Remote Monitoring and Data Collection for Decentralized Clinical Trials.

Importance: Less than 5% of patients with cancer enroll in a clinical trial, partly due to financial and logistic burdens, especially among underserved populations. The COVID-19 pandemic marked a substantial shift in the adoption of decentralized trial operations by pharmaceutical companies. Objective: To assess the current global state of adoption of decentralized trial technologies, understand factors that may be driving or preventing adoption, and highlight aspirations and direction for industry to enable more patient-centric trials. Design, Setting, and Participants: The Bloomberg New Economy International Cancer Coalition, composed of patient advocacy, industry, government regulator, and academic medical center representatives, developed a survey directed to global biopharmaceutical companies of the coalition from October 1 through December 31, 2022, with a focus on registrational clinical trials. The data for this survey study were analyzed between January 1 and 31, 2023. Exposure: Adoption of decentralized clinical trial technologies. Main Outcomes and Measures: The survey measured (1) outcomes of different remote monitoring and data collection technologies on patient centricity, (2) adoption of these technologies in oncology and all therapeutic areas, and (3) barriers and facilitators to adoption using descriptive statistics. Results: All 8 invited coalition companies completed the survey, representing 33% of the oncology market by revenues in 2021. Across nearly all technologies, adoption in oncology trials lags that of all trials. In the current state, electronic diaries and electronic clinical outcome assessments are the most used technology, with a mean (SD) of 56% (19%) and 51% (29%) adoption for all trials and oncology trials, respectively, whereas visits within local physician networks is the least adopted at a mean (SD) of 12% (18%) and 7% (9%), respectively. Looking forward, the difference between the current and aspired adoption rate in 5 years for oncology is large, with respondents expecting a 40% or greater absolute adoption increase in 8 of the 11 technologies surveyed. Furthermore, digitally enabled recruitment, local imaging capabilities, and local physician networks were identified as technologies that could be most effective for improving patient centricity in the long term. Conclusions and Relevance: These findings may help to galvanize momentum toward greater adoption of enabling technologies to support a new paradigm of trials that are more accessible, less burdensome, and more inclusive.

Antibiotics and the transplant patient: The good, the bad, and the ugly.

As a heart transplant recipient for 34 years, I have been asked to write an experience-based opinion on antibiotic stewardship programs (ASPs) in the transplant setting. The aim of this piece is to provide real-life examples-the good, the bad, and the ugly-to help contextualize the potential impact of an effective transplant-specific ASP model. The exigency of transplant ASPs is illuminated, and suggested changes that can help patients right away are provided.

Cartilage Wear Particles Induce an Inflammatory Response Similar to Cytokines in Human Fibroblast-Like Synoviocytes.

The synovium plays a key role in the development of osteoarthritis, as evidenced by pathological changes to the tissue observed in both early and late stages of the disease. One such change is the attachment of cartilage wear particles to the synovial intima. While this phenomenon has been well observed clinically, little is known of the biological effects that such particles have on resident cells in the synovium. The present work investigates the hypothesis that cartilage wear particles elicit a pro-inflammatory response in diseased and healthy human fibroblast-like synoviocytes, like that induced by key cytokines in osteoarthritis. Fibroblast-like synoviocytes from 15 osteoarthritic human donors and a subset of three non-osteoarthritic donors were exposed to cartilage wear particles, interleukin-1α or tumor necrosis factor-α for 6 days and analyzed for proliferation, matrix production, and release of pro-inflammatory mediators and degradative enzymes. Wear particles significantly increased proliferation and release of nitric oxide, interleukin-6 and -8, and matrix metalloproteinase-9, -10, and -13 in osteoarthritic synoviocytes, mirroring the effects of both cytokines, with similar trends in non-osteoarthritic cells. These results suggest that cartilage wear particles are a relevant physical factor in the osteoarthritic environment, perpetuating the pro-inflammatory and pro-degradative cascade by modulating synoviocyte behavior at early and late stages of the disease. Future work points to therapeutic strategies for slowing disease progression that target cell-particle interactions. © 2019 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 37:1979-1987, 2019.

A Functional Tissue-Engineered Synovium Model to Study Osteoarthritis Progression and Treatment.

IMPACT STATEMENT: The synovium envelops the diarthrodial joint and plays a key regulatory role in defining the composition of the synovial fluid through filtration and biosynthesis of critical boundary lubricants. Synovium changes often precede cartilage damage in osteoarthritis. We describe a novel in vitro tissue engineered model, validated against native synovium explants, to investigate the structure-function of synovium through quantitative solute transport measures. Synovium was evaluated in the presence of a proinflammatory cytokine, interleukin-1, or the clinically relevant corticosteroid, dexamethasone. We anticipate that a better understanding of synovium transport would support efforts to develop more effective strategies aimed at restoring joint health.

Fibroblast-like synoviocyte mechanosensitivity to fluid shear is modulated by interleukin-1α.

Fibroblast-like synoviocytes (FLS) reside in the synovial membrane of diarthrodial joints and are exposed to a dynamic fluid environment that presents both physical and chemical stimuli. The ability of FLS to sense and respond to these stimuli plays a key role in their normal function, and is implicated in the alterations to function that occur in osteoarthritis (OA). The present work characterizes the response of FLS to fluid flow-induced shear stress via real-time calcium imaging, and tests the hypothesis that this response is modulated by interleukin-1α (IL-1α), a cytokine elevated in OA. FLS demonstrated a robust calcium signaling response to fluid shear that was dose dependent upon stress level and required both external and internal calcium sources. Preconditioning with 10ng/mL IL-1α for 24h heightened this shear stress response by significantly increasing the percent of responding cells and peak magnitude, while significantly decreasing the time for a peak to occur. Intercellular communication via gap junctions was found to account for a portion of the FLS population response in normal conditions, and was significantly increased by IL-1α preconditioning. IL-1α was also found to significantly increase average length and incidence of the primary cilium, an organelle commonly implicated in shear mechanosensing. These findings suggest that the elevated levels of IL-1α found in the OA environment heighten FLS sensitivity to fluid shear by altering both intercellular communication and individual cell sensitivity, which could affect downstream functions and contribute to progression of the disease state.

Transient expression of the diseased phenotype of osteoarthritic chondrocytes in engineered cartilage.

Due to the degradation of osteoarthritic (OA) cartilage in post-traumatic OA (PTOA), these tissues are challenging to study and manipulate in vitro. In this study, chondrocytes isolated from either PTOA (meniscal-release (MR) model) or normal (contralateral limb) cartilage of canine knee joints were used to form micropellets to assess the maintenance of the OA chondrocyte phenotype in vitro. Media samples from the micropellet cultures were used to measure matrix metalloproteinase (MMP), chemokine, and cytokine concentrations. Significant differences in matrix synthesis were observed as a function of disease with OA chondrocytes generally synthesizing more extracellular matrix with increasing time in culture. No donor dependent differences were detected. Luminex multiplex analysis of pellet culture media showed disease and time-dependent differences in interleukin (IL)-8, keratinocyte chemoattractant (KC)-like protein, MMP-1, MMP-2, and MMP-3, which are differentially expressed in OA. This memory of their diseased phenotype persists for the first 2 weeks of culture. These results demonstrate the potential to use chondrocytes from an animal model of OA to study phenotype alterations during the progression and treatment of OA. © 2016 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 35:829-836, 2017.

Effect of early mobilization on sedation practices in the neurosciences intensive care unit: a preimplementation and postimplementation evaluation.

INTRODUCTION: The use of sedation and analgesia protocols, daily interruption of sedation, and early mobilization (EM) have been shown to decrease duration of mechanical ventilation and hospital length of stay (LOS). METHODS: A retrospective chart review was conducted during a 6-month premobilization (pre-EM) and 6-month postmobilization (post-EM) period. Patients older than 18 years who were admitted to the neurosciences intensive care unit (ICU) and mechanically ventilated for at least 24 hours without documentation of withdrawal of life support or brain death were included. RESULTS: Thirty-one pre-EM and 37 post-EM patients were included. Baseline demographics were similar with the exception of more ischemic stroke patients in the pre-EM group (P < .05). In the pre-EM and post-EM groups, patients received similar cumulative doses of propofol, dexmedetomidine, and benzodiazepines but higher median (interquartile range) doses of opioids (50.0 [13.8-165.0] vs 173.3 [41.2-463.2] µg of fentanyl equivalents [P < .05]) in the post-EM group. Neurosciences ICU LOS was 10 (6-19) and 13 (8-18) days, respectively (P = .188). CONCLUSIONS: After implementation of an EM program, an increase in opioid use and no significant change in other sedatives were observed. Despite an increase in the amount of physical therapy and occupational therapy provided to patients, there was no change in hospital and ICU LOS or duration of mechanical ventilation.

Sacrificial nanofibrous composites provide instruction without impediment and enable functional tissue formation.

The fibrous tissues prevalent throughout the body possess an ordered structure that underlies their refined and robust mechanical properties. Engineered replacements will require recapitulation of this exquisite architecture in three dimensions. Aligned nanofibrous scaffolds can dictate cell and matrix organization; however, their widespread application has been hindered by poor cell infiltration due to the tight packing of fibers during fabrication. Here, we develop and validate an enabling technology in which tunable composite nanofibrous scaffolds are produced to provide instruction without impediment. Composites were formed containing two distinct fiber fractions: slow-degrading poly(ε-caprolactone) and water-soluble, sacrificial poly(ethylene oxide), which can be selectively removed to increase pore size. Increasing the initial fraction of sacrificial poly(ethylene oxide) fibers enhanced cell infiltration and improved matrix distribution. Despite the removal of >50% of the initial fibers, the remaining scaffold provided sufficient instruction to align cells and direct the formation of a highly organized ECM across multiple length scales, which in turn led to pronounced increases in the tensile properties of the engineered constructs (nearly matching native tissue). This approach transforms what is an interesting surface phenomenon (cells on top of nanofibrous mats) into a method by which functional, 3D tissues (>1 mm thick) can be formed, both in vitro and in vivo. As such, this work represents a marked advance in the engineering of load-bearing fibrous tissues, and will find widespread applications in regenerative medicine.

Fabrication and evaluation of biomimetic-synthetic nanofibrous composites for soft tissue regeneration.

Electrospun scaffolds hold promise for the regeneration of dense connective tissues, given their nanoscale topographies, provision of directional cues for infiltrating cells and versatile composition. Synthetic slow-degrading scaffolds provide long-term mechanical support and nanoscale instructional cues; however, these scaffolds suffer from a poor infiltration rate. Alternatively, nanofibrous constructs formed from natural biomimetic materials (such as collagen) rapidly infiltrate but provide little mechanical support. To take advantage of the positive features of these constructs, we have developed a composite scaffold consisting in both a biomimetic fiber fraction (i.e., Type I collagen nanofibers) together with a traditional synthetic (i.e., poly-[ε-caprolactone], PCL) fiber fraction. We hypothesize that inclusion of biomimetic elements will improve initial cell adhesion and eventual scaffold infiltration, whereas the synthetic elements will provide controlled and long-term mechanical support. We have developed a method of forming and crosslinking collagen nanofibers by using the natural crosslinking agent genipin (GP). Further, we have formed composites from collagen and PCL and evaluated the long-term performance of these scaffolds when seeded with mesenchymal stem cells. Our results demonstrate that GP crosslinking is cytocompatible and generates stable nanofibrous type I collagen constructs. Composites with varying fractions of the biomimetic and synthetic fiber families are formed and retain their collagen fiber fractions during in vitro culture. However, at the maximum collagen fiber fractions (20%), cell ingress is limited compared with pure PCL scaffolds. These results provide a new foundation for the development and optimization of biomimetic/synthetic nanofibrous composites for in vivo tissue engineering.

The role of law in public health preparedness: opportunities and challenges.

We report the results of a study designed to assess and evaluate how the law shapes the public health system's preparedness activities. Based on 144 qualitative interviews conducted in nine states, we used a model that compared the objective legal environment with how practitioners perceived the laws. Most local public health and emergency management professionals relied on what they perceived the legal environment to be rather than on an adequate understanding of the objective legal requirements. Major reasons for the gap include the lack of legal training for local practitioners and the difficulty of obtaining clarification and consistent legal advice regarding public health preparedness. Narrowing the gap would most likely improve preparedness outcomes. We conclude that there are serious deficiencies in legal preparedness that can undermine effective responses to public health emergencies. Correcting the lack of legal knowledge, coupled with eliminating delays in resolving legal issues and questions during public health emergencies, could have measurable consequences on reducing morbidity and mortality.

Nonmedical use of prescription opioids and stimulants among student pharmacists.

OBJECTIVES: To examine the prevalence and patterns of nonmedical use of prescription opioid analgesics and stimulants among student pharmacists. DESIGN: Descriptive, nonexperimental, cross-sectional study. SETTING: Private urban college of pharmacy in the United States in fall 2006. PARTICIPANTS: 1,538 PharmD students. INTERVENTION: Online survey. MAIN OUTCOME MEASURES: Lifetime and past-year nonmedical prescription opioid and stimulant use. RESULTS: Response rate for the survey was 62%. Lifetime prevalence of opioid misuse was 8%, and 5% of students had misused in the past year. Lifetime prevalence of stimulant misuse was 7%, and 5% had misused in the past year. Whites and fraternity or sorority members were more likely than their peers to have ever misused opioids. Past-year opioid misuse was more likely among whites, men, and low academic achievers compared with their peers. Lifetime stimulant misuse was more likely among students who were white, older, and fraternity or sorority members, while past-year misuse was more likely among whites and low academic achievers. Common motives for opioid misuse were to have fun, to relax, and to deal with chronic pain. Stimulants were used to improve concentration and academic performance. Friends were the most common source of prescription opioids and stimulants. Nonmedical prescription use was associated with greater likelihood of alcohol and other illicit substance use. CONCLUSION: The prevalence of prescription medication misuse among student pharmacists was lower than (opioids) or comparable with (stimulants) reported rates in college populations. Subgroups of students demonstrated higher rates of nonmedical use, including whites, students involved with fraternities or sororities, and low academic achievers. That friends were the primary source of misused medications indicates that diversion of prescription-only controlled substances likely occurs among student pharmacists. Nonmedical prescription medication use should be considered in the context of other substance use.