A voice-based digital assistant for intelligent prompting of evidence-based practices during ICU rounds.

OBJECTIVE: To evaluate the technical feasibility and potential value of a digital assistant that prompts intensive care unit (ICU) rounding teams to use evidence-based practices based on analysis of their real-time discussions. METHODS: We evaluated a novel voice-based digital assistant which audio records and processes the ICU care team's rounding discussions to determine which evidence-based practices are applicable to the patient but have yet to be addressed by the team. The system would then prompt the team to consider indicated but not yet delivered practices, thereby reducing cognitive burden compared to traditional rigid rounding checklists. In a retrospective analysis, we applied automatic transcription, natural language processing, and a rule-based expert system to generate personalized prompts for each patient in 106 audio-recorded ICU rounding discussions. To assess technical feasibility, we compared the system's prompts to those created by experienced critical care nurses who directly observed rounds. To assess potential value, we also compared the system's prompts to a hypothetical paper checklist containing all evidence-based practices. RESULTS: The positive predictive value, negative predictive value, true positive rate, and true negative rate of the system's prompts were 0.45 ± 0.06, 0.83 ± 0.04, 0.68 ± 0.07, and 0.66 ± 0.04, respectively. If implemented in lieu of a paper checklist, the system would generate 56% fewer prompts per patient, with 50%±17% greater precision. CONCLUSION: A voice-based digital assistant can reduce prompts per patient compared to traditional approaches for improving evidence uptake on ICU rounds. Additional work is needed to evaluate field performance and team acceptance.

Illness-related suffering and need for palliative care in Rohingya refugees and caregivers in Bangladesh: A cross-sectional study.

BACKGROUND: Despite recognition that palliative care is an essential component of any humanitarian response, serious illness-related suffering continues to be pervasive in these settings. There is very limited evidence about the need for palliative care and symptom relief to guide the implementation of programs to alleviate the burden of serious illness-related suffering in these settings. A basic package of essential medications and supplies can provide pain relief and palliative care; however, the practical availability of these items has not been assessed. This study aimed to describe the illness-related suffering and need for palliative care in Rohingya refugees and caregivers in Bangladesh. METHODS AND FINDINGS: Between November 20 and 24, 2017, we conducted a cross-sectional study of individuals with serious health problems (n = 156, 53% male) and caregivers (n = 155, 69% female) living in Rohingya refugee camps in Bangladesh, using convenience sampling to recruit participants at the community level (i.e., going house to house to identify eligible individuals). The serious health problems, recent healthcare experiences, need for medications and medical supplies, and basic needs of participants were explored through interviews with trained Rohingya community members, using an interview guide that had been piloted with Rohingya individuals to ensure it reflected the specificities of their refugee experience and culture. The most common diagnoses were significant physical disabilities (n = 100, 64.1%), treatment-resistant tuberculosis (TB) (n = 32, 20.5%), cancer (n = 15, 9.6%), and HIV infection (n = 3, 1.9%). Many individuals with serious health problems were experiencing significant pain (62%, n = 96), and pain treatments were largely ineffective (70%, n = 58). The average age was 44.8 years (range 2-100 years) for those with serious health problems and 34.9 years (range 8-75 years) for caregivers. Caregivers reported providing an average of 13.8 hours of care per day. Sleep difficulties (87.1%, n = 108), lack of appetite (58.1%, n = 72), and lack of pleasure in life (53.2%, n = 66) were the most commonly reported problems related to the caregiving role. The main limitations of this study were the use of convenience sampling and closed-ended interview questioning. CONCLUSIONS: In this study we found that many individuals with serious health problems experienced significant physical, emotional, and social suffering due to a lack of access to pain and symptom relief and other essential components of palliative care. Humanitarian responses should develop and incorporate palliative care and symptom relief strategies that address the needs of all people with serious illness-related suffering and their caregivers.

Bright environmental light improves the sleepiness of nightshift ICU nurses.

BACKGROUND: Shift work can disturb circadian homeostasis and result in fatigue, excessive sleepiness, and reduced quality of life. Light therapy has been shown to impart positive effects in night shift workers. We sought to determine whether or not prolonged exposure to bright light during a night shift reduces sleepiness and enhances psychomotor performance among ICU nurses. METHODS: This is a single-center randomized, crossover clinical trial at a surgical trauma ICU. ICU nurses working a night shift were exposed to a 10-h period of high illuminance (1500-2000 lx) white light compared to standard ambient fluorescent lighting of the hospital. They then completed the Stanford Sleepiness Scale and the Psychomotor Vigilance Test. The primary and secondary endpoints were analyzed using the paired t test. A p value <0.05 was considered significant. RESULTS: A total of 43 matched pairs completed both lighting exposures and were analyzed. When exposed to high illuminance lighting subjects experienced reduced sleepiness scores on the Stanford Sleepiness Scale than when exposed to standard hospital lighting: mean (sem) 2.6 (0.2) vs. 3.0 (0.2), p = 0.03. However, they committed more psychomotor errors: 2.3 (0.2) vs. 1.7 (0.2), p = 0.03. CONCLUSIONS: A bright lighting environment for ICU nurses working the night shift reduces sleepiness but increases the number of psychomotor errors. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03331822 . Retrospectively registered on 6 November 2017.

Effects of Physician-targeted Pay for Performance on Use of Spontaneous Breathing Trials in Mechanically Ventilated Patients.

RATIONALE: Pay for performance is an increasingly common quality improvement strategy despite the absence of robust supporting evidence. OBJECTIVES: To determine the impact of a financial incentive program rewarding physicians for the completion of daily spontaneous breathing trials (SBTs) in three academic hospitals. METHODS: We compared data from mechanically ventilated patients from 6 months before to 2 years after introduction of a financial incentive program that provided annual payments to critical care physicians contingent on unit-level SBT completion rates. We used Poisson regression to compare the frequency of days on which SBTs were completed among eligible patients and days on which patients were excluded from SBT eligibility among all mechanically ventilated patients. We used multivariate regression to compare risk-adjusted duration of mechanical ventilation and in-hospital mortality. MEASUREMENTS AND MAIN RESULTS: The cohort included 7,291 mechanically ventilated patients with 75,621 ventilator days. Baseline daily SBT rates were 96.8% (hospital A), 16.4% (hospital B), and 74.7% (hospital C). In hospital A, with the best baseline performance, there was no change in SBT rates, exclusion rates, or duration of mechanical ventilation across time periods. In hospitals B and C, with lower SBT completion rates at baseline, there was an increase in daily SBT completion rates and a concomitant increase in exclusions from eligibility. Duration of mechanical ventilation decreased in hospital C but not in hospital B. Mortality was unchanged for all hospitals. CONCLUSIONS: In hospitals with low baseline SBT completion, physician-targeted financial incentives were associated with increased SBT rates driven in part by increased exclusion rates, without consistent improvements in outcome.

Effect of Ganciclovir on IL-6 Levels Among Cytomegalovirus-Seropositive Adults With Critical Illness: A Randomized Clinical Trial.

Importance: The role of cytomegalovirus (CMV) reactivation in mediating adverse clinical outcomes in nonimmunosuppressed adults with critical illness is unknown. Objective: To determine whether ganciclovir prophylaxis reduces plasma interleukin 6 (IL-6) levels in CMV-seropositive adults who are critically ill. Design, Setting, and Participants: Double-blind, placebo-controlled, randomized clinical trial (conducted March 10, 2011-April 29, 2016) with a follow-up of 180 days (November 10, 2016) that included 160 CMV-seropositive adults with either sepsis or trauma and respiratory failure at 14 university intensive care units (ICUs) across the United States. Interventions: Patients were randomized (1:1) to receive either intravenous ganciclovir (5 mg/kg twice daily for 5 days), followed by either intravenous ganciclovir or oral valganciclovir once daily until hospital discharge (n = 84) or to receive matching placebo (n = 76). Main Outcomes and Measures: The primary outcome was change in IL-6 level from day 1 to 14. Secondary outcomes were incidence of CMV reactivation in plasma, mechanical ventilation days, incidence of secondary bacteremia or fungemia, ICU length of stay, mortality, and ventilator-free days (VFDs) at 28 days. Results: Among 160 randomized patients (mean age, 57 years; women, 43%), 156 patients received 1or more dose(s) of study medication, and 132 patients (85%) completed the study. The mean change in plasma IL-6 levels between groups was -0.79 log10 units (-2.06 to 0.48) in the ganciclovir group and -0.79 log10 units (-2.14 to 0.56) in the placebo group (point estimate of difference, 0 [95% CI, -0.3 to 0.3]; P > .99). Among secondary outcomes, CMV reactivation in plasma was significantly lower in the ganciclovir group (12% [10 of 84 patients] vs 39% [28 of 72 patients]); absolute risk difference, -27 (95% CI, -40 to -14), P < .001. The ganciclovir group had more median VFDs in both the intention-to-treat (ITT) group and in the prespecified sepsis subgroup (ITT group: 23 days in ganciclovir group vs 20 days in the placebo group, P = .05; sepsis subgroup, 23 days in the ganciclovir group vs 20 days in the placebo group, P = .03). There were no significant differences between the ganciclovir and placebo groups in duration of mechanical ventilation (5 days for the ganciclovir group vs 6 days for the placebo group, P = .16), incidence of secondary bacteremia or fungemia (15% for the ganciclovir group vs 15% for the placebo group, P = .67), ICU length of stay (8 days for the ganciclovir group vs 8 days for the placebo group, P = .76), or mortality (12% for the ganciclovir group vs 15% for the placebo group, P = .54). Conclusions and Relevance: Among CMV-seropositive adults with critical illness due to sepsis or trauma, ganciclovir did not reduce IL-6 levels and the current study does not support routine clinical use of ganciclovir as a prophylactic agent in patients with sepsis. Additional research is necessary to determine the clinical efficacy and safety of CMV suppression in this setting. Trial Registration: clinicaltrials.gov Identifier: NCT01335932.

Incidence and Etiology of Potentially Preventable ICU Readmissions.

OBJECTIVES: The rate of unplanned ICU readmissions is often considered a measure of hospital performance. However, the degree to which these readmissions are preventable and the causes of preventable readmissions are unknown, creating uncertainty about the feasibility and value of reducing ICU readmission rates. To inform this issue, we sought to determine the frequency and underlying causes of potentially preventable ICU readmissions. DESIGN: Retrospective cohort study. SETTING: Urban, academic medical center in the mid-Atlantic United States. PATIENTS: Adult patients discharged alive from their first ICU admission with an unplanned readmission within 48 hours of discharge. MEASUREMENTS AND MAIN RESULTS: Each patient's medical chart was reviewed by two independent investigators who rated each readmission's preventability according to standardized scale and assessed the etiology of both preventable and nonpreventable readmissions. We assessed concordance between raters using the κ statistic and resolved disagreements through iterative discussion. Of 136 readmissions in the final analysis, 16 (11.8%; 95% CI, 6.9-18.4) were considered preventable and 120 (88.2%; 95% CI, 81.5-93.1) were considered nonpreventable. Of nonpreventable readmissions, 67 were due to a new clinical problem and 53 were due to an existing clinical problem. Among preventable readmissions, six were attributable to system errors, six were attributable to management errors, two were attributable to procedural events, one was attributable to a diagnostic error, and one was attributable to a medication error. Compared to nonpreventable readmissions, preventable readmissions tended to have shorter index ICU lengths of stay (2 vs 3 d; p = 0.05) and a shorter duration of time on the ward prior to readmission (16.6 vs 23.6 hr; p = 0.05). CONCLUSIONS: The majority of early ICU readmissions are nonpreventable, raising important concerns about ICU readmission rates as a measure of hospital performance.

A Randomized Dose-Escalation Study of the Safety and Anti-Inflammatory Activity of the p38 Mitogen-Activated Protein Kinase Inhibitor Dilmapimod in Severe Trauma Subjects at Risk for Acute Respiratory Distress Syndrome.

OBJECTIVES: There are no current pharmacological therapies for the prevention or treatment of acute respiratory distress syndrome. Early dysregulated inflammation likely plays a role in acute respiratory distress syndrome development and possibly acute respiratory distress syndrome outcomes. p38 mitogen-activated protein kinase is central to the regulation of multiple inflammatory mediators implicated in acute organ dysfunction and is the target for a novel class of cytokine-suppressive anti-inflammatory drugs. In preclinical models, p38 inhibitors reduce lung injury following pancreatitis and burn injury. DESIGN: We conducted a phase IIa, randomized, double-blind, placebo-controlled, parallel-group study to evaluate the safety and tolerability of dilmapimod, a novel p38 mitogen-activated protein kinase inhibitor, in patients at risk for developing acute respiratory distress syndrome admitted with an Injury Severity Score more than 16, excluding head trauma. Enrolled patients received 4- or 24-hour IV dilmapimod infusions at different doses or placebo, daily for 3 days, in four separate cohorts. SETTING: Multicenter randomized clinical trial of large, academic trauma centers. MEASUREMENTS AND MAIN RESULTS: Seventy-seven patients were enrolled. Although adverse events were common in this critically ill population, dilmapimod was well tolerated, with no clinically relevant safety findings. Pharmacokinetic models indicated that the higher dose of 10 mg given as continuous infusion over 24 hours had the most favorable plasma concentration profile. Likewise, measures of soluble inflammatory markers including interleukin-6, C-reactive peptide, interleukin-8, and soluble tumor necrosis factor receptor 1 were most different between this dosing arm and placebo. Although the study was not specifically designed with acute respiratory distress syndrome as an outcome, the number of patients who developed acute respiratory distress syndrome was small (2/77). CONCLUSIONS: The novel p38 mitogen-activated protein kinase inhibitor dilmapimod appears well tolerated and may merit further evaluation for prevention of acute respiratory distress syndrome and other organ injury in larger clinical trials. Furthermore, results of this early-phase trial may aid in design of future studies aimed at prevention of acute respiratory distress syndrome and other organ injury.

Impact of nurse-led remote screening and prompting for evidence-based practices in the ICU*.

OBJECTIVES: Evidence-based practices are not consistently applied in the ICU. We sought to determine if nurse-led remote screening and prompting for evidence-based practices using an electronic health record could impact ICU care delivery and outcomes in an academic medical center. DESIGN: Single-center, before-after evaluation of a quality improvement project. SETTING: Urban, academic medical center in the mid-Atlantic United States with eight subspecialty ICUs and 156 ICU beds. PATIENTS: Adult patients admitted to the ICU between January 1, 2011, and August 31, 2012. INTERVENTIONS: Beginning on July 25, 2011, trained ICU nurses screened all ICU patients for selected evidence-based practices on a daily basis. The screening was conducted from a remote office, facilitated by the electronic health record. Selected practices included compliance with a ventilator care bundle, assessment of appropriateness of indwelling venous and urinary catheters, and concordance between sedation orders and documented level of sedation. When gaps were observed, they were communicated to the point-of-care bedside nurse via telephone, page, or facsimile. MEASUREMENTS AND MAIN RESULTS: Fourteen thousand eight hundred twenty-three unique patients were admitted during the study period. We excluded 1,546 patients during a 2-month run-in period from July 1, 2011, to August 31, 2011, resulting in 4,339 patients in the 6-month preintervention period and 8,938 patients in the 12-month postintervention period. Compared with patients admitted in the preintervention period, patients admitted in the postintervention period were more likely to receive sedation interruption (incidence rate ratio, 1.57; 95% CI, 1.45-1.71) and a spontaneous breathing trial (incidence rate ratio, 1.24; 95% CI, 1.20-1.29). Hospital-acquired infection rates were not different between the two periods. Adjusting for patient characteristics and illness severity, patients in the postintervention period experienced shorter duration of mechanical ventilation (adjusted reduction, 0.61 d; 95% CI, 0.27-0.96; p < 0.001), shorter ICU length of stay (adjusted reduction, 0.22 d; 95% CI, 0.04-0.41; p = 0.02), and shorter hospital length of stay (adjusted reduction, 0.55 d; 95% CI, 0.15-0.93; p = 0.006). In-hospital mortality was unchanged (adjusted odds ratio, 0.96; 95% CI, 0.84-1.09; p = 0.54). The results were robust to tests for concurrent temporal trends and coincident interventions. CONCLUSIONS: A program by which nurses screened ICU patients for best practices from a remote location was associated with improvements in the quality of care and reductions in duration of mechanical ventilation and length of stay, but had no impact on mortality.

Iliac venous pressure estimates central venous pressure after laparotomy.

BACKGROUND: Central venous pressure (CVP) is traditionally obtained through subclavian or internal jugular central catheters; however, many patients who could benefit from CVP monitoring have only femoral lines. The accuracy of illiac venous pressure (IVP) as a measure of CVP is unknown, particularly following laparotomy. METHODS: This was a prospective, observational study. Patients who had both internal jugular or subclavian lines and femoral lines already in place were eligible for the study. Pressure measurements were taken from both lines in addition to measurement of bladder pressure, mean arterial pressure, and peak airway pressure. Data were evaluated using paired t-test, Bland-Altman analysis, and linear regression. RESULTS: Measurements were obtained from 40 patients, 26 of which had laparotomy. The mean difference between measurements was 2.2 mm Hg. There were no significant differences between patients who had laparotomy and nonsurgical patients (P = 0.93). Bland-Altman analysis revealed a bias of 1.63 ± 2.44 mm Hg. There was no correlation between IVP accuracy and bladder pressure, mean arterial pressure, or peak airway pressure. CONCLUSIONS: IVP is an adequate measure of CVP, even in surgical patients who have had recent laparotomy. Measurement of IVP to guide resuscitation is encouraged in patients who have only femoral venous catheter access.

The i-gel® supraglottic airway device compared to endotracheal intubation as the initial prehospital advanced airway device: A natural experiment during the COVID-19 pandemic.

Objective: Unlike randomized controlled trials, practical real-world studies can offer important information about implementation of prehospital interventions, particularly in community settings where there may be reluctance to adopt new practices. We present the results of a natural experiment that was driven by mandated COVID-19 pandemic-driven shift from endotracheal intubation (ETI) to the i-gel® supraglottic airway (SGA) as a primary advanced airway management device in the prehospital setting to reduce emergency medical services (EMS) personnel exposure to potentially infectious secretions. The objective was to compare first-pass success and timing to successful airway placement between ETI and the i-gel® SGA under extenuating circumstances. Methods: This pre/post study compared airway placement metrics in prehospital patients requiring advance airway management for non-trauma-related conditions. Data from EMS records were extracted over 2 years, 12 months pre-pandemic, and 12 months post-pandemic. During the pre-COVID-19 year, the EMS protocols utilized ETI as the primary advanced airway device (ETI group). Post-pandemic paramedics were mandated to utilize i-gel® SGA as the primary advanced airway device to reduce exposure to secretions (SGA group). Results: There were 199 adult patients, 83 (42%) in the ETI group and 116 (58%) in the SGA group. First-pass success was significantly higher with SGA 96% (92%-99%) than ETI 68% (57%-78%) with paramedics citing the inability to visualize the airway in 52% of ETI cases. Time to first-pass success was significantly shorter in the SGA group (5.9 min [5.1-6.7 min]) than in the ETI group (8.3 min [6.9-9.6 min]), as was time to overall successful placement at 6.0 min (5.1-6.8 min) versus 9.6 min (8.2-11.1 min), respectively. Multiple placement attempts were required in 26% of ETI cases and 1% of the SGA cases. There were no statistically significant differences in the number and types of complications between the cohorts. Return of spontaneous circulation (on/before emergency department [ED] arrival), mortality at 28 days, intensive care unit length of stay, or ventilator-free days between the groups were not statistically different between the groups. Conclusion: In this natural experiment, the SGA performed significantly better than ETI in first-pass airway device placement success and was significantly faster in achieving first-pass success, and overall airway placement, thus potentially reducing exposure to respiratory pathogens. Practical real-world studies can offer important information about implementation of prehospital interventions, particularly in community settings and in systems with a low frequency of tracheal intubations.

Clindamycin Plus Vancomycin Versus Linezolid for Treatment of Necrotizing Soft Tissue Infection.

Background: Necrotizing soft tissue infections (NSTIs) are life-threatening infections. The aim of this study is to evaluate the safety of clindamycin plus vancomycin versus linezolid as empiric treatment of NSTIs. Methods: This was a retrospective, single-center, quasi-experimental study of patients admitted from 1 June 2018 to 30 June 2019 (preintervention) and 1 May 2020 to 15 October 2021 (postintervention). Patients who received surgical management within 24 hours of NSTI diagnosis and at least 1 dose of linezolid or clindamycin were included. The primary endpoint was death at 30 days. The secondary outcomes included rates of acute kidney injury (AKI) and Clostridioides difficile infection (CDI). Results: A total of 274 patients were identified by admission diagnosis code for NSTI or Fournier gangrene; 164 patients met the inclusion criteria. Sixty-two matched pairs were evaluated. There was no difference in rates of 30-day mortality (8.06% vs 6.45%; hazard ratio [HR], 1.67 [95% confidence interval {CI}, .32-10.73]; P = .65). There was no difference in CDI (6.45% vs 1.61%; HR, Infinite [Inf], [95% CI, .66-Inf]; P = .07) but more AKI in the preintervention group (9.68% vs 1.61%; HR, 6 [95% CI, .73-276]; P = .05). Conclusions: In this small, retrospective, single-center, quasi-experimental study, there was no difference in 30-day mortality in patients receiving treatment with clindamycin plus vancomycin versus linezolid in combination with standard gram-negative and anaerobic therapy and surgical debridement for the treatment of NSTIs. A composite outcome of death, AKI, or CDI within 30 days was more common in the clindamycin plus vancomycin group.

Increasing Quality and Frequency of Goals-of-Care Documentation in the Highest-Risk Surgical Candidates: One-Year Results of the Surgical Pause Program.

Patient values may be obscured when decisions are made under the circumstances of constrained time and limited counseling. The objective of this study was to determine if a multidisciplinary review aimed at ensuring goal-concordant treatment and perioperative risk assessment in high-risk orthopaedic trauma patients would increase the quality and frequency of goals-of-care documentation without increasing the rate of adverse events. Methods: We prospectively analyzed a longitudinal cohort of adult patients treated for traumatic orthopaedic injuries that were neither life- nor limb-threatening between January 1, 2020, and July 1, 2021. A rapid multidisciplinary review termed a "surgical pause" (SP) was available to those who were ≥80 years old, were nonambulatory or had minimal ambulation at baseline, and/or resided in a skilled nursing facility, as well as upon clinician request. Metrics analyzed include the proportion and quality of goals-of-care documentation, rate of return to the hospital, complications, length of stay, and mortality. Statistical analysis utilized the Kruskal-Wallis rank and Wilcoxon rank-sum tests for continuous variables and the likelihood-ratio chi-square test for categorical variables. Results: A total of 133 patients were either eligible for the SP or referred by a clinician. Compared with SP-eligible patients who did not undergo an SP, patients who underwent an SP more frequently had goals-of-care notes identified (92.4% versus 75.0%, p = 0.014) and recorded in the appropriate location (71.2% versus 27.5%, p < 0.001), and the notes were more often of high quality (77.3% versus 45.0%, p < 0.001). Mortality rates were nominally higher among SP patients, but these differences were not significant (10.6% versus 5.0%, 5.1% versus 0.0%, and 14.3% versus 7.9% for in-hospital, 30-day, and 90-day mortality, respectively; p > 0.08 for all). Conclusions: The pilot program indicated that an SP is a feasible and effective means of increasing the quality and frequency of goals-of-care documentation in high-risk operative candidates whose traumatic orthopaedic injuries are neither life- nor limb-threatening. This multidisciplinary program aims for goal-concordant treatment plans that minimize modifiable perioperative risks. Level of Evidence: Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence.

Improving delivery of low tidal volume ventilation in 10 ICUs.

Low tidal volume ventilation (LTVV) is standard of care for mechanically ventilated patients with acute respiratory distress syndrome and has been shown to improve outcomes in the general mechanically ventilated population. Despite these improved outcomes, in clinical practice the LTVV standard of care is often not met. We aimed to increase compliance with LTVV in mechanically ventilated patients in 10 intensive care units at 3 hospitals within the University of Pittsburgh School of Medicine Department of Critical Care Medicine. Four Plan-Do-Study-Act (PDSA) cycles were implemented to improve compliance with LTVV. Initial compliance rates of 40.6%-60.1% improved to 91%-96% by the end of the fourth PDSA cycle. The most impactful step in the intervention was providing education and giving responsibility of selecting the tidal volume to the respiratory therapist. The overall intervention resulted in improved compliance with LTVV that has been sustained for multiple years after our active PDSA cycles.

Focal adhesion kinase inhibitors prevent osteoblast mineralization in part due to suppression of Akt-mediated stabilization of osterix.

Focal Adhesion Kinase (FAK) is an important regulator of tumor cell proliferation, survival and metastasis. As such it has become a therapeutic target of interest in cancer. Previous studies suggested that use of FAK tyrosine kinase inhibitors (TKIs) blocks osteolysis in in vivo models of bone metastasis. However, from these studies it was not clear whether FAK TKIs blocked bone degradation by osteoclasts or also promoted bone formation by osteoblasts. In this study we evaluated whether use of the FAK TKI PF-562,271 affected the differentiation of pre-osteoblasts, or activity of mature differentiated osteoblasts. MC3T3-E1 pre-osteoblastic cells were treated with various doses of PF-562,271 following 3 or 10 days of differentiation which led to the inhibition of alkaline phosphatase (ALP) expression and reduced viable cell numbers in a dose-dependent manner. MC3T3-E1 cells which had been differentiated for 21 days prior to treatment with PF-562,271 showed a dose dependent decrease in mineralization as assessed by Alizarin Red staining, with concomitant decreased expression of ALP which is known to facilitate the bone mineralization activity of osteoblasts, however mRNA levels of the transcription factors RUNX2 and osterix which are important for osteoblast maturation and mineralization appeared unaffected at this time point. We speculated that this may be due to altered function of RUNX2 protein due to inhibitory phosphorylation by GSK3ß. We found treatment with PF-562,271 resulted in increased GSK3ß activity as measured by reduced levels of phospho-Ser9-GSK3ß which would result in phosphorylation and inhibition of RUNX2. Treatment of 21 day differentiated MC3T3-E1 cells with PF-562,271 in combination with GSK3ß inhibitors partially restored mineralization however this was not statistically significant. As we observed that FAK TKI also resulted in suppression of Akt, which is known to alter osterix protein stability downstream of RUNX2, we examined protein levels by western blot and found a dose-dependent decrease in osterix in FAK TKI treated differentiated MC3T3-E1 cells which is likely responsible for the reduced mineralization observed. Taken together our results suggest that use of FAK TKIs as therapeutics in the bone metastatic setting may block new bone formation as an off-target effect and thereby exacerbate the defective bone regulation that is characteristic of the bone metastatic environment.

The transcriptional landscape analysis of basal cell carcinomas reveals novel signalling pathways and actionable targets.

Basal cell carcinoma (BCC) is the most common skin cancer and human malignancy. Although most BCCs are easily managed, some are aggressive locally, require Mohs micrographic surgery, or can even metastasize. In the latter, resistance to Sonic Hedgehog inhibitors may occur. Despite their frequent occurrence in clinical practice, their transcriptional landscape remains poorly understood. By analyzing BCC RNA sequencing data according to clinically important features (all BCCs versus normal skin, high-risk versus low-risk BCCs based solely on histopathological subtypes with aggressive features, advanced versus non-advanced BCCs, and vismodegib-resistant versus vismodegib-sensitive tumors), we have identified novel differentially regulated genes and new targetable pathways implicated in BCC tumorigenesis. Pathways as diverse as IL-17, TLR, Akt/PI3K, cadherins, integrins, PDGF, and Wnt/ß-catenin are promising therapeutic avenues for local and systemic agents in managing this common malignancy, including through drug re-purposing of existing medications. We experimentally validated several of these targets as biomarkers in our patient-derived cohort of primary BCC tumors.

The ectopic expression of meiCT genes promotes meiomitosis and may facilitate carcinogenesis.

Cancer meiomitosis is defined as the concurrent activation of both mitotic and meiotic machineries in neoplastic cells that confer a selective advantage together with increased genomic instability. MeiCT (meiosis-specific cancer/testis) genes that perform specialized functions in the germline events required for the first meiotic division are ectopically expressed in several cancers. Here we describe the expression profiles of meiCT genes and proteins across a number of cancers and review the proposed mechanisms that increase aneuploidy and elicit reduction division in polyploid cells. These mechanisms are centered on the overexpression and function of meiCT proteins in cancers under various conditions that includes a response to genotoxic stress. Since meiCT genes are transcriptionally repressed in somatic cells, their target offers a promising therapeutic approach with limited toxicity to healthy tissues. Throughout the review, we provide a detailed description of the roles for each gene in the context of meiosis and we discuss proposed functions and outcomes resulting from their ectopic reactivation in cancer.

In silico analyses of the tumor microenvironment highlight tumoral inflammation, a Th2 cytokine shift and a mesenchymal stem cell-like phenotype in advanced in basal cell carcinomas.

Basal Cell Carcinoma (BCC) represents the most common form of all cancers. BCC is characteristically surrounded by a fibromyxoid stroma. Previous studies have suggested a shift towards a Th2 response, an increase in T regulatory lymphocytes and the presence of cancer-associated fibroblasts in the BCC tumor microenvironment. In this study, we aimed to further characterize the BCC tumor microenvironment in detail by analyzing BCC RNA-Sequencing data and correlating it with clinically-relevant features via in silico RNA deconvolution. Using immune cell type deconvolution by CIBERSORT, we have identified a brisk lymphocytic infiltration, and more abundant macrophages in BCC tumors compared to normal skin. Using cell type enrichment by xCell, we confirmed the observed immune infiltration in BCC tumors and compared them to normal skin. We observed a shift towards Th2 immunity in advanced and vismodegib-resistant tumors. Tumoral inflammation induced by macrophage activity was associated with advanced BCCs, while lymphocytic infiltration was most significant in non-advanced tumors, likely related to an adaptive anti-tumoral response. In advanced and vismodegib-resistant BCCs, mesenchymal stem cell-like properties were observed. Particularly in vismodegib-resistant BCCs, fibroblasts and adipocytes were found at high number, which ultimately may contribute to the decreased drug delivery to the tumor. In conclusion, this study has revealed notable BCC tumor microenvironment findings associated with important clinical features. Microenvironment-altering agents may be used locally for "routine" BCCs and systematically for advanced or resistant BCCs.

Use of a nasal bridle prevents accidental nasoenteral feeding tube removal.

Reinserting feeding tubes that are accidentally removed exposes patients to risk and consumes hospital resources. We were interested to know if using a bridle to secure tubes would be more effective than tape at preventing accidental tube removal. This was a quality improvement project with a before-and-after design. Between May 2007 and August 2007, we prospectively followed 90 tubes (50 tape, 40 bridle). Tubes were followed up daily until accidental tube removal, ICU discharge, or planned tube removal. Our primary endpoint was accidental tube removal. We compared the 2 groups on the following: (1) proportion of tubes accidentally removed; (2) rate of accidental tube removal (per 100 tube-days); and (3) Kaplan-Meier survival analysis. Survival analysis data were right-censored at ICU discharge or planned tube removal. There were no significant differences between groups in any demographics. The proportion of tubes accidentally removed was 36% (18 of 50) in the tape group and 10% (4 of 40) in the bridle group; P<.05. The rate of accidental tube removal (per 100 tube-days) was 6.4 (18 in 281 tube-days) in the tape group and 1.6 (4 in 248 tube-days) in the bridle group; P<.05. Survival analysis showed a significant difference between the groups with a log-rank test for equality of survivor function of P<.05. Using a bridle to secure feeding tubes significantly reduces the proportion and rate of accidental tube removal and results in increased tube survival by Kaplan-Meier analysis.

Initial absence of N20 waveforms from median nerve somatosensory evoked potentials in a patient with cardiac arrest and good outcomes.

A 34-year-old male was brought to the hospital with a chest gunshot wound. Pulseless upon arrival, blood pressure was absent for 10 minutes. A thoracotomy resulted in return of spontaneous circulation. On hospital day 5, with brainstem reflexes present, he was unresponsive to call or pain, exhibited generalized hyperreflexia and bilateral Babinskys. Median nerve somatosensory evoked potentials (mSSEPs) and brainstem auditory evoked potentials were obtained. International Federation of Clinical Neurophysiology recommendations for mSSEPs and brainstem auditory evoked potentials were followed. Despite absence of the N20 responses from cortical mSSEPs no withdrawal from care was agreed upon. After awaking on day 7, mSSEPs were repeated and present. The patient survived and was discharged with minor deficits. Bilateral absence of N20 responses from mSSEPs performed beyond 48 hours after resuscitation from cardiac arrest is highly associated with bad neurological outcomes. However, variation due to hypothermia, noisy signals, medications, and brain hypo-perfusion must be taken into account.