudomonas aeruginosa or Acinetobacter baumanii: a descriptive analysis.

Background: Nearly 30% of patients infected with carbapenem-resistant Klebsiella pneumoniae (CRKP) were previously shown to be coinfected with carbapenem-resistant Pseudomonas aeruginosa (CRPA) or Acinetobacter baumannii (CRAB). Infections caused by multiple carbapenem-resistant pathogens present significant challenge to infection control and therapeutic management. The study objective was to identify risk factors for acquisition of multiple carbapenem-resistant pathogens and associated outcomes. Methods: A descriptive analysis of adults infected with either CRKP alone or coinfected with CRPA or CRAB was performed. Patient groups were compared on demographics, clinical characteristics, treatment, and outcome. Results: 86 patients with CRKP monoinfection and 60 patients with coinfections were evaluated. Respiratory tract was the predominant infection site for coinfected patients involving mostly CRPA whereas urinary tract was the primary site for CRKP-only group. More coinfected patients were severely debilitated, had prior carbapenem exposure (37% vs 13%, p<0.001) and history of pneumonia in the past year (67% vs 41%, p<0.01). More coinfected patients required direct ICU admission (45% vs 27%, p=0.02) and had prolonged length of stay (median 15 vs 10 days, p<0.01) than the CRKP-only group but mortality rates (18% vs 16%) were similar. Conclusions: CRKP coinfection with another carbapenem-resistant pathogen adds significant morbidity and healthcare burden overall. Empiric therapy with reliable activity against both CRKP and carbapenem-resistant Pseudomonas aeruginosa may be prudent for at risk patients with pneumonia.

Genomics and transcriptomic alterations of the glutamate receptors in acute myeloid leukemia.

Glutamine and glutamate have been widely explored as potential therapeutic targets in acute myeloid leukemia (AML). In addition to its bioenergetic role in leukemia cell proliferation, L-glutamate is a neurotransmitter that acts on glutamate receptors. However, the role of glutamate receptors in AML is largely understudied. Here, we comprehensively analyze the genomic and transcriptomic alterations of glutamate receptor genes in AML using publicly available data. We investigated the frequency of mutations in the glutamate receptor genes and whether an association exist between the presence of these mutations and clinical and molecular characteristics or patient's clinical outcome. We also assessed the dysregulation of glutamate receptor gene expression in AML with and without mutations and whether gene dysregulation is associated with clinical outcomes. We found that 29 (14.5%) of 200 patients with AML had a mutation in at least one glutamate receptor gene. The DNMT3A mutations were significantly more frequent in patients with mutations in at least one glutamate receptor gene compared with patients without mutations (13 of 29 [44.8%] vs. 41 of 171 [23.9%], p value: 0.02). Notably, patients with mutations in at least one glutamate receptor gene survived shorter than patients without mutations; however, the results did not reach statistical significance (overall survival: 15.5 vs. 19.0 months; p value: 0.10). Mutations in the glutamate receptor genes were not associated with changes in gene expression and the transcriptomic levels of glutamate receptor genes were not associated with clinical outcome.

Evaluating Change in Student Pharmacists' Familiarity, Attitudes, Comfort, and Knowledge as a Result of Integrating Digital Health Topics Into a Case Conference Series: Cohort Study.

BACKGROUND: The use of technology in health care, often referred to as digital health, has expanded rapidly because of the need to provide remote care during the COVID-19 pandemic. In light of this rapid boom, it is clear that health care professionals need to be trained in these technologies in order to provide high-level care. Despite the growing number of technologies used across health care, digital health is not a commonly taught topic in health care curricula. Several pharmacy organizations have called attention to the need to teach digital health to student pharmacists; however, there is currently no consensus on best methods to do so. OBJECTIVE: The objective of this study was to determine if there was a significant change in student pharmacist scores on the Digital Health Familiarity, Attitudes, Comfort, and Knowledge Scale (DH-FACKS) after exposure to digital health topics in a yearlong discussion-based case conference series. METHODS: Student pharmacists' initial comfort, attitudes, and knowledge were gathered by a baseline DH-FACKS score at the beginning of the fall semester. Digital health concepts were integrated into a number of cases in the case conference course series throughout the academic year. The DH-FACKS was administered again to students after completion of the spring semester. Results were matched, scored, and analyzed to assess any difference in DH-FACKS scores. RESULTS: A total of 91 of 373 students completed both the pre- and postsurvey (response rate of 24%). Using a scale from 1 to 10, the mean student-reported knowledge of digital health increased from 4.5 (SD 2.5) before intervention to 6.6 (SD 1.6) after intervention (P<.001) and the mean self-reported comfort increased from 4.7 (SD 2.5) before intervention to 6.7 (SD 1.8) after intervention (P<.001). There was a significant increase in scores for all 4 elements of the DH-FACKS. The mean familiarity scores increased from 11.6 (SD 3.7) to 15.8 (SD 2.2), out of a maximum of 20 (P<.001). The mean attitudes scores increased from 15.6 (SD 2.1) to 16.5 (SD 1.9), out of a maximum of 20 (P=.001). The mean comfort scores increased from 10.1 (SD 3.9) to 14.8 (SD 3.1), out of a maximum of 20 (P<.001). The mean knowledge scores increased from 9.9 (SD 3.4) to 12.8 (SD 3.9), out of a maximum of 20 (P<.001). CONCLUSIONS: Including digital health topics in a case conference series is an effective and approachable way of providing education on important digital health concepts to students. Students experienced an increase in familiarity, attitudes, comfort, and knowledge after the yearlong intervention. As case-based discussions are an important component of most pharmacy and other medical curricula, this method can be easily applied by other programs that wish to give their students practice applying their knowledge of digital health to complex case-based scenarios.

Prognostic significance of early platelet dynamics in Staphylococcus aureus bacteremia.

BACKGROUND: Platelets are recognized as key immune effectors, but they are targets of bacterial virulence factors. In the present study, we aimed to examine the relationship between early platelet dynamics and the outcome of Staphylococcus aureus bacteremia (SAB). METHOD: Electronic medical records of adult patients hospitalized for SAB between July 2012 and November 2020 were retrospectively reviewed for relevant demographic, laboratory, and clinical data. The outcome endpoints were mortality and microbial persistence. RESULTS: Among the 811 patients evaluated, 29% experienced thrombocytopenia on Day 1. Platelet count nadir occurred on Days 2-3 following SAB onset, and Day 4 was a determining point of platelet count trajectory and mortality. Mortality risk was 6% or less for those with normal platelet count by Day 4 regardless of whether they experienced thrombocytopenia on Day 1, but the risk increased to 16-21% for those who experienced thrombocytopenia on Day 4 regardless of whether they had normal platelet count on Day 1 or sustained thrombocytopenia. The duration of bacteremia was prolonged by one day (median 3 d vs. 2 d) for those with sustained thrombocytopenia compared to those without. CONCLUSION: Early platelet dynamics during SAB have prognostic significance and represent an early window for potential platelet-directed therapeutic interventions to improve outcome.

Machine learning to identify risk factors associated with the development of ventilated hospital-acquired pneumonia and mortality: implications for antibiotic therapy selection.

Background: Among patients with nosocomial bacterial pneumonia, those who decompensated to requiring mechanical ventilation (vHABP) faced the highest mortality followed by ventilator-associated pneumonia (VABP) and non-ventilated hospital-acquired pneumonia (nvHABP). The objectives of this study were to identify risk factors associated with the development and mortality of vHABP and to evaluate antibiotic management. Methods: A multicenter retrospective cohort study of adult inpatients with nosocomial pneumonia during 2014-2019 was performed. Groups were stratified by vHABP, nvHABP, and VABP and compared on demographics, clinical characteristics, treatment, and outcomes. Multivariable models were generated via machine learning to identify risk factors for progression to vHABP as well as pneumonia-associated mortality for each cohort. Results: 457 patients (32% nvHABP, 37% vHABP, and 31% VABP) were evaluated. The vHABP and nvHABP groups were similar in age (median age 66.4 years) with 77% having multiple comorbidities but more vHABP patients had liver disease (18.2% vs. 7.7% p = 0.005), alcohol use disorder (27% vs. 7.1%, p < 0.0001), and were hospitalized within the past 30 days (30.4% vs. 19.5%, p = 0.02). An immediate need for ventilatory support occurred in 70% of vHABP patients on the day of diagnosis. Mortality was the highest in vHABP followed by VABP and nvHABP groups (44.6% vs. 36% vs. 14.3%, p < 0.0001). Nearly all (96%) vHABP patients had positive cultures, with Gram-negative pathogens accounting for 58.8% whereby 33.0% were resistant to extended-spectrum ß-lactams (ESBLs), ceftriaxone (17.5%), fluoroquinolones (20.6%), and carbapenems (12.4%). Up to half of the vHABP patients with ESBL-Enterobacterales or P. aeruginosa did not receive an effective empiric regimen; over 50% increase in mortality rate was observed among patients whom effective therapy was initiated past the day of pneumonia diagnosis. Risk factors associated with vHABP development were alcohol use disorder, APACHE II score, vasopressor therapy prior to infection, and culture positive for ESBL-Enterobacterales whereas history of hospitalization in the past 30 days, active malignancy, isolation of ceftriaxone-resistant pathogens or Pseudomonas aeruginosa, and vasopressor therapy were risk factors for vHABP-associated mortality. Conclusion: Patients with vHABP experienced an acute and severe decompensation upon diagnosis. The risk factors identified in this study could provide actionable data for clinicians to identify those at risk for vHABP at the onset of pneumonia and to target antimicrobial stewardship efforts to improve treatment success.

Unvaccinated Non-Elderly Adult Population Hospitalized for COVID-19: Risk for Severe Disease and Poor Outcomes.

INTRODUCTION: Vaccination offers significant protection against hospitalization and death due to severe COVID-19. However, a significant portion of the nonelderly U.S. adult population remains unvaccinated. METHODS: This retrospective analysis of adult patients aged under 65 years hospitalized with PCR-confirmed SARS-CoV-2 between March and November 2021 assessed the age-biased risk for severe disease and outcome in non-elderly unvaccinated adults hospitalized for COVID-19. Main measures included predisposing risk factors, disease severity and progression, and outcomes in non-elderly adults compared between (1) vaccinated and unvaccinated individuals and (2) unvaccinated individuals grouped by 10-year age increment. RESULTS: Two hundred nineteen non-elderly adults were included; of whom, 82.6% were unvaccinated. Overall, unvaccinated patients were more likely to be obese (60% vs 29%, P < .001) while vaccinated patients were more likely to have cardiovascular disease (50% vs 29%, P = .03). Unvaccinated individuals had prolonged ICU stay (11 vs 2 days, P = .002) and overall length of stay (6 vs 5 days, P < .0001), and higher proportion requiring oxygen at discharge (54% vs 29%, P < .0001). An age-stratified analysis of the unvaccinated cohort found that the time to discharge increased with age (P = .003). Compared to unvaccinated patients aged <46 years, unvaccinated patients aged ≥46 years demonstrated 1.47- and 3.49-times higher likelihood of oxygen dependency upon discharge (P = .002) and requiring higher level of care or worse at discharge (P = .004), respectively. CONCLUSION: Results from our non-elderly cohort affirm the benefit of vaccination despite a subset requiring hospitalization for breakthrough infection. In unvaccinated non-elderly adults, risk for worse outcomes and severe disease increased substantially from middle age onward and provides strong support for vaccination efforts in this population.

Hispanic ethnicity and the rs4880 variant in SOD2 are associated with elevated liver enzymes and bilirubin levels in children receiving asparaginase-containing chemotherapy for acute lymphoblastic leukemia.

Asparaginase is an integral component of acute lymphoblastic leukemia (ALL)3 treatment. Hepatotoxicity related to asparaginase is one of the most common treatment-related toxicities in ALL therapy. Hispanic children are at higher risk of developing ALL, and toxicities from ALL therapy. The rs4880 variant in the superoxide dismutase 2 (SOD2)4 gene, a critical mitochondrial enzyme that protects cells against oxidative stress, was found to be associated with increased incidence of asparaginase-related hepatotoxicity in adult cohort of largely White non-Hispanics patients with ALL. The risk genotype (rs4880-CC) is more frequent among adult Hispanic patients with ALL. To assess the prevalence of hepatotoxicity and risk genotype among pediatric patients with ALL, particularly of Hispanic ethnicity, we conducted a prospective study of 143 pediatric patients with ALL (62.2% Hispanic). Bilirubin and hepatic transaminase levels were collected at different times during multiagent therapy including asparaginase treatment. Germline DNA blood samples were genotyped for the SOD2 rs4880. We found that the frequency of hepatotoxicity and the rs4880-CC risk genotype are higher in Hispanic patients than non-Hispanic. Patients with the CC genotype exhibit higher bilirubin and hepatic transaminase levels compared with patients with the TT and CT genotypes. In a multivariate Cox analysis, Hispanic ethnicity was identified as a strong predictor of hepatotoxicity (hazard ratio [HR] = 1.9, 95% confidence interval [95% CI] 1.0-3.5, p = 0.05). Altogether, these findings demonstrate that hepatotoxicity is highly prevalent among Hispanic pediatric patients with ALL, and those with rs4880-CC genotype.

Distance Between Home and the Admitting Hospital and Its Effect on Survival of Low Socioeconomic Status Population With Staphylococcus aureus Bacteremia.

OBJECTIVE: Bacteremia is the presence of bacteria in the bloodstream. The objective of this study was to determine the relationship between low socioeconomic status (SES) and the epidemiology, process of care, and outcomes of patients with Staphylococcus aureus bacteremia (SAB). METHODS: We conducted a multicenter, retrospective, cohort study that evaluated adult patients with SAB in 3 Los Angeles County hospitals from July 15, 2012, through May 31, 2018. We determined SES (low SES, intermediate SES, and high SES) for each patient and compared sociodemographic and epidemiologic characteristics, management of care received by patients with SAB (ie, process of care), and outcomes. We used a Cox proportional hazards model to determine predictors of 30-day mortality for each SES group. RESULTS: Of 915 patients included in the sample, 369 (40%) were in the low-SES group, 294 (32%) in the intermediate-SES group, and 252 (28%) in the high-SES group. Most significant predictors of 30-day mortality in the Cox proportional hazards model were admission to an intensive care unit (hazard ratio [HR] = 9.04; 95% CI, 4.26-19.14), Pitt bacteremia score ≥4 indicating critical illness (HR = 4.30; 95% CI, 2.49-7.44), having ≥3 comorbidities (HR = 2.05; 95% CI, 1.09-3.85), and advanced age (HR = 1.03; 95% CI, 1.01-1.05). Distance between home and admitting hospital affected mortality only in the low-SES group (HR = 1.02; 95% CI, 1.00-1.02). CONCLUSIONS: SES did not independently affect the outcome of SAB; however, the farther the patient's residence from the hospital, the greater the negative effect on survival in a low-SES population. Our findings underscore the need to develop multipronged, targeted public health efforts for populations that have transportation barriers to health care.

Prevalence of and incentives for board certification among hospital pharmacy departments in California.

PURPOSE: Board of Pharmacy Specialties (BPS) certification is endorsed to distinguish pharmacists for advanced practice areas, yet perceived value to stakeholders remains poorly described. This study characterized how board certification is integrated in hospital pharmacy departments across California. METHODS: A prospective, cross-sectional study was conducted in which a survey was administered to all hospital pharmacy directors in California between November 2019 and March 2020. Licensed institutions and corresponding pharmacy directors were identified from the California State Board of Pharmacy. The survey queried for institution and pharmacy director characteristics and if/how board certification was integrated. Multivariable logistic models identified predictors of institutions with at least 25% full-time board certified pharmacists and those that reward board certification. RESULTS: Surveys were completed by 29% of institutions. Most of these institutions were urban (81%) and nonteaching (57%), with fewer than 325 hospital beds (71%), and with fewer than 50 full-time pharmacist positions (86%). The majority reported that less than 25% of their pharmacists were board certified. Currently, 47% consider board certification during hiring and 38% reward board certified employees. Predictors of institutions with 25% or more board certified pharmacists included being a teaching institution (odds ratio [OR], 2.96; 95% confidence interval [CI], 1.24-7.06), having 325 or more beds (OR, 7.17; 95% CI, 2.86-17.97), and having a pharmacy director who was previously or currently board certified (OR, 3.69; 95% CI, 1.46-9.35). Hospitals with 100 or more pharmacist positions predicted institutions that reward board certification (OR, 16.69; 95% CI, 1.78-156.86). CONCLUSION: Board certification was an employment preference for almost half of the hospital survey respondents in California. Institutions more likely to reward board certified pharmacists are larger, urban, and teaching hospitals and have pharmacy directors who have been board certified.

Temporal Dynamics of Host Immune Response Associated With Disease Severity and Time to Recovery in Patients Hospitalized for COVID-19.

OBJECTIVES: The objective of this study was to compare the temporal dynamics of two viral-induced inflammatory proteins interferon gamma inducible protein-10 (IP-10) and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), as well as C-reactive protein (CRP) among patients hospitalized for COVID-19 and examine their prognostic significance. DESIGN: Prospective observational cohort study. SETTING: Multicenter, inpatient. PATIENTS: Adult patients infected with severe acute respiratory syndrome coronavirus 2 between March 2021 and October 2021. INTERVENTIONS: Patient sera were collected on days 1, 3, 5, and 7 of hospitalization. Levels of IP-10, TRAIL, and CRP were measured using a point-of-need diagnostic immunoassay platform (MeMed BV, MeMed, Haifa, Israel) and compared between patients grouped by disease severity (severe vs nonsevere). MEASUREMENTS AND MAIN RESULTS: Baseline characteristics were similar regardless of severity except for a higher prevalence of diabetes and heart failure among severe patients. The immune profile at admission was similar between groups; IP-10 and CRP levels generally decreased while TRAIL levels increased over time in all patients. However, the severe group had higher IP-10 (median 713 vs 328 pg/mL; p = 0.045) and lower TRAIL levels (median 21 vs 30 pg/mL; p = 0.003) on day 3 compared with nonsevere patients. A breakpoint IP-10 level of greater than or equal to 570 pg/mL and TRAIL level of less than 25 pg/mL on day 3 were associated with COVID-19 severity. Patients with elevated day 3 IP-10 levels (≥ 570 pg/mL) were more likely to experience prolonged recovery time (median 12 vs 3 d; p < 0.001). The severe group had prolonged use of corticosteroids (12 vs 5 d; p < 0.001) and had a higher rate of secondary infections (20% vs 6%; p = 0.04) and in-hospital mortality (20% vs 0%; p < 0.001) as compared with nonsevere patients. CONCLUSIONS: The observed patterns in host immune response revealed a turning point in COVID-19 disease on hospital day 3 and the potential utility of IP-10 and TRAIL as sensitive markers associated with disease severity and time to recovery.

Factors associated with prompt recovery among hospitalised patients with coronavirus disease 2019.

BACKGROUND: Patients who survived hospitalisation for COVID-19 experienced varying durations of illness but the factors associated with prompt recovery are unknown. This study identifies factors differentiating hospitalised patients who recovered promptly versus survived a prolonged course of illness because of COVID-19. METHODS: This was a retrospective study from March-August 2020 of hospitalised adults with COVID-19 which were grouped based on time to recovery: short (≤3 days), intermediate (4-10 days) and prolonged (>10 days). Recovery was defined as resolution of fever, tachypnea, hypotension, extubation and return of mental status at baseline. Multivariate analysis was used to evaluate factors associated with prompt recovery. RESULTS: Among 508 patients hospitalised for COVID-19, 401 (79%) survived. Of those, prompt recovery (within 3 days) was achieved in 43% (174/401), whereas 23% (92/401) recovered after a prolonged period of >10 days. Overall, median age was 64 years with 73% admitted from home and 25% from a skilled nursing facility. Predictors for prompt recovery upon admission included female sex (OR, 1.8; 95% CI, 1.1-2.7; P = .01), no fever (OR, 1.6; 95% CI, 1.1-2.6; P = .03), longer time from symptom onset to hospitalisation (OR, 1.1; 95% CI, 1.0-1.1; P = .001), no supplemental oxygen (OR, 1.9; 95% CI, 1.2-3.0; P = .004), no direct ICU admission (OR, 41.7; 95% CI, 2.4-740.4; P = .01) and absence of bacterial co-infections (OR, 2.5; 95% CI, 1.5-4.0, P = .0003). CONCLUSIONS: Our study provides relevant data that could help clinicians triage competing resources in health systems that are challenged by the ebb and flow of COVID-19 cases by identifying clinical features of COVID-19 patients who may require less intensive management including avoidance of unnecessary antibacterial therapy.

Cytokine measurements add value to clinical variables in predicting outcomes for Staphylococcus aureus bacteremia.

BACKGROUND: We demonstrated that an early dysregulated cytokine response [high interleukin-10 to tissue necrosis factor (IL-10/TNF) ratio] predicted poor outcomes in patients with Staphylococcus aureus bacteremia (SAB). However, high interpatient variability in cytokine levels were observed. We grouped cytokine measurements in quartiles and assessed their additive value to clinical variables for predicting bacterial persistence and 30-day mortality in patients with SAB. METHODS: A multicenter observational study was conducted in hospitalized patients with SAB. Medical charts were reviewed for relevant information. Blood samples were obtained for cytokine measurements by ELISA: interferon-gamma (IFNγ), interleukin (IL-1ß, IL-6, IL-8, IL-10, IL-17) and tissue necrosis factor (TNF). Cytokine measurements were grouped into quartiles. Significant predictors for bacterial persistence and 30-day mortality were determined by multivariable logistic regression analysis. Area under the ROC curve (AUC) analysis was performed and predictive performance was compared between models with and without cytokine quartiles. RESULTS: Among 606 patients with SAB, a subset of patients (n = 239) had Day 1 cytokine measurements and clinical data collected; of those, 53 (22%) had persistent bacteremia. Accounting for septic shock, the addition of either IL-10 (AUC 0.708) or TNF (AUC 0.714) quartiles measured on Day 1 improved model performance for predicting bacterial persistence. All patients had Day 4 cytokine measurements; 52 patients (8.5%) died within 30-days of SAB onset. Inclusion of either IL-10 (AUC 0.873) or TNF (AUC 0.879) quartiles, but not both, measured on Day 4 to the significant clinical predictors (coronary artery disease, Pitt bacteremia score ≥ 4, and septic shock) improved model performance for mortality. CONCLUSIONS: IL-10 or TNF levels falling within the range in the upper quartiles, when combined with clinical variables, improved model performance for predicting outcomes, and may potentially be used to support aggressive management and biomarker-guided studies to evaluate the benefit of adjunctive immunotherapy for SAB in the future.

Tolvaptan vs. furosemide-based diuretic regimens in patients hospitalized for heart failure with hyponatremia (AQUA-AHF).

AIMS: Hyponatremia is associated with poorer outcomes and diuretic response in patients hospitalized for heart failure. This study compared a tolvaptan-based vs. furosemide-based diuretic regimen on short-term clinical responses in hyponatremic acute heart failure. METHODS AND RESULTS: Prospective, randomized, open-label, parallel-group, single-centre study comparing oral tolvaptan vs. continuous infusion furosemide. Thirty-three subjects requiring hospitalization for acute congestive heart failure, and a serum sodium < 135 mmol/L, were randomized to tolvaptan 30 mg orally daily or furosemide 5 mg/h intravenously for initial 24 h, after which treatments could be escalated. Median daily dose throughout was tolvaptan 30 mg and furosemide 120 mg, with four subjects in each group requiring dose escalation. Urine output and net fluid balance were not different between groups at 24 h or subsequent time points up to 96 h. Changes in estimated glomerular filtration rate were comparable. Cystatin C improved at 24 h with tolvaptan compared with furosemide (-6.4 ± 11.8 vs. 4.1 ± 17.2% change, P = 0.036), but the effect was transient. No significant between group differences were seen for NT-proBNP, plasma renin activity, or urinary neutrophil gelatinase-associated lipocalin:Cr. Serum sodium, as well as copeptin levels, increased with tolvaptan compared with furosemide. CONCLUSIONS: Oral tolvaptan was associated with similar, but not superior, diuresis compared with intravenous furosemide for acute heart failure with concomitant hyponatremia.

Implementation and assessment of a pilot, community pharmacy-based, opioid pain medication management program.

OBJECTIVES: This study aimed to evaluate care gaps in risk- and harm-reduction strategies for patients prescribed opioids and to describe the implementation of a community pharmacy-based, pilot pain-management program. SETTING: The pilot program was established in a community pharmacy within an academic medical center. Patients enrolled were prescribed opioids for chronic pain by a rheumatology clinic. PRACTICE DESCRIPTION: The patients enrolled met 1 or more of the following criteria: they were prescribed more than 1 short-acting opioid; more than 90 morphine milligram equivalents/d; and more than 7 days' supply of medications for acute pain, including high-risk medication combinations. Comprehensive pain-medication assessments and pharmacist interventions were communicated to providers and implemented at follow-up. Data were analyzed using descriptive statistics. PRACTICE INNOVATION: A gap analysis was conducted by including 23 patients seen at the clinic over a 22-month period. The care gaps identified served as the basis for the pilot-program design. EVALUATION: Patients referred to the program were seen over a span of 1 to 2 visits; a total of 19 visits were documented. Pharmacists identified unaddressed issues with mood (68%). Recommendations made to the providers included additional adjuvant therapy (84%), dose adjustment (58%), and laboratory tests (74%). Naloxone was provided (58%), and education on naloxone use was provided at every visit. DISCUSSION: Untreated depression, anxiety, and insomnia were the most common problems identified by pharmacists. Pharmacists implemented and documented risk-reduction strategies and coprescribed naloxone more frequently compared with clinic providers. The program enhanced the pharmacists' ability to make safe and clinically appropriate decisions with regard to filling opioid prescriptions. CONCLUSION: The pilot program identified care gaps and provided an approach for engaging with patients and providers to optimize pain management, implement opioid risk-reduction strategies, and expand naloxone access.

Do pharmacist employers prefer or require board certification?

OBJECTIVE: The pharmacy profession has promoted the value of board certification, yet the impact of board certification on employment opportunities for pharmacists is largely unknown. This study aims to report employer preferences for board certification as indicated on job listings. DESIGN: A national search for pharmacy job postings from November 16, 2018, to March 8, 2019 was performed by reviewing websites and attending conferences. For each listing, data on the status of required, preferred, or neither for board certification, type of specialty, and the practice setting were recorded. Employers listing a preference or requirement for board certification were asked to complete a questionnaire to ascertain reasons for requiring or preferring board certification. SETTING AND PARTICIPANTS: The study includes job listings from various non-community pharmacy employers. OUTCOME MEASURES: The outcome measures were to (1) assess if board certification is required/preferred by pharmacist employers, (2) determine if predominantly clinical versus nonclinical job listings include board certification as a requirement or preference, (3) differentiate practice area and specialty with regard to requirement or preference for board certification, and (4) evaluate reasons behind the requirement or preference. RESULTS: More employers did not prefer or require board certification compared with those who listed such preferences (51% vs. 49%). Employers of jobs with a predominantly clinical component were more likely to require or prefer board certification (53% vs. 27% [no clinical component]). The board certification most often requested was pharmacotherapy, followed by oncology and psychiatry. Most employers (98%) who prefer board certification and those who require board certification (79%) believe that credentialing verifies competence in a specialty practice (P = 0.03) and ensures acquisition of knowledge and skills within the specialized field (P = 0.03). CONCLUSION: More pharmacy employers do not require or prefer board certification. Employers are more likely to prefer or require board certification for predominantly clinical jobs.

Pharmacogenetics of Warfarin in a Diverse Patient Population.

INTRODUCTION: Many warfarin-related genotypes have shown to impact the average daily warfarin (ADW) dose requirements; however, information in non-Caucasian populations is limited. OBJECTIVES: To identify the frequencies of 4 warfarin-related gene polymorphisms in an ethnically diverse patient population and to examine their impact with other clinical variables on ADW dose requirements. METHODS: Patients were recruited from 2 anticoagulation clinics in the Los Angeles area. Blood samples were collected and genotyped for vitamin K epoxide reductase (VKORC1), CYP2C9*2, CYP2C9*3, and CYP4F2 after informed consent. Charts were reviewed to collect demographic, clinical, and warfarin dosing data. RESULTS: A total of 291 patients were included (120 Caucasians, 127 Hispanics, and 44 Asians). In patients with wild-type genotypes for VKORC1, CYP2C9*2, CYP2C9*3, and CYP4F2, the highest warfarin requirement was found in Caucasians, lower in Hispanics, and lowest in Asians. Homozygous VKORC1 variant carriers were detected in 15%, 15%, and 79% in Caucasians, Hispanics, and Asians, respectively. Progressive lowering of ADW doses were associated with each VKORC1 variant in Caucasians and Hispanics, but the results in wild-type/ heterozygote Asians were unclear. CYP2C9 variants were associated with lower ADW doses; frequencies of CYP2C9*2 and CYP2C9*3 mutations were higher in Caucasians than in Hispanics but rare to none in Asians. The frequencies of CYP4F2 variant were similar across all ethnicities, but their impact on warfarin dose requirement were insignificant. Clinical factors such as age, body surface area, history of coronary artery disease, deep vein thrombosis or atrial fibrillation, and concomitant amiodarone or HMG-CoA reductase inhibitors had varying impact on the ADW requirements in the ethnicities studied. CONCLUSIONS: Our study demonstrated differences among 3 ethnic groups in terms of ADW dose requirements and the impact of associated clinical variables. The results suggest that a single model for all ethnicities may not provide the best performance in predicting warfarin dose requirements.

Utility of qSOFA score in identifying patients at risk for poor outcome in Staphylococcus aureus bacteremia.

BACKGROUND: The prognostic capability of the quick Sequential Organ Failure Assessment (qSOFA) bedside scoring tool is uncertain in non-ICU patients with sepsis due to bacteremia given the low number of patients previously evaluated. METHODS: We performed a retrospective cohort study of adult hospitalized patients with Staphylococcus aureus bacteremia (SAB). Medical charts were reviewed to determine qSOFA score, systemic inflammatory response syndrome (SIRS) criteria, and Pitt bacteremia score (PBS) at initial presentation; their predictive values were compared for ICU admission within 48 h, ICU stay duration > 72 h, and 30-day mortality. RESULTS: Four hundred twenty-two patients were included; 22% had qSOFA score ≥2. Overall, mean age was 56y and 75% were male. More patients with qSOFA ≥2 had altered mentation (23% vs 5%, p < 0.0001), were infected with MRSA (42% vs 30%, p = 0.03), had endocarditis or pneumonia (29% vs 15%, p = 0.0028), and bacterial persistence ≥4d (34% vs 20%, p = 0.0039) compared to qSOFA <2 patients. Predictive performance based on AUROC was better (p < 0.0001) with qSOFA than SIRS criteria for all three outcomes, but similar to PBS ≥2. qSOFA≥2 was the strongest predictor for poor outcome by multivariable analysis and showed improved specificity but lower sensitivity than SIRS ≥2. CONCLUSIONS: qSOFA is a simple 3-variable bedside tool for use at the time of sepsis presentation that is more specific than SIRS and simpler to calculate than PBS in identifying septic patients at high risk for poor outcomes later confirmed to have S. aureus bacteremia.

Clinical Pharmacy Services in a Multidisciplinary Specialty Pain Clinic.

PURPOSE: To describe a model of clinical pharmacy services as part of a multidisciplinary specialty pain clinic by discussing (1) the role of a clinical pharmacist in a specialty setting, including clinical interventions implemented, and (2) how integration of a clinical pharmacist may translate into an improved patient care model for the management of chronic pain. METHODS: A retrospective chart review was conducted of pharmacist visits from October 1, 2013, to September 30, 2015, in a specialty pain clinic at an academic medical center in Los Angeles, California. Data were collected regarding medication-related problems (MRPs) identified by the pharmacist, interventions implemented to resolve the MRPs, and types of medication care coordination activities (MCCAs) performed by the pharmacist, such as responding to medication refill requests and insurance issues. Descriptive statistics were used. Institutional review board approval was obtained prior to initiating the study. RESULTS: At least 1 MRP was identified in 98.7% of the 380 visits. Problems identified by the clinical pharmacist were divided into 5 categories: medication refills needed (43%), medication appropriateness/effectiveness (18%), miscellaneous (17%), safety (16%), and nonadherence/patient variables (6%). Interventions focused on referral to appropriate providers, medication counseling, medication initiation, dose adjustment, and medication discontinuation. The most common MCCA was responding to refill requests. CONCLUSION: A clinical pharmacist can identify many MRPs and implement interventions in chronic pain management. Integration of clinical pharmacy services may improve practice management by facilitating the completion of MCCAs and increase access to patients' needs outside the clinic.

Topical Ketamine in the Treatment of Complex Regional Pain Syndrome.

The purpose of this study was to evaluate the effectiveness and adverse effects of topical ketamine in the treatment of complex regional pain syndrome. Retrospective charts were reviewed of patients 18 years or older diagnosed with complex regional pain syndrome and treated with topical ketamine during the study period of May 2006 to April 2013 in an academic medical center specialty pain clinic. Exclusion criteria consisted of subjects who 1) were treated with topical ketamine for pain syndromes other than complex regional pain syndrome, 2) initiated other pain therapies concurrently with topical ketamine, 3) had less than two documented visits, 4) began use of topical ketamine prior to the start of the study period, 5) were under 18 years of age. Subjects with ICD-9 diagnoses codes complex regional pain syndrome-1 or complex regional pain syndrome-2 were identified from encounter-based data and billing records. Data collected for each subject included demographics, description of complex regional pain syndrome, concurrent medications and medical conditions, type of ketamine compound prescribed, duration of therapy, side effects, reasons for discontinuation (if any), and pain scores (numerical pain rating scale; 0 to 10). Data were analyzed using descriptive statistics. Institutional Review Board approval was obtained prior to initiating the study. Sixteen subjects met the inclusion/exclusion criteria for the study, 69% of which were female with an average age of 46 years (range: 24 to 60). Subjects took an average of 3.7 other pain medications (range: 2 to 8), had an average of 2.7 other co-morbid pain conditions (range: 1 to 5), and 1.6 other co-morbid non-pain conditions (range: 0 to 4). Eight (50%) reported that their pain had improved, while 7 (44%) reported a worsening of pain. One reported no change in pain score. No subjects reported adverse effects. Based on the findings in this study, the use of topical ketamine in the treatment of complex regional pain syndrome shows promise due to the overall limited options available to treat this condition, as well as the favorable safety profile of topical agents. Future prospective controlled studies are needed to demonstrate a clear benefit.