Development and implementation of "handshake rounds": An antibiotic stewardship intervention for hospitalized adult patients with hematologic malignancies.

Objective: To design and implement "handshake rounds" as an antibiotic stewardship intervention to reduce inpatient intravenous (IV) antibiotic use in patients with hematologic malignancies. Design: Quasi-experimental analysis of antibiotic use (AU) and secondary outcomes before and and after handshake rounds were implemented. Setting: Quaternary-care, academic medical center. Patients: Hospitalized adults with hematologic malignancies receiving IV antibiotics. Methods: We performed a retrospective review of a preintervention cohort prior to the intervention. A multidisciplinary team developed criteria for de-escalation of antibiotics, logistics of handshake rounds, and outcome metrics. Eligible patients were discussed during scheduled handshake rounds between a hematology-oncology pharmacist and transplant-infectious diseases (TID) physician. Prospective data were collected over 30 days in the postintervention cohort. Due to small sample size, 2:1 matching was used to compare pre- to and postintervention AU. Total AU in days of therapy per 1,000 patient days (DOT/1,000 PD) was reported. Mean AU per patient was analyzed using Wilcoxon rank-sum test. A descriptive analysis of secondary outcomes of pre- and postintervention cohorts was performed. Results: Total AU was substantially lower after the intervention, with 517 DOT/1,000 PD compared to 865 DOT/1,000 PD before the intervention. There was no statistically significant difference in the mean AU per patient between the 2 cohorts. There was a lower rate of 30-day mortality in the postintervention cohort and rates of ICU admissions were similar. Conclusions: Conducting handshake rounds is a safe and effective way to implement an antibiotic stewardship intervention among high-risk patient population such as those with hematologic malignancies.

Association of antibiotics with veteran visit satisfaction and antibiotic expectations for upper respiratory tract infections.

Background and objective: Veterans' Affairs (VA) healthcare providers perceive that Veterans expect and base visit satisfaction on receiving antibiotics for upper respiratory tract infections (URIs). No studies have tested this hypothesis. We sought to determine whether receiving and/or expecting antibiotics were associated with Veteran satisfaction with URI visits. Methods: This cross-sectional study included Veterans evaluated for URI January 2018-December 2019 in an 18-clinic ambulatory VA primary-care system. We evaluated Veteran satisfaction via the Patient Satisfaction Questionnaire Short Form (RAND Corporation), an 18-item 5-point Likert scale survey. Additional items assessed Veteran antibiotic expectations. Antibiotic receipt was determined via medical record review. We used multivariable regression to evaluate whether antibiotic receipt and/or Veteran antibiotic expectations were associated with satisfaction. Subgroup analyses focused on Veterans who accurately remembered antibiotic prescribing during their URI visit. Results: Of 1,329 eligible Veterans, 432 (33%) participated. Antibiotic receipt was not associated with differences in mean total satisfaction (adjusted score difference, 0.6 points; 95% confidence interval [CI], -2.1 to 3.3). However, mean total satisfaction was lower for Veterans expecting an antibiotic (adjusted score difference -4.4 points; 95% CI -7.2 to -1.6). Among Veterans who accurately remembered the visit and did not receive an antibiotic, those who expected an antibiotic had lower mean satisfaction scores than those who did not (unadjusted score difference, -16.6 points; 95% CI, -24.6 to -8.6). Conclusions: Veteran expectations for antibiotics, not antibiotic receipt, are associated with changes in satisfaction with outpatient URI visits. Future research should further explore patient expectations and development of patient-centered and provider-focused interventions to change patient antibiotic expectations.

Development of the Three Antimicrobial Stewardship E's (TASE) Framework and Association Between Stewardship Interventions and Intended Results Analysis to Identify Key Facility-Specific Interventions and Strategies for Successful Antimicrobial Stewardship.

BACKGROUND: Successful antimicrobial stewardship (AS) interventions have been described previously. Currently, a uniform operational approach to planning and implementing successful AS interventions does not exist. From 2015 to 2019, concomitant vancomycin and piperacillin-tazobactam use (CVPTU) for >48 hours at Vanderbilt University Medical Center (VUMC) significantly decreased through AS efforts. We analyzed the interventions that led to this change and created a model to inform future intervention planning and development. METHODS: Adult admissions at VUMC from January 2015 to August 2019 were evaluated for CVPTU. The percentage of admissions receiving CVPTU for >48 hours, the primary outcome, was evaluated using statistical process control charts. We created the Three Antimicrobial Stewardship E's (TASE) framework and Association between Stewardship Interventions and Intended Results (ASIR) analysis to assess potential intensity and impact of interventions associated with successful change during this time period and to identify guiding principles for development of future initiatives. RESULTS: The mean percentage of admissions receiving CVPTU per month declined from 4.2% to 0.7%. Over 8 time periods, we identified 4 periods with high, 3 with moderate, and 1 with low intervention intensity. Continuous provider-level AS education was present throughout. Creation and dissemination of division and department algorithms and reinforcement via computerized provider order entry sets preceded the largest reduction in CVPTU and sustained prescribing practice changes. CONCLUSIONS: The TASE framework and ASIR analysis successfully identified pivotal interventions and strategies needed to effect and sustain change at VUMC. Further research is needed to validate the effectiveness of this framework as a stewardship intervention planning tool at our institution and others.

Antimicrobial de-escalation in patients with high-risk febrile neutropenia: Attitudes and practices of adult hospital care providers.

In a survey of adult hospital providers regarding antibiotic use in the treatment of febrile neutropenia, clinical fellows, and pharmacists showed higher comfort levels with early antimicrobial de-escalation compared to hematology-oncology and transplant infectious diseases physicians. These frontline team members are ideal partners to champion antimicrobial stewardship interventions in febrile neutropenia.

Changes in antimicrobial utilization during the coronavirus disease 2019 (COVID-19) pandemic after implementation of a multispecialty clinical guidance team.

OBJECTIVE: Evaluate changes in antimicrobial use during COVID-19 and after implementation of a multispecialty COVID-19 clinical guidance team compared to pre-COVID-19 antimicrobial use. DESIGN: Retrospective observational study. SETTING: Tertiary-care academic medical center. PARTICIPANTS: Internal medicine and medical intensive care unit (MICU) provider teams and hospitalized COVID-19 patients. METHODS: Difference-in-differences analyses of antibiotic days of therapy per 1,000 patient days present (DOT) for internal medicine and MICU teams treating COVID-19 patients versus teams that did not were performed for 3 periods: before COVID-19, initial COVID-19 period, and after implementation of a multispecialty COVID-19 clinical guidance team which included daily, patient-specific antimicrobial stewardship recommendations. Patient characteristics associated with antibiotic DOT were evaluated using multivariable Poisson regression. RESULTS: In the initial COVID-19 period, compared to the pre-COVID-19 period, internal medicine and MICU teams increased weekly antimicrobial use by 145.3 DOT (95% CI, 35.1-255.5) and 204.0 DOT (95% CI, -16.9 to 424.8), respectively, compared to non-COVID-19 teams. In the intervention period, internal medicine and MICU COVID-19 teams both had significant weekly decreases of 362.3 DOT (95% CI, -443.3 to -281.2) and 226.3 DOT (95% CI, -381.2 to -71.3). Of 131 patients hospitalized with COVID-19, 86 (65.6%) received antibiotics; no specific patient factors were significantly associated with an expected change in antibiotic days. CONCLUSIONS: Antimicrobial use initially increased for COVID-19 patient care teams compared to pre-COVID-19 levels but significantly decreased after implementation of a multispecialty clinical guidance team, which may be an effective strategy to reduce unnecessary antimicrobial use.

Creating a Framework to Integrate Residency Program and Medical Center Approaches to Quality Improvement and Patient Safety Training.

Quality improvement and patient safety (QIPS) are core components of graduate medical education (GME). Training programs and affiliated medical centers must partner to create an environment in which trainees can learn while meaningfully contributing to QIPS efforts, to further the shared goal of improving patient care. Numerous challenges have been identified in the literature, including lack of resources, lack of faculty expertise, and siloed QIPS programs. In this article, the authors describe a framework for integrated QIPS training for residents in the University of Washington Internal Medicine Residency Program, beginning in 2014 with the creation of a dedicated QIPS chief resident position and assistant program director for health systems position, the building of a formal curriculum, and integration with medical center QIPS efforts. The postgraduate year (PGY) 1 curriculum focused on the culture of patient safety and entering traditional patient safety event (PSE) reports. The PGY-2 curriculum highlighted QIPS methodology and how to conduct mentored PSE reviews of cases that were of educational value to trainees and a clinical priority to the medical center. Additional PGY-2/PGY-3 training focused on the active report, presentation, and evaluation of cases during morbidity and mortality conferences while on clinical services, as well as how to lead longitudinal QIPS work. Select residents led mentored QI projects as part of an additional elective. The hallmark feature of this framework was the depth of integration with medical center priorities, which maximized educational and operational value. Evaluation of the program demonstrated improved attitudes, knowledge, and behavior changes in trainees, and significant contributions to medical center QIPS work. This specialty-agnostic framework allowed for training program and medical center integration, as well as horizontal integration across GME specialties, and can be a model for other institutions.

A Narrative Review of Early Oral Stepdown Therapy for the Treatment of Uncomplicated Staphylococcus aureus Bacteremia: Yay or Nay?

Historically, intravenous (IV) antibiotics have been the cornerstone of treatment for uncomplicated Staphylococcus aureus bacteremia (SAB). However, IV antibiotics are expensive, increase the rates of hospital readmission, and can be associated with catheter-related complications. As a result, the potential role of oral antibiotics in the treatment of uncomplicated SAB has become a subject of interest. This narrative review article aims to summarize key arguments for and against the use of oral antibiotics to complete treatment of uncomplicated SAB and evaluates the available evidence for specific oral regimens. We conclude that evidence suggests that oral step-down therapy can be an alternative for select patients who meet the criteria for uncomplicated SAB and will comply with medical treatment and outpatient follow-up. Of the currently studied regimens discussed in this article, linezolid has the most support, followed by fluoroquinolone plus rifampin.

Analysis of a high-prescribing state's 2016 outpatient antibiotic prescriptions: Implications for outpatient antimicrobial stewardship interventions.

OBJECTIVE: To identify prescriber characteristics that predict antibiotic high-prescribing behavior to inform statewide antimicrobial stewardship interventions. DESIGN: Retrospective analysis of 2016 IQVIA Xponent, formerly QuintilesIMS, outpatient retail pharmacy oral antibiotic prescriptions in Tennessee. SETTING: Statewide retail pharmacies filling outpatient antibiotic prescriptions. PARTICIPANTS: Prescribers who wrote at least 1 antibiotic prescription filled at a retail pharmacy in Tennessee in 2016. METHODS: Multivariable logistic regression, including prescriber gender, birth decade, specialty, and practice location, and patient gender and age group, to determine the association with high prescribing. RESULTS: In 2016, 7,949,816 outpatient oral antibiotic prescriptions were filled in Tennessee: 1,195 prescriptions per 1,000 total population. Moreover, 50% of Tennessee's outpatient oral antibiotic prescriptions were written by 9.3% of prescribers. Specific specialties and prescriber types were associated with high prescribing: urology (odds ratio [OR], 3.249; 95% confidence interval [CI], 3.208-3.289), nurse practitioners (OR, 2.675; 95% CI, 2.658-2.692), dermatologists (OR, 2.396; 95% CI, 2.365-2.428), physician assistants (OR, 2.382; 95% CI, 2.364-2.400), and pediatric physicians (OR, 2.340; 95% CI, 2.320-2.361). Prescribers born in the 1960s were most likely to be high prescribers (OR, 2.574; 95% CI, 2.532-2.618). Prescribers in rural areas were more likely than prescribers in all other practice locations to be high prescribers. High prescribers were more likely to prescribe broader-spectrum antibiotics (P < .001). CONCLUSIONS: Targeting high prescribers, independent of specialty, degree, practice location, age, or gender, may be the best strategy for implementing cost-conscious, effective outpatient antimicrobial stewardship interventions. More information about high prescribers, such as patient volumes, clinical scope, and specific barriers to intervention, is needed.

Phenotypic Characterization of Insulin-Resistant and Insulin-Sensitive Obesity.

CONTEXT: Whereas insulin resistance and obesity coexist, some obese individuals remain insulin sensitive. OBJECTIVE: We examined phenotypic and metabolic factors associated with insulin sensitivity in both muscle and liver in obese individuals. DESIGN AND PARTICIPANTS: Sixty-four nondiabetic obese adults (29 males) underwent hyperinsulinemic (15 and 80 mU/m(2) · min)-euglycemic clamps with deuterated glucose. Top tertile subjects for glucose infusion rate during the high-dose insulin clamp were assigned Musclesen and those in the lower two tertiles were assigned Muscleres. Secondarily, top tertile subjects for endogenous glucose production suppression during the low-dose insulin clamp were deemed Liversen and the remainder Liverres. MAIN OUTCOMES MEASURES: Clinical and laboratory parameters and visceral, subcutaneous, liver, and pancreatic fat were compared. RESULTS: Musclesen and Muscleres had similar body mass index and total fat (P > .16), but Musclesen had lower glycated hemoglobin (P < .001) and systolic (P = .01) and diastolic (P = .03) blood pressure (BP). Despite similar sc fat (P = 1), Musclesen had lower visceral (P < .001) and liver (P < .001) fat. Liversen had lower visceral (P < .01) and liver (P < .01) fat and C-reactive protein (P = .02) than Liverres. When subjects were grouped by both glucose infusion rate during the high-dose insulin clamp and endogenous glucose production suppression, insulin sensitivity at either muscle or liver conferred apparent protection from the adverse metabolic features that characterized subjects insulin resistant at both sites. High-density lipoprotein-cholesterol, 1-hour glucose, systolic BP, and triglycerides explained 54% of the variance in muscle insulin sensitivity. CONCLUSIONS: Obese subjects who were insulin sensitive at muscle and/or liver exhibited favorable metabolic features, including lower BP, liver and visceral adiposity. This study identifies factors associated with, and possibly contributing to, insulin sensitivity in obesity.

A certified plasmid reference material for the standardisation of BCR-ABL1 mRNA quantification by real-time quantitative PCR.

Serial quantification of BCR-ABL1 mRNA is an important therapeutic indicator in chronic myeloid leukaemia, but there is a substantial variation in results reported by different laboratories. To improve comparability, an internationally accepted plasmid certified reference material (CRM) was developed according to ISO Guide 34:2009. Fragments of BCR-ABL1 (e14a2 mRNA fusion), BCR and GUSB transcripts were amplified and cloned into pUC18 to yield plasmid pIRMM0099. Six different linearised plasmid solutions were produced with the following copy number concentrations, assigned by digital PCR, and expanded uncertainties: 1.08±0.13 × 10(6), 1.08±0.11 × 10(5), 1.03±0.10 × 10(4), 1.02±0.09 × 10(3), 1.04±0.10 × 10(2) and 10.0±1.5 copies/µl. The certification of the material for the number of specific DNA fragments per plasmid, copy number concentration of the plasmid solutions and the assessment of inter-unit heterogeneity and stability were performed according to ISO Guide 35:2006. Two suitability studies performed by 63 BCR-ABL1 testing laboratories demonstrated that this set of 6 plasmid CRMs can help to standardise a number of measured transcripts of e14a2 BCR-ABL1 and three control genes (ABL1, BCR and GUSB). The set of six plasmid CRMs is distributed worldwide by the Institute for Reference Materials and Measurements (Belgium) and its authorised distributors (https://ec.europa.eu/jrc/en/reference-materials/catalogue/; CRM code ERM-AD623a-f).

EuroClonality/BIOMED-2 guidelines for interpretation and reporting of Ig/TCR clonality testing in suspected lymphoproliferations.

PCR-based immunoglobulin (Ig)/T-cell receptor (TCR) clonality testing in suspected lymphoproliferations has largely been standardized and has consequently become technically feasible in a routine diagnostic setting. Standardization of the pre-analytical and post-analytical phases is now essential to prevent misinterpretation and incorrect conclusions derived from clonality data. As clonality testing is not a quantitative assay, but rather concerns recognition of molecular patterns, guidelines for reliable interpretation and reporting are mandatory. Here, the EuroClonality (BIOMED-2) consortium summarizes important pre- and post-analytical aspects of clonality testing, provides guidelines for interpretation of clonality testing results, and presents a uniform way to report the results of the Ig/TCR assays. Starting from an immunobiological concept, two levels to report Ig/TCR profiles are discerned: the technical description of individual (multiplex) PCR reactions and the overall molecular conclusion for B and T cells. Collectively, the EuroClonality (BIOMED-2) guidelines and consensus reporting system should help to improve the general performance level of clonality assessment and interpretation, which will directly impact on routine clinical management (standardized best-practice) in patients with suspected lymphoproliferations.

Equivalent activation of the hippocampus by face-face and face-laugh paired associate learning and recognition.

The human hippocampus is known to play an important role in relational memory. Both patient lesion studies and functional-imaging studies have shown that it is involved in the encoding and retrieval from memory of arbitrary associations. Two recent patient lesion studies, however, have found dissociations between spared and impaired memory within the domain of relational memory. Recognition of associations between information of the same kind (e.g., two faces) was spared, whereas recognition of associations between information of different kinds (e.g., face-name or face-voice associations) was impaired by hippocampal lesions. Thus, recognition of associations between information of the same kind may not be mediated by the hippocampus. Few imaging studies have directly compared activation at encoding and recognition of associations between same and different types of information. Those that have have shown mixed findings and been open to alternative interpretation. We used fMRI to compare hippocampal activation while participants studied and later recognized face-face and face-laugh paired associates. We found no differences in hippocampal activation between our two types of stimulus materials during either study or recognition. Study of both types of paired associate activated the hippocampus bilaterally, but the hippocampus was not activated by either condition during recognition. Our findings suggest that the human hippocampus is normally engaged to a similar extent by study and recognition of associations between information of the same kind and associations between information of different kinds.

Significantly improved PCR-based clonality testing in B-cell malignancies by use of multiple immunoglobulin gene targets. Report of the BIOMED-2 Concerted Action BHM4-CT98-3936.

Polymerase chain reaction (PCR) assessment of clonal immunoglobulin (Ig) and T-cell receptor (TCR) gene rearrangements is an important diagnostic tool in mature B-cell neoplasms. However, lack of standardized PCR protocols resulting in a high level of false negativity has hampered comparability of data in previous clonality studies. In order to address these problems, 22 European laboratories investigated the Ig/TCR rearrangement patterns as well as t(14;18) and t(11;14) translocations of 369 B-cell malignancies belonging to five WHO-defined entities using the standardized BIOMED-2 multiplex PCR tubes accompanied by international pathology panel review. B-cell clonality was detected by combined use of the IGH and IGK multiplex PCR assays in all 260 definitive cases of B-cell chronic lymphocytic leukemia (n=56), mantle cell lymphoma (n=54), marginal zone lymphoma (n=41) and follicular lymphoma (n=109). Two of 109 cases of diffuse large B-cell lymphoma showed no detectable clonal marker. The use of these techniques to assign cell lineage should be treated with caution as additional clonal TCR gene rearrangements were frequently detected in all disease categories. Our study indicates that the BIOMED-2 multiplex PCR assays provide a powerful strategy for clonality assessment in B-cell malignancies resulting in high Ig clonality detection rates particularly when IGH and IGK strategies are combined.

A case of hepatosplenic gamma-delta T-cell lymphoma with a transient response to fludarabine and alemtuzumab.

Hepatosplenic gamma-delta T-cell lymphoma is a rare, usually fatal lymphoma and available literature on management is sparse. Allografting is probably the only curative option. We describe a further case with a dramatic, though transient response to Fludarabine and Alemtuzumab combination, following a failure of conventional chemotherapy. Given the dreadful prognosis with conventional chemotherapy, it is a regimen worth pursuing as a disease reduction strategy prior to allograft where appropriate.

Pyoderma gangrenosum as a cause of splenomegaly and association with a T-cell clone.

The spectrum of clinical presentation of haematological disease is wide. We highlight two features of this principle: a rare cause of a 'haematological' presentation and a possible haematological cause of a disease not normally considered as such. A case of systemic pyoderma gangrenosum presented with splenomegaly in the absence of a rash. A clonal gamma- and beta-T-cell receptor rearrangement was demonstrated. Such clones may be a general phenomenon involved in the pathogenesis of this condition.

Inactivation of the p16INK4A gene by methylation is not a frequent event in sporadic ovarian carcinoma.

The p16INK4A tumour suppressor gene (p16) encodes for a cyclin-dependant kinase inhibitor which plays a role in the phosphorylation of the retinoblastoma protein (pRb) during regulation of the G1-S phase of the cell cycle. Loss of heterozygosity at 9p21, the chromosomal location of the p16 gene, has been reported in a broad range of tumours and this is usually indicative of the presence of a tumour suppressor gene, the second allele being frequently inactivated by mutation or deletion. The p16 gene, however, is often found not be mutated or deleted and it has been suggested that hypermethylation of the CpG islands of the gene may be an alternative mechanism of gene inactivation. We sought to determine the levels of p16 abnormality in a series of epithelial ovarian carcinomas in an attempt to clarify the presently conflicting evidence of whether or not hypermethylation of the p16 gene plays a role in ovarian carcinogenesis. We analysed 57 primary ovarian tumours and their corresponding blood DNA using SSCP analysis, sequencing and the methylation specific PCR (MSP) technique. We found low levels of mutation (6.7% of malignant tumours) and no evidence of methylation in any of our samples, suggesting that neither mutation or hypermethylation of the CpG islands of the p16 gene play an important role in ovarian carcinogenesis.

A cross-linguistic PET study of tone perception in Mandarin Chinese and English speakers.

PET was used in a cross-linguistic study to determine whether neural mechanisms subserving pitch perception differ as a function of linguistic relevance. We compared tone perception in 12 native Mandarin speakers, who use tonal patterns to distinguish lexical meaning, with that of 12 native speakers of a nontone language, English. Subjects were scanned under two conditions: a silent resting baseline and a tonal task involving discrimination of pitch patterns in Mandarin words. Both groups showed common regions of CBF increase, but only Mandarin speakers showed additional activation in frontal, parietal, and parieto-occipital regions of the left hemisphere; this latter finding indicates that language experience may influence brain circuitry in the processing of auditory cues. In contrast, only the English group showed activity in the right inferior frontal cortex, consistent with a right-hemispheric role in pitch perception.

Teaching undergraduates about familial breast cancer: comparison of a computer assisted learning (CAL) package with a traditional tutorial approach.

We have developed a computer assisted learning package for teaching clinical medical students about familial breast cancer. It explains the principles of genetic predisposition to breast cancer, the association with other cancers, the principles of family history taking and confirmation, risk assessment and possible interventions. Clinical medical students were randomised to either conventional teaching or CAL, 48 students attended the evaluation session. Students randomised to conventional teaching received a 20 min mini-lecture, those randomised to CAL completed the package with technical, but not academic support available. At the end of the intervention both groups of students completed a short written assessment of acceptability and knowledge and understanding of breast cancer genetics. There was no significant difference between the CAL and mini-lecture groups in terms of marks or acceptability. Thus CAL appears to be an acceptable and effective method of teaching clinical medical students about familial breast cancer. Although time consuming to develop, CAL can be used in a variety of settings to increase curriculum flexibility. Methods of motivating students to complete the CAL, and of providing educational support are being explored.

Loss of recent memory after bilateral hippocampal lesions. 1957.

Bilateral medial temporal lobe resection in man results in a persistent impairment of recent memory whenever the removal is carried far enough posteriorly to damage portions of the anterior hippocampus and hippocampal gyrus. This conclusion is based on formal psychological testing of nine cases (eight psychotic and one epileptic) carried out from one and one-half to four years after operation. The degree of memory loss appears to depend on the extent of hippocampal removal. In two cases in which bilateral resection was carried to a distance of 8 cm posterior to the temporal tips the loss was particularly severe. Removal of only the uncus and amygdala bilaterally does not appear to cause memory impairment. A case of unilateral inferior temporal lobectomy with radical posterior extension to include the major portion of the hippocampus and hippocampal gyrus showed no lasting memory loss. This is consistent with Milner and Penfield's negative findings in a long series of unilateral removals for temporal lobe epilepsy. The memory loss in these cases of medial temporal lobe excision involved both anterograde and some retrograde amnesia, but left early memories and technical skills intact. There was no deterioration in personality or general intelligence, and no complex perceptual disturbance such as is seen after a more complete bilateral temporal lobectomy. It is concluded that the anterior hippocampus and hippocampal gyrus, either separately or together, are critically concerned in the retention of current experience. It is not known whether the amygdala plays any part in this mechanismi, since the hippocampal complex has not been removed alone, but always together with uncus and amygdala.