Short Timeframe Prediction of Kidney Failure among Patients with Advanced Chronic Kidney Disease.

BACKGROUND: Development of a short timeframe (6-12 months) kidney failure risk prediction model may serve to improve transitions from advanced chronic kidney disease (CKD) to kidney failure and reduce rates of unplanned dialysis. The optimal model for short timeframe kidney failure risk prediction remains unknown. METHODS: This retrospective study included 1757 consecutive patients with advanced CKD (mean age 66 years, estimated glomerular filtration rate 18 mL/min/1.73 m2). We compared the performance of Cox regression models using (a) baseline variables alone, (b) time-varying variables and machine learning models, (c) random survival forest, (d) random forest classifier in the prediction of kidney failure over 6/12/24 months. Performance metrics included area under the receiver operating characteristic curve (AUC-ROC) and maximum precision at 70% recall (PrRe70). Top-performing models were applied to 2 independent external cohorts. RESULTS: Compared to the baseline Cox model, the machine learning and time-varying Cox models demonstrated higher 6-month performance [Cox baseline: AUC-ROC 0.85 (95% CI 0.84-0.86), PrRe70 0.53 (95% CI 0.51-0.55); Cox time-varying: AUC-ROC 0.88 (95% CI 0.87-0.89), PrRe70 0.62 (95% CI 0.60-0.64); random survival forest: AUC-ROC 0.87 (95% CI 0.86-0.88), PrRe70 0.61 (95% CI 0.57-0.64); random forest classifier AUC-ROC 0.88 (95% CI 0.87-0.89), PrRe70 0.62 (95% CI 0.59-0.65)]. These trends persisted, but were less pronounced, at 12 months. The random forest classifier was the highest performing model at 6 and 12 months. At 24 months, all models performed similarly. Model performance did not significantly degrade upon external validation. CONCLUSIONS: When predicting kidney failure over short timeframes among patients with advanced CKD, machine learning incorporating time-updated data provides enhanced performance compared with traditional Cox models.

The MedSafer Study-Electronic Decision Support for Deprescribing in Hospitalized Older Adults: A Cluster Randomized Clinical Trial.

IMPORTANCE: Scalable deprescribing interventions may reduce polypharmacy and the use of potentially inappropriate medications (PIMs); however, few studies have been large enough to evaluate the impact that deprescribing may have on adverse drug events (ADEs). OBJECTIVE: To evaluate the effect of an electronic deprescribing decision support tool on ADEs after hospital discharge among older adults with polypharmacy. DESIGN, SETTING, AND PARTICIPANTS: This was a cluster randomized clinical trial of older (≥65 years) hospitalized patients with an expected survival of more than 3 months who were admitted to 1 of 11 acute care hospitals in Canada from August 22, 2017, to January 13, 2020. At admission, participants were taking 5 or more medications per day. Data analyses were performed from January 3, 2021, to September 23, 2021. INTERVENTIONS: Personalized reports of deprescribing opportunities generated by MedSafer software to address usual home medications and measures of prognosis and frailty. Deprescribing reports provided to the treating team were compared with usual care (medication reconciliation). MAIN OUTCOMES AND MEASURES: The primary outcome was a reduction of ADEs within the first 30 days postdischarge (including adverse drug withdrawal events) captured through structured telephone surveys and adjudicated blinded to intervention status. Secondary outcomes were the proportion of patients with 1 or more PIMs deprescribed at discharge and the proportion of patients with an adverse drug withdrawal event (ADWE). RESULTS: A total of 5698 participants (median [range] age, 78 [72-85] years; 2858 [50.2%] women; race and ethnicity data were not collected) were enrolled in 3 clusters and were adjudicated for the primary outcome (control, 3204; intervention, 2494). Despite cluster randomization, there were group imbalances, eg, the participants in the intervention arm were older and had more PIMS prescribed at baseline. After hospital discharge, 4989 (87.6%) participants completed an ADE interview. There was no significant difference in ADEs within 30 days of discharge (138 [5.0%] of 2742 control vs 111 [4.9%] of 2247 intervention participants; adjusted risk difference [aRD] -0.8%; 95% CI, -2.9% to 1.3%). Deprescribing increased from 795 (29.8%) of 2667 control to 1249 (55.4%) of 2256 intervention participants [aRD, 22.2%; 95% CI, 16.9% to 27.4%]. There was no difference in ADWEs between groups. Several post hoc sensitivity analyses, including the use of a nonparametric test to address the low cluster number, group imbalances, and potential biases, did not alter study conclusions. CONCLUSIONS AND RELEVANCE: This cluster randomized clinical trial showed that providing deprescribing clinical decision support during acute hospitalization had no demonstrable impact on ADEs, although the intervention was safe and led to improvements in deprescribing. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03272607.

A Mobile App for Wound and Symptom Surveillance After Colorectal Surgery: Protocol for a Feasibility Randomized Controlled Trial.

BACKGROUND: Surgical site infections (SSIs) are the most common nosocomial infection and occur in 16.3% of patients undergoing colorectal surgery at our institution (The Ottawa Hospital), the majority of which are identified after discharge from hospital. Patients who suspect having an SSI generally present to the emergency department or surgery clinic. Both options for in-person interaction are costly to the health care system and patients. A mobile app, how2trak, has proven to be beneficial for patients with complex wounds at our institution by facilitating at-home monitoring and virtual consultations. OBJECTIVE: This study aims to assess the feasibility of a randomized controlled trial to assess if how2trak can improve patients' experience and increase detection of SSIs after colorectal surgery while reducing patients' risk of COVID-19 exposure. METHODS: In this single-center prospective feasibility trial, eligible patients undergoing colorectal surgery will be randomized to either standard care or how2trak postoperative monitoring of their incision, symptoms, and ostomy function. Patient self-assessments will be monitored by a nurse specialized in wound and ostomy care who will follow-up with patients with a suspected SSI. The primary outcome is feasibility as measured by enrollment, randomization, app usability, data extraction, and resource capacity. RESULTS: This study was approved by our institution's ethics board on February 26, 2021, and received support from The Ottawa Hospital Innovation and Care Funding on November 12, 2021. Recruitment started June 3, 2021, and 29 were patients enrolled as of September 2021. We expect to publish results in spring 2022. CONCLUSIONS: This study will determine the feasibility of using a mobile app to monitor patients' wounds and detect SSIs after colorectal surgery. If feasible, we plan to assess if this mobile app facilitates SSI detection, enhances patient experience, and optimizes their care. TRIAL REGISTRATION: ClinicalTrials.gov NCT04869774; https://clinicaltrials.gov/ct2/show/NCT04869774. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/26717.

COVID-SAFER: Deprescribing Guidance for Hydroxychloroquine Drug Interactions in Older Adults.

BACKGROUND/OBJECTIVES: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection causes high morbidity and mortality in older adults with chronic illnesses. Several trials are currently underway evaluating the antimalarial drug hydroxychloroquine as a potential treatment for acute infection. However, polypharmacy predisposes patients to increased risk of drug-drug interactions with hydroxychloroquine and may render many in this population ineligible to participate in trials. We aimed to quantify the degree of polypharmacy and burden of potentially inappropriate medications (PIMs) that older hospitalized adults are taking that would interact with hydroxychloroquine. METHODS: We reanalyzed data from the cohort of patients 65 years and older enrolled in the MedSafer pilot study. We first identified patients taking medications with potentially harmful drug-drug interactions with hydroxychloroquine that might exclude them from participation in a typical 2019 coronavirus disease (COVID-19) therapeutic trial. Next, we identified medications that were flagged by MedSafer as potentially inappropriate and crafted guidance around medication management if contemplating the use of hydroxychloroquine. RESULTS: The cohort contained a total of 1,001 unique patients with complete data on their home medications at admission. Of these 1,001 patients, 590 (58.9%) were receiving one or more home medications that could potentially interact with hydroxychloroquine, and of these, 255 (43.2%) were flagged as potentially inappropriate by the MedSafer tool. Common classes of PIMs observed were antipsychotics, cardiac medications, and antidiabetic agents. CONCLUSION: The COVID-19 pandemic highlights the importance of medication optimization and deprescribing PIMs in older adults. By acting now to reduce polypharmacy and use of PIMs, we can better prepare this vulnerable population for inclusion in trials and, if substantiated, pharmacologic treatment or prevention of COVID-19. J Am Geriatr Soc 68:1636-1646, 2020.

The MedSafer Study: A Controlled Trial of an Electronic Decision Support Tool for Deprescribing in Acute Care.

OBJECTIVES: Polypharmacy is common, costly, and harmful for hospitalized older adults. Scalable strategies to reduce the burden of potentially inappropriate medications (PIMs) are needed. We sought to leverage medication reconciliation in hospitalized older adults by pairing with MedSafer, an electronic decision support tool for deprescribing. DESIGN: This was a nonrandomized controlled before-and-after study. SETTING: The study took place on four internal medicine clinical teaching units. PARTICIPANTS: Subjects were aged 65 years and older, had an expected prognosis of 3 or more months, and were taking five or more usual home medications. INTERVENTION: In the baseline phase, patients received usual care that was medication reconciliation. Patients in the intervention arm also had a "deprescribing opportunity report" generated by MedSafer and provided to their in-hospital treating team. MEASUREMENTS: The primary outcome was ascertained at the time of hospital discharge and was the proportion of patients who had one or more PIMs deprescribed. RESULTS: A total of 1066 patients were enrolled, and deprescribing opportunities were present for 873 (82%; 418 during the control and 455 during the intervention phases, respectively). The proportion of patients with one or more PIMs deprescribed at discharge increased from 46.9% in the control period to 54.7% in the intervention period with an adjusted absolute risk difference of 8.3% (2.9%-13.9%). Not all classes of drugs in the intervention arm were associated with an increase in deprescribing, and new PIM starts were equally common in both arms of the study. CONCLUSION: Using an electronic decision support tool for deprescribing, we increased the proportion of patients with one or more PIMs deprescribed at hospital discharge as compared with usual care. Although this type of intervention may help address medication overload in hospitalized patients, it also underscores the importance of powering future trials for a reduction in adverse drug events. TRIAL REGISTRATION: NCT02918058. J Am Geriatr Soc 67:1843-1850, 2019.

Building a CTU Orientation Handbook iPad® application for first-year residents.

BACKGROUND: The General Internal Medicine Clinical Teaching Unit (CTU) is a challenging rotation for new residents and the optimal format of orientation has not been determined. We hypothesized that an iPad® application (app) would be a useful reference tool after residents completed their traditional large group orientation. METHODS: Postgraduate year 1 (PGY1) residents were sent a link to download the free app one week before the start of their rotation. A pre-usage survey at initial login collected basic demographics. Usage data was collected to determine the sections, duration, and the timeframe from which the app was utilized. RESULTS: Pre-usage survey data revealed that 63% of participants were female, 69% felt the app would improve orientation, and 94% were comfortable using mobile technology for medical education. Usage data showed "Teaching Sessions and Schedules," "The Consult Note," and "Admission Orders" were the three sections most commonly used. The most usage was during the evening call shift (10pm to 6am), followed by the morning shift (6am to 5pm). CONCLUSION: The CTU Orientation App was a useful supplement to the traditional orientation. Researchers may not be able to predict what content would be most valuable in an iPad® app, thus pre-development needs-assessments and usage feedback are crucial.

Clinical factors contributing to high cost hospitalizations in a Canadian tertiary care centre.

BACKGROUND: Like much of the developed world, healthcare costs in Canada are rising. A small proportion of patients account for a large proportion of healthcare spending and much of this spending occurs in acute care settings. The purpose of our study was to determine potentially modifiable factors related to care processes that contribute to high-cost admissions. METHODS: Using a mixed-methods study design, factors contributing to high-cost admissions were identified from literature and case review. We defined pre- and post-admission factors contributing to high-cost admissions. Pre-admission factors included reason for admission (e.g. complex medical, elective surgery, trauma, etc.). Post-admission factors included medical complications, disposition delays, clinical services delays, and inefficient clinical decision-making. We selected a random sample of admissions in the top decile of inpatient cost from the Ottawa Hospital between January 1 and December 31, 2010. A single reviewer classified cases based on the pre- and post-admission factors. We combined this information with data derived from the Ottawa Hospital Data Warehouse to describe patient-level clinical and demographic characteristics and costs incurred. RESULTS: We reviewed 200 charts which represents ~5% of all high cost admissions within the Ottawa Hospital in 2010. Post-admission factors contributing to high-cost admissions were: complications (60%), disposition delays (53%), clinical service delays (39%), and inefficient clinical decision-making (13%). Further, these factors varied substantially across service delivery lines. The mean (standard deviation (SD)) cost per admission was $49,923 CDN ($45,773). The most common reason for admission was "complex medical" (49%) and the overall median (IQR) length of stay was 27 (18-48) days. Approximately 1 in 3 high cost admissions (29%) included time in the intensive care unit (ICU). CONCLUSIONS: While high cost admissions often include time in ICU and have long lengths of stay, a substantial proportion of costs were attributable to complications and potentially preventable delays in care processes. These findings suggest opportunities exist to improve outcomes and reduce costs for this diverse patient population.

Effectiveness of an extended period of flashing lights and strategic signage to increase the salience of alcohol-gel dispensers for improving hand hygiene compliance.

BACKGROUND: Multiple factors affect compliance with hand hygiene, including conspicuity of alcohol-gel dispensers. Previous studies have shown that flashing lights increase hand hygiene compliance; however, the durability of this effect has not been studied. METHODS: We affixed flashing lights to hand sanitizer dispensers for a total of 6 weeks. Regression analysis was used to compare compliance rates between the beginning and end of the intervention. Our secondary objective was to determine whether compliance rates in cold weather could be improved by adding a sign separated in time and space from the dispensers. RESULTS: Flashing lights improved hand hygiene compliance from 11.8% to 20.7%, and this effect was unchanged over the 6-week study period. Fully charged lights resulted in a greater compliance increase. A preemptive sign did not have a significant effect on hand hygiene rates nor did absolute temperatures. CONCLUSIONS: Flashing lights are a simple, inexpensive way of improving hand hygiene. Brighter lights appear to have a greater effect; however, this must be balanced with annoyance in specific settings. Temperature did not have a significant effect; however, this may be because the relationship does not fit a linear model. Other interventions, such as signs, may need to be tailored specifically to individual hospital environments.

A study of the efficacy of flashing lights to increase the salience of alcohol-gel dispensers for improving hand hygiene compliance.

BACKGROUND: Many interventions have been implemented to improve hand hygiene compliance, each with varying effects and monetary costs. Although some previous studies have addressed the issue of conspicuousness, we found only 1 study that considered improving hand hygiene by using flashing lights. METHOD: Our attention theory-based hypothesis tested whether a simple red light flashing at 2-3 Hz affixed to the alcohol gel dispensers, within the main hospital entrance, would increase hand hygiene compliance over the baseline rate. Baseline and intervention observations were completed over five 60-minute periods (Monday-Friday) from 7:30 to 8:30 AM using a covert observation method. RESULTS: Baseline hand hygiene compliance was 12.4%. Our intervention increased compliance to 23.5% during cold weather and 27.1% during warm weather. Overall, our pooled compliance rate increased to 25.3% (P < .0001). CONCLUSIONS: A simple, inexpensive flashing red light affixed to alcohol gel dispensers was sufficiently salient to approximately double overall hand hygiene compliance within the main hospital entrance. We hypothesize that our intervention drew attention to the dispensers, which then reminded employees and visitors alike to wash their hands. Compliance was worse during cold days, presumably related to more individuals wearing gloves.

Specific route mapping visualized with GFP of single-file streaming contralateral and systemic metastasis of Lewis lung carcinoma cells beginning within hours of orthotopic implantation [correction of implantion].

In this study, we visualized the origin of Lewis lung carcinoma metastasis after transducing tumor cells with green fluorescent protein (GFP) and transplanting them orthotopically in the middle lobe of the right lung of nude mice. Metastasis was visualized in live tissue at single cell resolution by GFP-expression as early as 18 h post-tumor transplant. At this time, single-file streaming lung carcinoma cells already had invaded inferiorly via a tubular lymphatic structure crossing the lower lobes of the lung to the ipsilateral diaphragmatic surface. By post-implantation day 2, the ipsilateral lower lobes of the lung were involved with metastatic cells. By post-implantation day 3, the ipsilateral lower lobes of the lung and the ipsilateral diaphragmatic surface were highly involved with streaming metastatic cells trafficking in single file. By day 4 post-implantation, cancer cells invaded across the diaphragm to the contralateral diaphragmatic surface. Metastatic cells then invaded superiorly through a lymphatic vessel to involve the contralateral mediastinal lymph nodes. In this model of lung cancer, the origin of metastasis was an inferior invasion from the implanted tumor via a lymphatic duct to the ipsilateral diaphragmatic surface. The cancer cells from this site invaded on the surface of the diaphragm to the contralateral diaphragmatic surface and proceeded superiorly through a lymphatic duct to contralateral lymph nodes. Other organs such as the kidneys and the adrenal glands later became involved with metastasis with the contralateral mediastinal lymph nodes as the source. The use of GFP and the highly metastatic orthotopic lung cancer model allowed the visualization of the origin of metastasis at the single-cell level and demonstrated the critical role of lymphatic ducts and the diaphragmatic surface as the path to the contralateral side.

Tumor suppressor LATS1 is a negative regulator of oncogene YAP.

LATS (large tumor suppressor) or warts is a Ser/Thr kinase that belongs to the Ndr/LATS subfamily of AGC (protein kinase A/PKG/PKC) kinases. It is a tumor suppressor gene originally isolated from Drosophila and recently isolated from mice and humans. Drosophila or mice mutant for LATS develop tumors in various tissues. Recent studies in Drosophila demonstrate that LATS is a central player of an emerging tumor suppressor pathway called the Hippo-LATS/Warts pathway that suppresses tumor growth by regulating cell proliferation, cell growth, and cell death. Although tremendous progress has been made toward understanding the roles of LATS in tumorigenesis, the kinase substrates of LATS or downstream target proteins mediating LATS function remain largely unknown. In this study, we have provided convincing evidence that the LATS1 tumor suppressor can bind to and phosphorylate transcription regulator and oncogene YAP in vitro and in vivo. We have also identified HX(R/H/K)XX(S/T) as the consensus phosphorylation sequence for LATS/Ndr kinase substrates. Significantly, we have discovered that LATS1 inactivates YAP oncogenic function by suppressing its transcription regulation of cellular genes via sequestration of YAP in the cytoplasm after phosphorylation of YAP. Finally, by using microarray analysis, we have also identified many oncogenes or tumor suppressor genes up-regulated or down-regulated by YAP. These research findings will have profound impacts on our understanding of the molecular mechanism of the LATS tumor suppressor and the emerging Hippo-LATS/Warts pathway.