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Libraries composed of licensed drugs represent a vast repertoire of molecules modulating physiological processes in humans, providing unique opportunities for the discovery of host-targeting antivirals. We screened the Repurposing, Focused Rescue, and Accelerated Medchem (ReFRAME) repurposing library with approximately 12,000 molecules for broad-spectrum coronavirus antivirals and discovered 134 compounds inhibiting an alphacoronavirus and mapping to 58 molecular target categories. Dominant targets included the 5-hydroxytryptamine receptor, the dopamine receptor, and cyclin-dependent kinases. Gene knock-out of the drugs' host targets including cathepsin B and L (CTSB/L; VBY-825), the aryl hydrocarbon receptor (AHR; Phortress), the farnesyl-diphosphate farnesyltransferase 1 (FDFT1; P-3622), and the kelch-like ECH-associated protein 1 (KEAP1; Omaveloxolone), significantly modulated HCoV-229E infection, providing evidence that these compounds inhibited the virus through acting on their respective host targets. Counter-screening of all 134 primary compound candidates with SARS-CoV-2 and validation in primary cells identified Phortress, an AHR activating ligand, P-3622-targeting FDFT1, and Omaveloxolone, which activates the NFE2-like bZIP transcription factor 2 (NFE2L2) by liberating it from its endogenous inhibitor KEAP1, as antiviral candidates for both an Alpha- and a Betacoronavirus. This study provides an overview of HCoV-229E repurposing candidates and reveals novel potentially druggable viral host dependency factors hijacked by diverse coronaviruses.

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PURPOSE: To assess the effects of group therapy focused on the experience of living with prostate cancer (PC) on depression and mental well-being among men with the disease and to explore participant experiences of a guided opportunity to 'speak the unspeakable' as it pertains to living with PC. METHODS: We used a mixed-method convergent design. Participants completed four validated self-report questionnaires at baseline, immediately after the final session, and at three, six, and 12 months follow-up. A repeated measures mixed-effect model examined the effects of the program on depression, mental well-being, and masculinity. Seven focus groups (n = 37) and 39 semi-structured individual interviews explored participant reactions at follow-up. RESULTS: Thirty-nine (93%) participants completed the questionnaires at all follow-ups. Responses indicated improved mental well-being up to three months (p < 0.01) and a decrease in depressive symptoms to 12 months (p < 0.05). Qualitative analysis revealed how the cohesive group environment alleviated psychological stress, enabled participants to identify significant issues and concerns in their lives, and improved communication and relationship skills that were of value in the group as well as with family and friends. The facilitation was essential to guiding participants to 'speak the unspeakable.' CONCLUSION: Men with PC who speak of their experience in a group setting with a guided process incorporating features of a life review appear to gain insight into the impact of PC in their lives, experience diminished features of depression and isolation, and enhance their communication skills within the groups as well as with family members and friends.

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AIM: Organ and Tissue Donation Coordinators (OTDCs) are healthcare professionals who manage deceased organ donation cases. This study investigated the experiences and perceptions of OTDCs, pertaining to compassion fatigue, burnout, and resilience as it relates to their daily work. METHODOLOGY: A qualitative descriptive study was undertaken using semi-structured interviews conducted with a convenience sample of OTDCs. SETTING: A Canadian Organ Donation Organization. FINDINGS: Seven out of the ten OTDCs contacted participated in this study. Coordinators all agreed that they work in a high-pressure and demanding environment and the constant exposure to work-related stress and grief has resulted in the majority of them experiencing signs and symptoms of burnout and compassion fatigue occurring throughout their career. Participants described that the emotional toll of work-related stressors and difficult cases led them to use a variety of defence strategies to protect and support their well-being. They also recognised that more strategies to help mitigate work-related stressors and to prevent burnout and compassion fatigue are needed and that management and institutions should lead the development of such interventions. CONCLUSION: Our results describe how coordinators' mental health is affected by their daily work. Further research is needed to comprehensively examine these work-related stressors and to generate additional data to support the development of interventions to mitigate burnout and compassion fatigue among OTDCs.

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BACKGROUND: Adequate counseling from a pharmacist concerning anticoagulation therapy is crucial to the wellbeing of patients. No studies have fully examined the relationship between health literacy, patient-pharmacist communication, and anticoagulation control. OBJECTIVE(S): To evaluate the relationship between health literacy and the perceived quality of patient-pharmacist communication among those receiving anticoagulation therapy. METHODS: This investigation utilized structured telephone interviews to evaluate the relationship between health literacy and perceived quality patient-pharmacist communication among patients receiving anticoagulation therapy. Two hundred-twenty participants prescribed anticoagulation therapy continuously for at least 6-months served as the sample for this study. A previously validated one-item screening tool was utilized to estimate health literacy. The primary outcome was patients' perceptions regarding the general communication process with pharmacists, according to the Interpersonal Process of Care questionnaire. RESULTS: Patients possessing inadequate health literacy reported significantly less favorable ratings for the perceived quality of pharmacist communication on the domains of general clarity (p = 0.02), responsiveness to patient concerns (p=<0.01), empowerment (p = 0.01), and consideration of patients' desire and ability to comply with recommendations (p = 0.01). Inadequate health literacy was found to be independently associated with poorer quality interpersonal processes of care across the domains of responsiveness to patient concerns and empowerment, (ß = -0.207, P = <0.01 and ß = -0.137, P = 0.04, respectively). Patients with inadequate health literacy did not differ significantly from those with adequate health literacy in terms of time within therapeutic INR range or percent of INRs in therapeutic range over the previous 12 months. CONCLUSIONS: Patients receiving anticoagulation therapy and possessing inadequate health literacy appear more likely to percieve poorer communication with pharmacists. This seems especially true as it relates to the percieved time and attention pharmacist devote to the communication encounter, as well as the sense pharmacists provide patients concerning their ability to influence health outcomes.

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BACKGROUND: Domains other than those commonly measured (physical, psychological, social, and sometimes existential/spiritual) are important to the quality of life of people with life-threatening illness. The McGill Quality of Life Questionnaire (MQOL) - Revised measures the four common domains. The aim of this study was to create a psychometrically sound instrument, MQOL - Expanded, to comprehensively measure quality of life by adding to MQOL-Revised the domains of cognition, healthcare, environment, (feeling like a) burden, and possibly, finance. METHODS: Confirmatory factor analyses were conducted on three datasets to ascertain whether seven new items belonged with existing MQOL-Revised domains, whether good model fit was obtained with their addition as five separate domains to MQOL-Revised, and whether a second-order factor representing overall quality of life was present. People with life-threatening illnesses (mainly cancer) or aged > 80 were recruited from 15 healthcare sites in seven Canadian provinces. Settings included: palliative home care and inpatient units; acute care units; oncology outpatient clinics. RESULTS: Good model fit was obtained when adding each of the five domains separately to MQOL-Revised and for the nine correlated domains. Fit was acceptable for a second-order factor model. The financial domain was removed because of low importance. The resulting MQOL-Expanded is a 21-item instrument with eight domains (fit of eight correlated domains: Comparative Fit Index = .96; Root Mean Square Error of Approximation = .033). CONCLUSIONS: MQOL-Expanded builds on MQOL-Revised to more comprehensively measure the quality of life of people with life-threatening illness. Our analyses provide validity evidence for the MQOL-Expanded domain and summary scores; the need for further validation research is discussed. Use of MQOL-Expanded will enable a more holistic understanding of the quality of life of people with a life-threatening illness and the impact of treatments and interventions upon it. It will allow for a better understanding of less commonly assessed but important life domains (cognition, healthcare, environment, feeling like a burden) and their relationship to the more commonly assessed domains (physical, psychological, social, existential/spiritual).

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OBJECTIVE: To determine the prevalence of suicidal ideation and burnout among family practice residents at the University of British Columbia (UBC), and to compare the identified rates with those found in other studies. DESIGN: Web-based survey. SETTING: University of British Columbia in Vancouver. PARTICIPANTS: A total of 235 family practice residents from UBC. MAIN OUTCOME MEASURES: The Web-based survey included an evaluation of suicide risk with questions adapted from the Meehan Inventory, and an evaluation of burnout with the Maslach Burnout Inventory. A univariate descriptive analysis and a bivariate analysis were used to define the prevalence of suicidal ideation and burnout, as well as relationships with demographic variables. RESULTS: In the fall of 2010, among the 109 survey respondents (46.4% response rate), the rate of suicidal ideation during family practice residency was 33.3%, the rate of suicidal ideation with a plan during residency was 18.1%, and the rate of suicide attempt during residency was 2.9%. The prevalence of burnout during residency was identified in 73.5% of respondents and was represented by a perceived lack of personal accomplishment. The identified prevalence of suicidal ideation was considerably higher than in other studies, and the identified prevalence of burnout was comparable to similar studies. CONCLUSION: This study identified a high rate of suicidal ideation and burnout among Canadian family medicine residents at UBC. Further research is needed to improve suicide prevention, as well as identification and support of residents in distress.

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BACKGROUND: Pregnant women receiving low-molecular-weight heparin for therapeutic anticoagulation are often converted to unfractionated heparin in anticipation of labor. We aim to characterize the impact of maternal body mass index on attainment of target anticoagulation during the conversion process. METHODS: We conducted a five-year retrospective study of a pregnancy cohort converted from low-molecular-weight heparin to unfractionated heparin in the third trimester. Patient demographics, anticoagulation regimens, and clinical outcomes were extracted from the medical record. Nonparametric statistical methods were used for analysis by body mass index (<30, 30-35, and >35). RESULTS: Thirty-one subjects were evenly distributed by body mass index (p = 0.97). Linear regression revealed an inverse correlation between patient body mass index and unfractionated heparin dose needed to achieve therapeutic anticoagulation (p = 0.04). Subjects with body mass index > 35 attained therapeutic activated partial thromboplastin time levels at 18 U (Units)/kg/h, while subjects with body mass index < 30 required 25 U/kg/h (p = 0.02). CONCLUSION: Higher doses of unfractionated heparin are needed to achieve anticoagulation in patients with body mass index < 30 during pregnancy. This paradoxical relationship may be explained by physiologic characteristics that increase unfractionated heparin elimination, including diminished adiposity and increased renal clearance.

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BACKGROUND: Candida is a leading cause of infection in the intensive care unit. Colonization versus infection remains a challenge. A Candida Score (CS) of 3 or greater has been used to target antifungal therapy in surgical patients at risk of candidemia but has not been well evaluated in medical patients with sepsis. OBJECTIVES: The aim of this study was to assess utility of the CS in detecting candidemia early in patients with sepsis. METHODS: This was a secondary analysis of patients with sepsis (n = 77) who were followed up for development of new infections. Patients with known fungal infection at admission were excluded. Candida colonization was defined as Candida cultured from any baseline culture, except blood, as a part of routine clinical care. RESULTS: Candidemia was detected in 8 of 77 participants (10.4%; 4 [15.4%] with a CS ≥3 and 4 [7.8%] with a CS <3). Demographic variables (age, race, sex) were similar among those who did and did not develop candidemia. Using the recommended CS of 3 or greater, sensitivity was (4/8) 50%, specificity was (47/69) 68.1%, positive predictive value was (4/26) 15.4%, and negative predictive value was (47/51) 92.2%. Baseline colonization was significantly higher among those who developed candidemia (50% vs 11.6%; P = .02), but no significant differences were observed among CS components or total scores. CONCLUSIONS: Despite a relatively poor sensitivity, a reasonable specificity with a strong negative predictive value makes this tool a viable option for screening medically ill patients who may require antifungal agents. The CS should be evaluated in a larger, more inclusive, medical population.

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OBJECTIVES: The desire for death in terminally ill patients is associated with depression and anxiety, but not all patients who report it meet criteria for mental disorders. We examined the characteristics of subgroups of palliative cancer patients who expressed a desire for death that occurred either with or without a concurrent depressive or anxiety disorder. DESIGN: Cross-sectional survey. SETTING: Eight Canadian palliative care programs. PARTICIPANTS: 377 patients with cancer. MAIN OUTCOME MEASURES: Desire for Death Rating Scale; Structured Interview of Symptoms and Concerns. RESULTS: Most participants (69.5%) had no desire for death. Of the remainder, 69 (18.3%) acknowledged occasional transient thoughts, and 46 (12.2%) reported an apparently genuine desire to die. In the latter group, 24 individuals (52.2%) were diagnosed with a mental disorder and 22 (44.8%) were not. Individuals with no serious desire for death and no mental disorder reported the least distress in physical, social, existential, and psychological symptoms and concerns; those with a mental disorder and a significant desire for death reported the most. The subgroup of patients with a serious desire for death but no concurrent mental disorders still reported increased distress due to physical symptoms and social concerns, as well as a higher prevalence of global suffering. CONCLUSIONS: The expression of a desire for death by a terminally ill patient should raise a suspicion about mental health problems, but is not in itself clearly indicative of one. Nevertheless, it may serve as a catalyst to review the individual's physical symptom management and interpersonal concerns, and overall sense of suffering.

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BACKGROUND: Health care-associated infections (HAIs) are the target of many well-known preventive measures in the intensive care unit (ICU); however, little is known about post-sepsis-induced immunosuppression. OBJECTIVES: This study explores the relationship between baseline plasma levels of inflammatory cytokines interleukin 6 (IL-6), IL-10, and IL-6:IL-10 and subsequent development of HAIs in patients with admitted with sepsis. METHODS: Prospective observational study was conducted among veterans admitted to the ICU with sepsis and monitored daily through ICU discharge (up to 28 days) to investigate HAI development. Baseline plasma IL-6 and IL-10 levels were measured with a multiplex bead based assay. Exaggerated systemic inflammation was defined as the fourth quartile (IL-6 and IL-10) compared with other quartiles. RESULTS: We recruited 78 patients over 18 months, primarily older (65.5 ± 12.6 years) men (94.9%) with underlying comorbidities (93.9%) and a high severity of illness (Acute Physiologic and Chronic Health Evaluation II score 20.6 ± 6.4). Seventeen patients (21.7%) developed at least 1 HAI, and candidemia was the leading infection. Patients with exaggerated baseline systemic inflammation developed a nonsignificantly higher proportion of HAI as compared with those not developing HAI (IL-6: 31.6% vs 18.6%, P = .55; IL-10: 26.3% vs 20.3%, P = .43). DISCUSSION: Patients with exaggerated systemic inflammation had a higher severity of illness, but not a statistically significant higher incidence of HAI. A larger, more adequately powered sample with serial cytokine measures is needed. Routine surveillance cultures are needed. Health care-associated infection may occur in the absence of fever, and the emerging incidence of Candida is a concern. Immune suppression after sepsis should be recognized as a risk for HAI development. Antibiotic therapy should be targeted with prompt de-escalation of empiric therapy per established guidelines to preserve normal flora.

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The Teams of Interprofessional Staff (TIPS) project consisted of five healthcare teams from across Ontario, participating in three, two-day face-to-face interprofessional educational (IPE) sessions over an 8-month period. The purpose of TIPS was to explore whether interprofessional team development for practicing healthcare professionals, makes a difference in team functioning, team member satisfaction, ability to work effectively both individually and as a team, and improved patient well-being. A comprehensive formative and summative evaluation revealed that all teams perceived they benefitted from and engaged in successful team development. Success meant different things to each team reflecting the continuum of team development from building a safe, trusted group to becoming leaders of team development for other interprofessional teams. Effective teamwork is crucial to nurses who often take on the role of coordinator of care on a day-to-day basis, or are in managerial roles in interprofessional clinics or clinical program teams.

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UNLABELLED: Longitudinal studies in nondemented Parkinson disease (PD) subjects offer an opportunity to study the earliest regional cerebral subcortical and cortical metabolic changes underlying incident dementia in this disorder. METHODS: Twenty-three PD subjects without dementia (Hoehn and Yahr stages I-III; age, 61.8 ± 9.7 y; Mini-Mental State Examination, 28.0 ± 1.4) and 27 controls (age, 59.8 ± 11.5 y) underwent (18)F-FDG PET at study entry. PD subjects underwent yearly clinical assessment to determine conversion to dementia. The mean duration of follow-up was 3.9 ± 1.2 y (range, 2.0-6.8 y). Follow-up (18)F-FDG PET was available in a subset of subjects at 2 or more years. Both volume-of-interest and 3-dimensional stereotactic surface projection (3D-SSP) analyses were performed. RESULTS: Six subjects became demented (PDD), with a mean time of 3.8 ± 1.7 y (range, 1.9-6.0 y) to development of dementia. Mean duration of disease before onset of dementia was 9.7 ± 4.2 y (range, 3.1-14 y). There were significant metabolic reductions in the occipital (-11.8% vs. controls, F((2,22)) = 7.0, P = 0.002) and posterior cingulate (-12.1% vs. controls, F((2,22)) = 5.2, P = 0.009) cortices in PDD subjects at baseline, before diagnosis of dementia, compared with controls. Metabolism was most diminished in the visual association cortex (Brodmann area [BA] 18; -20.0% vs. control, F((2,22)) = 8.45, P = 0.0007) of PDD subjects. There was mild hypometabolism in the caudate nucleus (-8.4% vs. control, F((2,22)) = 3.2, P < 0.05). There was no significant hypometabolism in the temporal or frontal lobes. PD subjects who did not become demented (non-PDD), compared with controls, had reduced cerebral metabolism in the primary occipital cortex (BA 17) that was revealed only by 3D-SSP analysis. Follow-up scans in 5 PDD subjects at 2 y after study entry demonstrated a significant interval within-subject change in the thalamus (-11.4%), posterior cingulate (-9%), occipital (-7%), parietal (-7%), and frontal cortices (-7%) and mild reductions in the temporal cortex (-5%) and hippocampus (-3%), compared with study entry scans. CONCLUSION: Incident dementia in idiopathic PD is heralded by decreased metabolism in the visual association (BA 18) and posterior cingulate cortices, with mild involvement also of the caudate nucleus. Two-year follow-up data from 5 PDD converters show that progression to dementia is associated with mixed subcortical and cortical changes that involve the mesiofrontal lobes also. These findings provide insights into early metabolic features of parkinsonian dementia.

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OBJECTIVES: To determine the accuracy of medication reconciliation in an internal medicine clinic and to evaluate pharmacist interventions targeted at improving the accuracy of medication reconciliation. DESIGN: Prospective case series. SETTING: Memphis, TN, from October 2007 to March 2008. PATIENTS: 180 adults attending an internal medicine appointment. INTERVENTION: On patient arrival, a nurse completed the medication reconciliation form. In Phase 1 of the study, a pharmacist randomly selected and reviewed a patient's medication reconciliation form, interviewed the patient, and verified information if indicated. A total of 90 forms were reviewed and compared to determine baseline medication reconciliation accuracy. Education interventions were held with the medical and nursing staff, targeting areas for improvement. In Phase 2 of the study, 90 additional medication reconciliation forms were reviewed in the same manner. Phase 1 and Phase 2 results were compared to evaluate differences in accuracy after the pharmacist's education interventions. MAIN OUTCOME MEASURES: Accuracy of medication reconciliation forms and number of potentially significant errors at baseline and after pharmacist interventions. RESULTS: In Phase 1, 14.4% of medication reconciliation forms were correct. The remaining forms contained 190 potentially significant errors. After the education interventions, 18.9% of medication reconciliation forms were correct and the others contained 139 potentially significant errors. CONCLUSION: Medication reconciliation accuracy is poor. Although education interventions showed a trend toward improvement, continued education training for staff and patients is needed in addition to other interventions to optimize this process and prevent medication errors.

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BACKGROUND: Pain is a common problem for people with cancer who are nearing the ends of their lives. OBJECTIVE: In the present multicentre Canadian study of palliative cancer care, the prevalence of pain, its perceived severity and its correlates across a range of physical, social, psychological, and existential symptoms and concerns were examined. METHODS: Semistructured interviews were conducted with 381 patients. In addition to inquiring about pain, the interview also assessed 21 other symptoms and concerns, and collected information about demographic characteristics, functional status and medication use. RESULTS: Pain of any intensity was reported by 268 (70.3%) participants, although for 139 (36.5%), the severity was rated as minimal or mild. For 129 (33.9%) individuals, pain was reported as moderate to extreme, and considered by the respondents to be an important ongoing problem. Patients who reported moderate to extreme pain were younger than other participants, but had lower functional status and a shorter median survival duration. They were more likely than other participants to be treated with opioid medications (P<0.001) and, less reliably, with benzodiazepines (P=0.079). Compared with participants with no, minimal or mild pain, those with moderate to extreme pain had a higher prevalence of distressing problems on 11 of 21 other symptoms and concerns. The strongest correlations were with general malaise (rho = 0.44), suffering (rho = 0.40), nausea (rho = 0.34), weakness (rho = 0.31), drowsiness (rho = 0.29) and anxiety (rho = 0.29). CONCLUSIONS: Pain continues to be a difficult problem for many patients who are receiving palliative cancer care, particularly younger individuals who are nearing death.

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PURPOSE: To identify the impact of prognostic acceptance/nonacceptance on the physical, psychological, and existential well-being of patients with advanced cancer. PATIENTS AND METHODS: A Canadian multicenter prospective national survey was conducted of patients diagnosed with advanced cancer with an estimated survival duration of 6 months or less (n = 381) receiving palliative care services. RESULTS: Of the total number of participants, 74% reported accepting their situation and 8.6% reported accepting with "moderate" to "extreme" difficulty. More participants with acceptance difficulties than without acceptance difficulties met diagnostic criteria for a depressive or anxiety disorder (chi(2) = 8.67; P < .01). Nonacceptors were younger (t = 4.13; P < .000), had more than high school education (chi(2) = 4.69; P < .05), and had smaller social networks (t = 2.53; P < .05) than Acceptors. Of the Nonacceptors, 42% described their experience as one of "moderate" to "extreme" suffering compared with 24.1% of Acceptors (chi(2) = 5.28; P < .05). More than one third (37.5%) of Nonacceptors reported feeling hopeless compared with 8.6% who had no difficulty accepting (chi(2) = 24.76; P < .000). Qualitatively, participants described active and passive coping strategies that helped them accept what was happening to them, as well as barriers that made it difficult to come to terms with their current situation. CONCLUSION: The challenge of coming to terms with a terminal prognosis is a complex interplay between one's basic personality, the availability of social support, and one's spiritual and existential views on life. Nonacceptance appears to be highly associated with feelings of hopelessness, a sense of suffering, depression, and anxiety, along with difficulties in terms of social-relational concerns.

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PURPOSE: This study compared steady-state concentrations achieved with a dosing strategy using first-dose kinetics to individualize vancomycin regimens with the steady-state concentrations achieved using standardized nomograms. METHODS: Neonatal intensive care unit patients receiving vancomycin according to published nomograms (phase 1) were compared with patients receiving vancomycin using first-dose pharmacokinetic information to individualize the dosing regimen (phase 2). Retrospective chart review was used to gather demographic and patient-specific pharmacokinetic data. Data collected included gestational and postnatal ages, birth and dosing weights, first-dose peak and trough concentrations, serum creatinine, and information related to infection. Data were analyzed to determine the percentage of therapeutic concentrations at a steady state in each group. RESULTS: Phase 1 included 108 patients given doses according to published nomograms, and phase 2 included 85 patients who received vancomycin with first-dose pharmacokinetics. Steady-state concentrations were collected in 108 patients in phase 1 and 39 patients in phase 2. Both peak and trough concentrations were therapeutic at steady state in 39% in phase 1 versus 63% in phase 2 (p < 0.02). Therapeutic steady-state peak concentrations were achieved in 70% versus 76% while therapeutic steady-state trough concentrations were achieved in 50% versus 82% (p < 0.02) in phase 1 and phase 2, respectively. CONCLUSION: Compared with the use of nomograms, individualization of vancomycin regimens after the first dose in neonatal patients significantly increased the percentage of patients with target steady-state trough concentrations and with both target peak and trough concentrations. The benefits of individualized dosing were attained without additional venous sampling.

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