Pharmacokinetics and pharmacodynamics of Hedgehog pathway inhibitors used in the treatment of advanced or treatment-refractory basal cell carcinoma.

INTRODUCTION: Sonidegib and vismodegib are currently the only US Food and Drug Administration and European Medicines Agency-approved small-molecule Hedgehog pathway inhibitors (HHIs)for treating adults with advanced or refractory basal cell carcinoma (BCC) that is not amenable to conventional surgery or radiotherapy. At this time, there are no head-to-head clinical trials comparing these two HHIs for efficacy and safety to assist clinicians with determining which HHI may be best suited for their patients. AREAS COVERED: This review briefly describes the pathogenesis of BCC, provides a detailed overview of the key pharmacokinetic profile differences between sonidegib and vismodegib, explains their pharmacodynamics, and highlights the therapeutic considerations when either HHI is used to treat special patient populations. EXPERT OPINION: Although both HHIs act at the same molecular target in the Hedgehog pathway, there are significant differences in their pharmacokinetic profiles that may play a potential role in their efficacy and safety. Evidence-based recommendations serve to inform clinicians until direct comparative clinical trials of sonidegib versus vismodegib are conducted to determine the clinical relevance of the reported differences in their pharmacokinetic properties.

Educational Policy Development as a Leadership Experience: Inclusive Institutional Change.

Medical students have a unique opportunity to advocate for educational policies that promote best practices in undergraduate medical education. At the Geisel School of Medicine at Dartmouth, students play a crucial role in the development of medical education policies. This article describes two innovative, inclusive, and effective approaches to increase student engagement: (1) restructuring Medical Education Subcommittees to diversify student perspectives and (2) including students in a values-based design thinking approach to the development of new academic advancement and promotion and conduct policies. Through deliberate participation, medical students gain valuable skills that can be applied as future educators and academic leaders.

New Device Makes Tracheostomy Dressing Changes Easier and More Comfortable.

PURPOSE: This study compared the use of the tracheostomy dressing applicator (TDA) to the standard procedure for tracheostomy dressing changes. DESIGN: A prospective quasi-experimental study was performed. METHODS: Nineteen patients and 117 nurses answered a survey after changing the tracheostomy dressing with the TDA and using standard procedure. FINDINGS: Nurses rated the TDA easier to use in patients with average-sized necks and more favorably on observed discomfort in patients with average-sized and larger necks. Patients rated less discomfort with the TDA compared with the standard method of dressing change. CONCLUSION: The TDA is an effective device to facilitate tracheostomy dressing changes, possibly improving compliance and decreasing skin complications. CLINICAL RELEVANCE: The TDA is a useful device that can improve efficiency of dressing changes with the potential to save time and improve outcomes.

Multidisciplinary Tracheostomy Quality Improvement in the COVID-19 Pandemic: Building a Global Learning Community.

OBJECTIVES: To report experience with a global multidisciplinary tracheostomy e-learning initiative. METHODS: An international multidisciplinary panel of experts convened to build a virtual learning community for tracheostomy care, comprising a web-based platform, five distance learning (interactive webinar) sessions, and professional discourse over 12 months. Structured pre- and post-webinar surveys were disseminated to global participants including otolaryngologists, intensivists, nurses, allied health professionals, and patients/caregivers. Data were collected on audio-visual fidelity, demographics, and pre- and post-tutorial assessments regarding experience and skill acquisition. Participants reported confidence levels for NICU, pediatric, adult, and family care, as well as technical skills, communication, learning, assessment, and subdomains. RESULTS: Participants from 197 institutions in 22 countries engaged in the virtual education platform, including otolaryngologists, speech pathologists, respiratory therapists, specialist nurses, patients, and caregivers. Significant improvements were reported in communication (P < .0001), clinical assessments (P < .0001), and clinical governance (P < .0001), with positive impact on pediatric decannulation (P = .0008), adult decannulation (P = .04), and quality improvement (P < .0001). Respondents reported enhanced readiness to integrate knowledge into practice. Barriers included time zones, internet bandwidth, and perceived difficulty of direct clinical translation of highly technical skills. Participants rated the implementation highly in terms of length, ability for discussion, satisfaction, applicability to professional practice, and expertise of discussants (median scores: 4, 4, 4, 4 and 5 out of 5). CONCLUSIONS: Virtual learning has dominated the education landscape during COVID-19 pandemic, but few data are available on its effectiveness. This study demonstrated feasibility of virtual learning for disseminating best practices in tracheostomy, engaging a diverse, multidisciplinary audience. Learning of complex technical skills proved a hurdle, however, suggesting need for hands-on experience for technical mastery. While interactive videoconferencing via webinar affords an engaging and scalable strategy for sharing knowledge, further investigation is needed on clinical outcomes to define effective strategies for experiential online learning and virtual in-service simulations.

Critical Care Guidance for Tracheostomy Care During the COVID-19 Pandemic: A Global, Multidisciplinary Approach.

PURPOSE: Critical care nurses caring for patients with a tracheostomy are at high risk because of the predilection of SARS-CoV-2 for respiratory and mucosal surfaces. This review identifies patient-centered practices that ensure safety and reduce risk of infection transmission to health care workers during the coronavirus disease 2019 (COVID-19) pandemic. METHODS: Consensus statements, guidelines, institutional recommendations, and scientific literature on COVID-19 and previous outbreaks were reviewed. A global interdisciplinary team analyzed and prioritized findings via electronic communications and video conferences to develop consensus recommendations. RESULTS: Aerosol-generating procedures are commonly performed by nurses and other health care workers, most notably during suctioning, tracheostomy tube changes, and stoma care. Patient repositioning, readjusting circuits, administering nebulized medications, and patient transport also present risks. Standard personal protective equipment includes an N95/FFP3 mask with or without surgical masks, gloves, goggles, and gown when performing aerosol-generating procedures for patients with known or suspected COVID-19. Viral testing of bronchial aspirate via tracheostomy may inform care providers when determining the protective equipment required. The need for protocols to reduce risk of transmission of infection to nurses and other health care workers is evident. CONCLUSION: Critical care nurses and multidisciplinary teams often care for patients with a tracheostomy who are known or suspected to have COVID-19. Appropriate care of these patients relies on safeguarding the health care team. The practices described in this review may greatly reduce risk of infectious transmission.

Global Tracheostomy Collaborative: data-driven improvements in patient safety through multidisciplinary teamwork, standardisation, education, and patient partnership.

There is growing recognition of the need for a coordinated, systematic approach to caring for patients with a tracheostomy. Tracheostomy-related adverse events remain a pervasive global problem, accounting for half of all airway-related deaths and hypoxic brain damage in critical care units. The Global Tracheostomy Collaborative (GTC) was formed in 2012 to improve patient safety and quality of care, emphasising knowledge, skills, teamwork, and patient-centred approaches. Inspired by quality improvement leads in Australia, the UK, and the USA, the GTC implements and disseminates best practices across hospitals and healthcare trusts. Its database collects patient-level information on quality, safety, and organisational efficiencies. The GTC provides an organising structure for quality improvement efforts, promoting safety of paediatric and adult patients. Successful implementation requires instituting key drivers for change that include effective training for health professionals; multidisciplinary team collaboration; engagement and involvement of patients, their families, and carers; and data collection that allows tracking of outcomes. We report the history of the collaborative, its database infrastructure and analytics, and patient outcomes from more than 6500 patients globally. We characterise this patient population for the first time at such scale, reporting predictors of adverse events, mortality, and length of stay indexed to patient characteristics, co-morbidities, risk factors, and context. In one example, the database allowed identification of a previously unrecognised association between bleeding and mortality, reflecting ability to uncover latent risks and promote safety. The GTC provides the foundation for future risk-adjusted benchmarking and a learning community that drives ongoing quality improvement efforts worldwide.

Inducible Nitric Oxide Synthase and CD11b+Gr1+ Cells Impair Lymphatic Contraction of Tumor-Draining Lymphatic Vessels.

Background: Metastatic tumor cells spread through lymphatic vessels and colonize draining lymph nodes (LNs). It is known that tumors induce lymphangiogenesis to enhance lymphatic metastasis and that metastatic cancer cells are carried by lymph flow to LNs. Methods and Results: Here, we investigated the molecular and cellular regulation of collecting lymphatic vessel contraction in vessels draining a metastatic tumor using intravital microscopy. In tumor-draining collecting lymphatic vessels, we found vessel contraction was suppressed. The infiltration of peritumor tissue by inducible nitric oxide synthase positive and CD11b+Gr1+ myeloid cells played a critical role in the suppression of lymphatic contraction. Depletion of Gr1+ cells with an anti-Gr1 antibody improved contraction of tumor-draining lymphatic vessels. In addition, inducing tumor cell death restored lymphatic contraction in nude mice. Conclusions: These findings indicate that tumors contribute to regulation of lymphatic transport in a reversible manner, warranting further investigation into the role of impaired lymphatic transport in cancer progression.

A Patient-Centered Emergency Department Management Strategy for Sickle-Cell Disease Super-Utilizers.

INTRODUCTION: A subpopulation of sickle-cell disease patients, termed super-utilizers, presents frequently to emergency departments (EDs) for vaso-occlusive events and may consume disproportionate resources without broader health benefit. To address the healthcare needs of this vulnerable patient population, we piloted a multidisciplinary intervention seeking to create and use individualized patient care plans that alter utilization through coordinated care. Our goals were to assess feasibility primarily, and to assess resource use secondarily. METHODS: We evaluated the effects of a single-site interventional study targeted at a population of adult sickle-cell disease super-utilizers using a pre- and post-implementation design. The pre-intervention period was 06/01/13 to 12/31/13 (seven months) and the post-intervention period was 01/01/14 to 02/28/15 (14 months). Our approach included patient-specific best practice advisories (BPA); an ED management protocol; and formation of a "medical home" for these patients. RESULTS: For 10 subjects targeted initially we developed and implemented coordinated care plans; after deployment, we observed a tendency toward reduction in ED and inpatient utilization across all measured indices. Between the annualized pre- and post-implementation periods we found the following: ED visits decreased by 16.5 visits/pt-yr (95% confidence interval [CI] [-1.32-34.2]); ED length of state (LOS) decreased by 115.3 hours/pt-yr (95% CI [-82.9-313.5]); in-patient admissions decreased by 4.20 admissions/pt-yr (95% CI [-1.73-10.1]); in-patient LOS decreased by 35.8 hours/pt-yr (95% CI [-74.9-146.7]); and visits where the patient left before treatment were reduced by an annualized total of 13.7 visits. We observed no patient mortality in our 10 subjects, and no patient required admission to the intensive care unit 72 hours following discharge. CONCLUSION: This effort suggests that a targeted approach is both feasible and potentially effective, laying a foundation for broader study.

Process Improvements to Reduce Cardiac Troponin Turnaround Time in the Emergency Department.

BACKGROUND: An efficient testing process is a key to a timely diagnosis of acute myocardial infarction in the emergency department (ED). This includes a rapid evaluation cardiac biomarkers. METHODS: We conducted a quality and process improvement project to reduce troponin-T turnaround time (TAT) in the central laboratory at our facility. An interdisciplinary team, including front-line staff members, reviewed each step of troponin-T processing in both the ED and the central laboratory. A series of improvements were implemented during 2013, including changes to specimen labeling, elimination of duplicate test ordering, and efficiencies within the laboratory. Data from January 2013 to December 2014 on 31,496 patients with troponin tests were included in the analysis. RESULTS: Over the 2-year period of the projects, median troponin-T TAT decreased from 74 minutes to consistently less than 60 minutes. CONCLUSIONS: With an interdisciplinary team of health care professionals, we successfully reduced troponin-T TAT for possible acute coronary syndrome patients in our ED by 19%, consistently achieving laboratory results in less than 60 minutes.

Restoring Speech to Tracheostomy Patients.

Tracheostomies may be established as part of an acute or chronic illness, and intensive care nurses can take an active role in helping restore speech in patients with tracheostomies, with focused nursing assessments and interventions. Several different methods are used to restore speech, whether a patient is spontaneously breathing, ventilator dependent, or using intermittent mechanical ventilation. Restoring vocal communication allows patients to fully express themselves and their needs, enhancing patient satisfaction and quality of life.

Undergraduate Neuropharmacology: A Model for Delivering College-Level Neuroscience to High School Students in situ.

Our university course for non-majors (Biology 100) on the neurobiology of drug addiction was recently retooled for delivery at high schools around the state of Washington in order to engage younger students in the study of psychoactive drugs. Many of these students are earning both high school and university credits (dual-enrollment). This paper outlines the course design principles we used to ensure that high school students are earning valid college credits. We present an analysis of learning gains experienced by both university and high school students as measured by before and after course knowledge surveys. We also describe how assessment strategies used for on-campus students have been transferred to our high school partner teachers and how generous interchange and observation ensure that the high school students are engaging deeply in their study of neuroscience. Indeed, many have had a transformative experience that inspires them to contemplate the field of neuroscience as they transition into university study.

The importance of tracheostomy progression in the intensive care unit.

A plan to progress a tracheostomy toward decannulation should be initiated unless the tracheostomy has been placed for irreversible conditions. In most cases, tracheostomy progression can begin once a patient is free from ventilator dependence. Progression often begins with cuff deflation, which frequently results in the patient's ability to phonate. A systematic approach to tracheostomy progression involves assessing (1) hemodynamic stability, (2) whether the patient has been free from ventilator support for at least 24 hours, (3) swallowing, cough strength, and aspiration risk, (4) management of secretions, and (5) toleration of cuff deflation, followed by (6) changing to a cuffless tube, (7) capping trials, (8) functional decannulation trials, (9) measuring cough strength, and (10) decannulation. Critical care nurses can facilitate the process and avoid unnecessary delays and complications.

Tracheostomy care and complications in the intensive care unit.

Tracheotomy is a common procedure in intensive care units, and nurses must provide proper care to tracheostomy patients to prevent complications. One of the most important considerations is effective mobilization of secretions, and a suction catheter is the most important tool for that purpose. Each bedside should be equipped with a functional suctioning system, an oxygen source, a manual resuscitation bag, and a complete tracheostomy kit, which should accompany patients wherever they go in the hospital. Complications include infection, tracheomalacia, skin breakdown, and tracheoesophageal fistula. Tracheostomy emergencies include hemorrhage, tube dislodgement and loss of airway, and tube obstruction; such emergencies are managed more effectively when all necessary supplies are readily available at the bedside. This article describes how to provide proper care in the intensive care unit, strategies for preventing complications, and management of tracheostomy emergencies.

A proteasome inhibitor fails to attenuate dystrophic pathology in mdx mice.

Dystrophin deficiency leads to increased proteasome activity in skeletal muscle. Previous observations suggest short-term inhibition of the proteasome restores dystrophin expression. Contrary to our hypothesis, eight days of MG-132 administration to mdx mice increased susceptibility to contraction induced injury and Evan's blue dye penetration compared to controls. Following six weeks of MG-132 administration muscle function was similar to control animals. These data suggest that proteasome inhibition does not reduce the severity of muscle dysfunction caused by dystrophin-deficiency.

"Tap and twist": preventing deep vein thrombosis in neuroscience patients through foot and ankle range-of-motion exercises.

Neurosurgical patients tend to have the highest rate of deep vein thrombosis (DVT) rate among other postsurgical patients. The methods and timing of DVT prevention and treatment continue to be debated among neurointensivists. The greatest opportunity to intervene is early during the stay in the intensive care unit. There are many factors, however, that can make this the most neglected time for aggressive prevention measures. For large university teaching hospitals, the target of the University Health System Consortium is to achieve an average DVT rate at or below half that of previous reported rates. The current recommendations are effective only if there is compliance with these measures during the majority of the patients' hospitalization. Our hypothesis states that without changing any of the current measures to prevent DVT, a structured program of foot and ankle range-of-motion (ROM) exercises will decrease the incidence of DVT in the neuroscience intensive care patient population. This quasi-experimental study was a quality improvement project examining 315 individuals over the age of 18 years, who were admitted to the neurospine intensive care unit and who received a new program of foot exercises as a method of DVT prevention. Data for the outcome measures were derived from bedside measurement of lower extremity doppler, the percentage of time the exercises were performed, patient history, and standard DVT prevention measures. Overall, there was no difference in DVT rates for those receiving the foot ROM intervention during the study period in 2008-2009 compared with the usual nursing practice for the previous year. However, during the study period, those who developed DVT had a significantly lower compliance rate with the ROM exercises (38.7%) than did those who did not develop DVT (58.4%; p < .001). Therefore, foot and ankle ROM exercises may have a promising role in reducing the incidence of DVT in neuroscience intensive care patients when there is diligent performance of the exercises.

Fecal containment in bedridden patients: economic impact of 2 commercial bowel catheter systems.

BACKGROUND: Fecal contamination is a major challenge in patients in acute/critical care settings that is associated with increased cost of care and supplies and with development of pressure ulcers, incontinence dermatitis, skin and soft tissue infections, and urinary tract infections. OBJECTIVES: To assess the economic impact of fecal containment in bedridden patients using 2 different indwelling bowel catheters and to compare infection rates between groups. METHODS: A multicenter, observational study was done at 12 US sites (7 that use catheter A, 5 that use catheter B). Patients were followed from insertion of an indwelling bowel catheter system until the patient left the acute/critical care unit or until 29 days after enrollment, whichever came first. Demographic data, frequency of bedding/dressing changes, incidence of infection, and Braden scores (risk of pressure ulcers) were recorded. RESULTS: The study included 146 bedridden patients (76 with catheter A, 70 with catheter B) who had similar Braden scores at enrollment. The rate of bedding/dressing changes per day differed significantly between groups (1.20 for catheter A vs 1.71 for catheter B; P = .004). According to a formula that accounted for personnel resources and laundry cycle costs, catheter A cost $13.94 less per patient per day to use than did catheter B. Catheter A was less likely than was catheter B to be removed during the observational period (P = .03). Observed infection rates were low. CONCLUSION: Catheter A may be more cost-effective than catheter B because it requires fewer unscheduled linen changes per patient day.

Outcome evaluation of a new model of critical care orientation.

BACKGROUND: The shortage of critical care nurses and the service expansion of 2 intensive care units provided a unique opportunity to create a new model of critical care orientation. The goal was to design a program that assessed critical thinking, validated competence, and provided learning pathways that accommodated diverse experience. OBJECTIVES: To determine the effect of a new model of critical care orientation on satisfaction, retention, turnover, vacancy, preparedness to manage patient care assignment, length of orientation, and cost of orientation. METHODS: A prospective, quasi-experimental design with both quantitative and qualitative methods. RESULTS: The new model improved satisfaction scores, retention rates, and recruitment of critical care nurses. Length of orientation was unchanged. Cost was increased, primarily because a full-time education consultant was added. CONCLUSIONS: A new model for nurse orientation that was focused on critical thinking and competence validation improved retention and satisfaction and serves as a template for orientation of nurses throughout the medical center.