Impact of extended-infusion piperacillin-tazobactam in a Canadian community hospital.

Background: Studies have demonstrated improved clinical outcomes with extended infusion (EI) piperacillin/tazobactam (TZP) compared to standard infusion (SI). However, there is less evidence on its benefits in noncritically-ill patients. Hospital-wide EI TZP was implemented at our site on February 21, 2012. Our objectives were to compare clinical, safety and economic outcomes between EI and SI TZP. Methods: A retrospective cohort study of all adult patients who received EI TZP (3.375 g IV q8h infused over 4 hours and SI TZP for ≥ 48 hours during 3 years pre-and postimplementation was conducted. The primary study outcome was 14-day mortality while secondary outcomes included length of hospital stay (LOS), nursing plus pharmacy cost, occurrence of Clostridioides difficile infection, readmission within 30 days and change in Pseudomonas aeruginosa minimum inhibitory concentration (MIC) distribution for TZP. The primary outcome and binary secondary outcomes were analyzed using a logistic regression model. LOS was examined using time to event analysis. Cost was examined using linear regression modelling. Results: Overall, 2034 patients received EI TZP and 1364 patients received SI TZP. EI TZP was associated with lower odds of mortality (OR 0.76, 95% CI 0.63-0.91), lower odds of C. difficile infection (OR 0.59, 95% CI 0.41-0.84) and 8% lower cost (estimate 0.92, 95% CI 0.87-0.98) compared to SI TZP. Conclusions: Hospital-wide implementation of EI TZP was associated with lower odds of 14-day mortality and incidence of C. difficile infection with cost savings at our institution.

Evaluating a pilot, structured, face-to-face, antimicrobial stewardship, prospective audit-and-feedback program in emergency general surgery service in a community hospital.

Background: Prospective audit and feedback (PAF) is an established practice in critical care settings but not in surgical populations. We pilot-tested a structured face-to-face PAF program for our acute-care surgery (ACS) service. Methods: This was a mixed-methods study. For the quantitative analysis, the structured PAF period was from August 1, 2017, to April 30, 2019. The ad hoc PAF period was from May 1, 2019, to January 31, 2021. Interrupted time-series segmented negative binomial regression analysis was used to evaluate change in antimicrobial usage measured in days of therapy per 1,000 patient days for all systemic and targeted antimicrobials. Secondary outcomes included C. difficile infections, length of stay and readmission within 30 days. Each secondary outcome was analyzed using a logistic regression or negative binomial regression model. For the qualitative analyses, all ACS surgeons and trainees from November 23, 2015, to April 30, 2019, were invited to participate in an email-based anonymous survey developed using implementation science principles. Responses were measured using counts. Results: In total, 776 ACS patients were included in the structured PAF period and 783 patients were included in the in ad hoc PAF period. No significant changes in level or trend for antimicrobial usage were detected for all and targeted antimicrobials. Similarly, no significant differences were detected for secondary outcomes. The survey response rate was 25% (n = 10). Moreover, 50% agreed that PAF provided them with skills to use antimicrobials more judiciously, and 80% agreed that PAF improved the quality of antimicrobial treatment for their patients. Conclusion: Structured PAF showed clinical outcomes similar to ad hoc PAF. Structured PAF was well received and was perceived as beneficial by surgical staff.

Organoid cultures for cancer modeling.

Organoids derived from adult stem cells (ASCs) and pluripotent stem cells (PSCs) are important preclinical models for studying cancer and developing therapies. Here, we review primary tissue-derived and PSC-derived cancer organoid models and detail how they have the potential to inform personalized medical approaches in different organ contexts and contribute to the understanding of early carcinogenic steps, cancer genomes, and biology. We also compare the differences between ASC- and PSC-based cancer organoid systems, discuss their limitations, and highlight recent improvements to organoid culture approaches that have helped to make them an even better representation of human tumors.

Escape from cell-cell and cell-matrix adhesion dependence underscores disease progression in gastric cancer organoid models.

OBJECTIVE: Cell-cell (CC) and cell-matrix (CM) adhesions are essential for epithelial cell survival, yet dissociation-induced apoptosis is frequently circumvented in malignant cells. DESIGN: We explored CC and CM dependence in 58 gastric cancer (GC) organoids by withdrawing either ROCK inhibitor, matrix or both to evaluate their tumorigenic potential in terms of apoptosis resistance, correlation with oncogenic driver mutations and clinical behaviour. We performed mechanistic studies to determine the role of diffuse-type GC drivers: ARHGAP fusions, RHOA and CDH1, in modulating CC (CCi) or CM (CMi) adhesion independence. RESULTS: 97% of the tumour organoids were CMi, 66% were CCi and 52% were resistant to double withdrawal (CCi/CMi), while normal organoids were neither CMi nor CCi. Clinically, the CCi/CMi phenotype was associated with an infiltrative tumour edge and advanced tumour stage. Moreover, the CCi/CMi transcriptome signature was associated with poor patient survival when applied to three public GC datasets. CCi/CMi and CCi phenotypes were enriched in diffuse-type GC organoids, especially in those with oncogenic driver perturbation of RHO signalling via RHOA mutation or ARHGAP fusions. Inducible knockout of ARHGAP fusions in CCi/CMi tumour organoids led to resensitisation to CC/CM dissociation-induced apoptosis, upregulation of focal adhesion and tight junction genes, partial reversion to a more normal cystic phenotype and inhibited xenograft formation. Normal gastric organoids engineered with CDH1 or RHOA mutations became CMi or CCi, respectively. CONCLUSIONS: The CCi/CMi phenotype has a critical role in malignant transformation and tumour progression, offering new mechanistic information on RHO-ROCK pathway inhibition that contributes to GC pathogenicity.

A Bayesian model for identifying cancer subtypes from paired methylation profiles.

Aberrant DNA methylation is the most common molecular lesion that is crucial for the occurrence and development of cancer, but has thus far been underappreciated as a clinical tool for cancer classification, diagnosis or as a guide for therapeutic decisions. Partly, this has been due to a lack of proven algorithms that can use methylation data to stratify patients into clinically relevant risk groups and subtypes that are of prognostic importance. Here, we proposed a novel Bayesian model to capture the methylation signatures of different subtypes from paired normal and tumor methylation array data. Application of our model to synthetic and empirical data showed high clustering accuracy, and was able to identify the possible epigenetic cause of a cancer subtype.

Evaluating the impact of mandatory indications on antibiotic utilization in a community hospital.

Objective: We evaluated the impact of introducing a mandatory indication field into electronic order entry for targeted antibiotics in adult inpatients. Design: Retrospective, before-and-after trial. Setting: A 400-bed community hospital. Interventions: All adult electronic intravenous (IV) and enteral orders for targeted antibiotics (moxifloxacin, ciprofloxacin, clindamycin, vancomycin, and metronidazole) had a mandatory indication field added. Control antibiotics (amoxicillin-clavulanate, ceftriaxone and piperacillin-tazobactam) were chosen to track shifts in antibiotic prescribing due to the introduction of mandatory indication field. Methods: Descriptive statistics were used to summarize the primary outcome, measured in Defined Daily Doses (DDD) per 1000 patient days (PD). Interrupted time-series (ITS) analysis was performed to compare levels and trends in antibiotic usage of targeted and control antibiotics during 24 months before and after the intervention. Additionally, a descriptive analysis of mandatory indication fields for targeted antibiotics in the postintervention period was conducted. Results: In total, 4,572 study antibiotic orders were evaluated after the intervention. Preset mandatory indications were selected for 30%-55% of orders. There was decreased usage of targeted antibiotics (mean, 92.02 vs 72.07 DDD/1000-PD) with increased usage of control antibiotics (mean, 102.73 vs 119.91 DDD/1000-PD). ITS analysis showed no statistically significant difference in overall antibiotic usage before and after the intervention for all targeted antibiotics. Conclusion: This study showed moderate use of preset mandatory indications, suggesting that the preset list of indications can be optimized. There was no impact on overall antibiotic usage with the use of mandatory indications. More prospective research is needed to study the utility of this intervention in different contexts.

Trends in hospital antibiotic utilization during the coronavirus disease 2019 (COVID-19) pandemic: A multicenter interrupted time-series analysis.

Objective: To describe the evolution of respiratory antibiotic prescribing during the coronavirus disease 2019 (COVID-19) pandemic across 3 large hospitals that maintained antimicrobial stewardship services throughout the pandemic. Design: Retrospective interrupted time-series analysis. Setting: A multicenter study was conducted including medical and intensive care units (ICUs) from 3 hospitals within a Canadian epicenter for COVID-19. Methods: Interrupted time-series analysis was used to analyze rates of respiratory antibiotic utilization measured in days of therapy per 1,000 patient days (DOT/1,000 PD) in medical units and ICUs. Each of the first 3 waves of the pandemic were compared to the baseline. Results: Within the medical units, use of respiratory antibiotics increased during the first wave of the pandemic (rate ratio [RR], 1.76; 95% CI, 1.38-2.25) but returned to the baseline in waves 2 and 3 despite more COVID-19 admissions. In ICU, the use of respiratory antibiotics increased in wave 1 (RR, 1.30; 95% CI, 1.16-1.46) and wave 2 of the pandemic (RR, 1.21; 95% CI, 1.11-1.33) and returned to the baseline in the third wave, which had the most COVID-19 admissions. Conclusions: After an initial surge in respiratory antibiotic prescribing, we observed the normalization of prescribing trends at 3 large hospitals throughout the COVID-19 pandemic. This trend may have been due to the timely generation of new research and guidelines developed with frontline clinicians, allowing for the active application of new research to clinical practice.

Oncogenic mutations drive intestinal cancer initiation through paracrine remodeling.

Three articles in Nature show that intestinal stem cells with cancer-promoting mutations could shape the surrounding normal tissue in their favor to promote clonal fixation and field expansion, raising the possibility of developing therapeutic strategies that maintain or enhance the health of normal cells to out-compete the mutant cells.

Barriers and facilitators of implementing an antimicrobial stewardship intervention for urinary tract infection in a long-term care facility.

BACKGROUND: Fifty percent of antibiotic courses in long-term care facilities (LTCFs) are unnecessary, leading to increased risk of harm. Most studies to improve antibiotic prescribing in LTCFs showed modest and unsustained results. We aimed to identify facilitators, barriers and strategies in implementing a urinary tract infection (UTI)-focused antimicrobial stewardship (AS) intervention at a LTCF, with the secondary objective of exploring the pharmacist's potential roles. METHODS: The study used a qualitative descriptive design. Participants attended either a focus group or one-on-one interview. Data were analyzed inductively using a codebook modified in an iterative analytic process. Barrier and facilitator themes were mapped using the capability, opportunity, motivation and behaviour (COM-B) model. Similarly, themes were identified from the transcripts regarding the pharmacist's roles. RESULTS: Sixteen participants were interviewed. Most barriers and facilitators mapped to the opportunities domain of the COM-B model. The main barrier themes were lack of access, lack of knowledge, ineffective communication, lack of resources and external factors, while the main facilitator themes were education, effective collaboration, good communication, sufficient resources and access. For the pharmacist's role, the barrier themes were ineffective collaboration and communication. CONCLUSION: This study supports the importance of tailoring interventions to target factors underlying barriers to behaviour change. At this LTCF, an effective antimicrobial stewardship intervention should incorporate strategies to improve access, knowledge, communication and collaboration in its design, having sufficient resources and addressing external factors to optimize its success and long-term sustainability. Can Pharm J (Ott) 2021;154:xx-xx.

Antibiotics: easier to start than to stop? Predictors of antimicrobial stewardship recommendation acceptance.

OBJECTIVES: Acceptance of prospective audit and feedback antimicrobial stewardship programme (ASP) recommendations has been shown to vary, but the drivers of recommendation acceptance are not well understood. We sought to identify the factors associated with recommendation acceptance at a large community teaching hospital. METHODS: Data from an ASP recommendation registry were collected from 2010 to 2018. Variables included data about the infection, the prescriber, and the recommendation, categorized by whether they increase, decrease, or are neutral to antibiotic exposure. The primary outcome was acceptance of ASP recommendations. Adjusted odds ratios and 95% confidence intervals were estimated using logistic regression models with random intercepts in order to account for clustering by prescriber. RESULTS: Over the 8-year period, a total of 11 014 evaluable recommendations were made to 146 prescribers, and 9058 (82.2%) were accepted. The most common recommendations were: reduce duration (n = 2796; 25%), stop antibiotics (n = 2184; 20%), de-escalate (n = 1876; 17%) and increase duration (n = 1176; 11%). Acceptance by service ranged from 70% (n = 843/1196) (surgery) to 86% (n = 6378/7444) (general medicine). In the multivariable analysis, compared to recommendations that have a neutral impact on antibiotic exposure, recommendations to decrease antibiotic exposure had lower odds of acceptance (aOR 0.73; 95%CI 0.64-0.84) while recommendations to increase exposure were associated with greater acceptance (aOR 2.00; 95%CI 1.62-2.45). Other factors associated with increased acceptance included the presence of the ASP physician during rounds and making the recommendation verbally. CONCLUSIONS: Recommendations to decrease antibiotic exposure had lower odds of acceptance than those to increase antibiotic exposure. This study presents important considerations for ASPs with prospective audit and feedback programmes aiming to evaluate and increase the impact of their recommendations.

Organoid cultures of early-onset colorectal cancers reveal distinct and rare genetic profiles.

OBJECTIVE: Sporadic early-onset colorectal cancer (EOCRC) has bad prognosis, yet is poorly represented by cell line models. We examine the key mutational and transcriptomic alterations in an organoid biobank enriched in EOCRCs. DESIGN: We established paired cancer (n=32) and normal organoids (n=18) from 20 patients enriched in microsatellite-stable EOCRC. Exome and transcriptome analysis was performed. RESULTS: We observed a striking diversity of molecular phenotypes, including PTPRK-RSPO3 fusions. Transcriptionally, RSPO fusion organoids resembled normal colon organoids and were distinct from APC mutant organoids, with high BMP2 and low PTK7 expression. Single cell transcriptome analysis confirmed the similarity between RSPO fusion organoids and normal organoids, with a propensity for maturation on Wnt withdrawal, whereas the APC mutant organoids were locked in progenitor stages. CRISPR/Cas9 engineered mutation of APC in normal human colon organoids led to upregulation of PTK7 protein and suppression of BMP2, but less so with an engineered RNF43 mutation. The frequent co-occurrence of RSPO fusions with SMAD4 or BMPR1A mutation was confirmed in TCGA database searches. RNF43 mutation was found in organoid from a leukaemia survivor with a novel mutational signature; and organoids with POLE proofreading mutation displayed ultramutation. The cancer organoid genomes were stable over long culture periods, while normal human colon organoids tended to be subject to clonal dominance over time. CONCLUSIONS: These organoid models enriched in EOCRCs with linked genomic data fill a gap in existing CRC models and reveal distinct genetic profiles and novel pathway cooperativity.

High versus low intensity: What is the optimal approach to prospective audit and feedback in an antimicrobial stewardship program?

BACKGROUND: Antimicrobial stewardship program (ASP) interventions, such as prospective audit and feedback (PAF), have been shown to reduce antimicrobial use and improve patient outcomes. However, the optimal approach to PAF is unknown. OBJECTIVE: We examined the impact of a high-intensity interdisciplinary rounds-based PAF compared to low-intensity PAF on antimicrobial use on internal medicine wards in a 400-bed community hospital. METHODS: Prior to the intervention, ASP pharmacists performed low-intensity PAF with a focus on targeted antibiotics. Recommendations were made directly to the internist for each patient. High-intensity, rounds-based PAF was then introduced sequentially to 5 internal medicine wards. This PAF format included twice-weekly interdisciplinary rounds, with a review of all internal medicine patients receiving any antimicrobial agent. Antibiotic use and clinical outcomes were measured before and after the transition to high-intensity PAF. An interrupted time-series analysis was performed adjusting for seasonal and secular trends. RESULTS: With the transition from low-intensity to high-intensity PAF, a reduction in overall usage was seen from 483 defined daily doses (DDD)/1,000 patient days (PD) during the low-intensity phase to 442 DDD/1,000 PD in the high-intensity phase (difference, -42; 95% confidence interval [CI], -74 to -9). The reduction in usage was more pronounced in the adjusted analysis, in the latter half of the high intensity period, and for targeted agents. There were no differences seen in clinical outcomes in the adjusted analysis. CONCLUSIONS: High-intensity PAF was associated with a reduction in antibiotic use compared to a low-intensity approach without any adverse impact on patient outcomes. A decision to implement high-intensity PAF approach should be weighed against the increased workload required.

Breakthrough Moments: Organoid Models of Cancer.

Five years ago, Li et al. (2014) and Gao et al. (2014) reported the power and unique advantages of cancer organoids. We shine a spotlight on the platform's enormous potential for studying cancer biology and as a preclinical human tumor model that can facilitate drug discovery and personalized therapy.

The Use and Effects of Electronic Health Tools for Patient Self-Monitoring and Reporting of Outcomes Following Medication Use: Systematic Review.

BACKGROUND: Electronic health (eHealth) tools are becoming increasingly popular for helping patients' self-manage chronic conditions. Little research, however, has examined the effect of patients using eHealth tools to self-report their medication management and use. Similarly, there is little evidence showing how eHealth tools might prompt patients and health care providers to make appropriate changes to medication use. OBJECTIVE: The objective of this systematic review was to determine the impact of patients' use of eHealth tools on self-reporting adverse effects and symptoms that promote changes to medication use. Related secondary outcomes were also evaluated. METHODS: MEDLINE, EMBASE, and CINAHL were searched from January 1, 2000, to April 25, 2018. Reference lists of relevant systematic reviews and included articles from the literature search were also screened to identify relevant studies. Title, abstract, and full-text review as well as data extraction and risk of bias assessment were performed independently by 2 reviewers. Due to high heterogeneity, results were not meta-analyzed and instead presented as a narrative synthesis. RESULTS: A total of 14 studies, including 13 randomized controlled trials (RCTs) and 1 open-label intervention, were included, from which 11 unique eHealth tools were identified. In addition, 14 RCTs found statistically significant increases in positive medication changes as a result of using eHealth tools, as did the single open-label study. Moreover, 8 RCTs found improvement in patient symptoms following eHealth tool use, especially in adolescent asthma patients. Furthermore, 3 RCTs showed that eHealth tools might improve patient self-efficacy and self-management of chronic disease. Little or no evidence was found to support the effectiveness of eHealth tools at improving medication recommendations and reconciliation by clinicians, medication-use behavior, health service utilization, adverse effects, quality of life, or patient satisfaction. eHealth tools with multifaceted functionalities and those allowing direct patient-provider communication may be more effective at improving patient self-management and self-efficacy. CONCLUSIONS: Evidence suggests that the use of eHealth tools may improve patient symptoms and lead to medication changes. Patients generally found eHealth tools useful in improving communication with health care providers. Moreover, health-related outcomes among frequent eHealth tool users improved in comparison with individuals who did not use eHealth tools frequently. Implementation issues such as poor patient engagement and poor clinician workflow integration were identified. More high-quality research is needed to explore how eHealth tools can be used to effectively manage use of medications to improve medication management and patient outcomes.

A Comprehensive Human Gastric Cancer Organoid Biobank Captures Tumor Subtype Heterogeneity and Enables Therapeutic Screening.

Gastric cancer displays marked molecular heterogeneity with aggressive behavior and treatment resistance. Therefore, good in vitro models that encompass unique subtypes are urgently needed for precision medicine development. Here, we have established a primary gastric cancer organoid (GCO) biobank that comprises normal, dysplastic, cancer, and lymph node metastases (n = 63) from 34 patients, including detailed whole-exome and transcriptome analysis. The cohort encompasses most known molecular subtypes (including EBV, MSI, intestinal/CIN, and diffuse/GS, with CLDN18-ARHGAP6 or CTNND1-ARHGAP26 fusions or RHOA mutations), capturing regional heterogeneity and subclonal architecture, while their morphology, transcriptome, and genomic profiles remain closely similar to in vivo tumors, even after long-term culture. Large-scale drug screening revealed sensitivity to unexpected drugs that were recently approved or in clinical trials, including Napabucasin, Abemaciclib, and the ATR inhibitor VE-822. Overall, this new GCO biobank, with linked genomic data, provides a useful resource for studying both cancer cell biology and precision cancer therapy.

MICMIC: identification of DNA methylation of distal regulatory regions with causal effects on tumorigenesis.

Aberrant promoter methylation is a common mechanism for tumor suppressor inactivation in cancer. We develop a set of tools to identify genome-wide DNA methylation in distal regions with causal effect on tumorigenesis called MICMIC. Many predictions are directly validated by dCas9-based epigenetic editing to support the accuracy and efficiency of our tool. Oncogenic and lineage-specific transcription factors are shown to aberrantly shape the methylation landscape by modifying tumor-subtype core regulatory circuitry. Notably, the gene regulatory networks orchestrated by enhancer methylation across different cancer types are seen to converge on a common architecture. MICMIC is available on https://github.com/ZhangJlab/MICMIC .

Id1 suppresses anti-tumour immune responses and promotes tumour progression by impairing myeloid cell maturation.

A central mechanism of tumour progression and metastasis involves the generation of an immunosuppressive 'macroenvironment' mediated in part through tumour-secreted factors. Here we demonstrate that upregulation of the Inhibitor of Differentiation 1 (Id1), in response to tumour-derived factors, such as TGFß, is responsible for the switch from dendritic cell (DC) differentiation to myeloid-derived suppressor cell expansion during tumour progression. Genetic inactivation of Id1 largely corrects the myeloid imbalance, whereas Id1 overexpression in the absence of tumour-derived factors re-creates it. Id1 overexpression leads to systemic immunosuppression by downregulation of key molecules involved in DC differentiation and suppression of CD8 T-cell proliferation, thus promoting primary tumour growth and metastatic progression. Furthermore, advanced melanoma patients have increased plasma TGFß levels and express higher levels of ID1 in myeloid peripheral blood cells. This study reveals a critical role for Id1 in suppressing the anti-tumour immune response during tumour progression and metastasis.