ProPACC: Protocol for a Trial of Integrated Specialty Palliative Care for Critically Ill Older Adults.

BACKGROUND: Each year, approximately one million older adults die in American intensive care units (ICUs) or survive with significant functional impairment. Inadequate symptom management, surrogates' psychological distress and inappropriate healthcare use are major concerns. Pioneering work by Dr. J. Randall Curtis paved the way for integrating palliative care (PC) specialists to address these needs, but convincing proof of efficacy has not yet been demonstrated. DESIGN: We will conduct a multicenter patient-randomized efficacy trial of integrated specialty PC (SPC) vs. usual care for 500 high-risk ICU patients over age 60 and their surrogate decision-makers from five hospitals in Pennsylvania. INTERVENTION: The intervention will follow recommended best practices for inpatient PC consultation. Patients will receive care from a multidisciplinary SPC team within 24 hours of enrollment that continues until hospital discharge or death. SPC clinicians will meet with patients, families, and the ICU team every weekday. SPC and ICU clinicians will jointly participate in proactive family meetings according to a predefined schedule. Patients in the control arm will receive routine ICU care. OUTCOMES: Our primary outcome is patient-centeredness of care, measured using the modified Patient Perceived Patient-Centeredness of Care scale. Secondary outcomes include surrogates' psychological symptom burden and health resource utilization. Other outcomes include patient survival, as well as interprofessional collaboration. We will also conduct prespecified subgroup analyses using variables such as PC needs, measured by the Needs of Social Nature, Existential Concerns, Symptoms, and Therapeutic Interaction scale. CONCLUSIONS: This trial will provide robust evidence about the impact of integrating SPC with critical care on patient, family, and health system outcomes.

Protocol for a randomised trial of an interprofessional team-delivered intervention to support surrogate decision-makers in ICUs.

INTRODUCTION: Although shortcomings in clinician-family communication and decision making for incapacitated, critically ill patients are common, there are few rigorously tested interventions to improve outcomes. In this manuscript, we present our methodology for the Pairing Re-engineered Intensive Care Unit Teams with Nurse-Driven Emotional support and Relationship Building (PARTNER 2) trial, and discuss design challenges and their resolution. METHODS AND ANALYSIS: This is a pragmatic, stepped-wedge, cluster randomised controlled trial comparing the PARTNER 2 intervention to usual care among 690 incapacitated, critically ill patients and their surrogates in five ICUs in Pennsylvania. Eligible subjects will include critically ill patients at high risk of death and/or severe long-term functional impairment, their main surrogate decision-maker and their clinicians. The PARTNER intervention is delivered by the interprofessional ICU team and overseen by 4-6 nurses from each ICU. It involves: (1) advanced communication skills training for nurses to deliver support to surrogates throughout the ICU stay; (2) deploying a structured family support pathway; (3) enacting strategies to foster collaboration between ICU and palliative care services and (4) providing intensive implementation support to each ICU to incorporate the family support pathway into clinicians' workflow. The primary outcome is surrogates' ratings of the quality of communication during the ICU stay as assessed by telephone at 6-month follow-up. Prespecified secondary outcomes include surrogates' scores on the Hospital Anxiety and Depression Scale, the Impact of Event Scale, the modified Patient Perception of Patient Centredness scale, the Decision Regret Scale, nurses' scores on the Maslach Burnout Inventory, and length of stay during and costs of the index hospitalisation.We also discuss key methodological challenges, including determining the optimal level of randomisation, using existing staff to deploy the intervention and maximising long-term follow-up of participants. ETHICS AND DISSEMINATION: We obtained ethics approval through the University of Pittsburgh, Human Research Protection Office. The findings will be published in peer-reviewed journals. TRIAL REGISTRATION NUMBER: NCT02445937.

An acellular biologic scaffold treatment for volumetric muscle loss: results of a 13-patient cohort study.

Volumetric muscle loss (VML) is a severe and debilitating clinical problem. Current standard of care includes physical therapy or orthotics, which do not correct underlying strength deficits, and surgical tendon transfers or muscle transfers, which involve donor site morbidity and fall short of restoring function. The results of a 13-patient cohort study are described herein and involve a regenerative medicine approach for VML treatment. Acellular bioscaffolds composed of mammalian extracellular matrix (ECM) were implanted and combined with aggressive and early physical therapy following treatment. Immunolabeling of ultrasound-guided biopsies, and magnetic resonance imaging and computed tomography imaging were performed to analyse the presence of stem/progenitor cells and formation of new skeletal muscle. Force production, range-of-motion and functional task performance were analysed by physical therapists. Electrodiagnostic evaluation was used to analyse presence of innervated skeletal muscle. This study is registered with ClinicalTrials.gov, numbers NCT01292876. In vivo remodelling of ECM bioscaffolds was associated with mobilisation of perivascular stem cells; formation of new, vascularised, innervated islands of skeletal muscle within the implantation site; increased force production; and improved functional task performance when compared with pre-operative performance. Compared with pre-operative performance, by 6 months after ECM implantation, patients showed an average improvement of 37.3% (P<0.05) in strength and 27.1% improvement in range-of-motion tasks (P<0.05). Implantation of acellular bioscaffolds derived from ECM can improve strength and function, and promotes site-appropriate remodelling of VML defects. These findings provide early evidence of bioscaffolding as a viable treatment of VML.

Arsenic induces sustained impairment of skeletal muscle and muscle progenitor cell ultrastructure and bioenergetics.

Over 4 million individuals in the United States, and over 140 million individuals worldwide, are exposed daily to arsenic-contaminated drinking water. Human exposures can range from below the current limit of 10 µg/L to over 1mg/L, with 100 µg/L promoting disease in a large portion of those exposed. Although increased attention has recently been paid to myopathy following arsenic exposure, the pathogenic mechanisms underlying clinical symptoms remain poorly understood. This study tested the hypothesis that arsenic induces lasting muscle mitochondrial dysfunction and impairs metabolism. Compared to nonexposed controls, mice exposed to drinking water containing 100 µg/L arsenite for 5 weeks demonstrated impaired muscle function, mitochondrial myopathy, and altered oxygen consumption that were concomitant with increased mitochondrial fusion gene transcription. There were no differences in the levels of inorganic arsenic or its monomethyl and dimethyl metabolites between controls and exposed muscles, confirming that arsenic does not accumulate in muscle. Nevertheless, muscle progenitor cells isolated from exposed mice recapitulated the aberrant myofiber phenotype and were more resistant to oxidative stress, generated more reactive oxygen species, and displayed autophagic mitochondrial morphology, compared to cells isolated from nonexposed mice. These pathological changes from a possible maladaptive oxidative stress response provide insight into declines in muscle functioning caused by exposure to this common environmental contaminant.

Targeted rehabilitation after extracellular matrix scaffold transplantation for the treatment of volumetric muscle loss.

Rehabilitation therapy is an important aspect of recovery after volumetric muscle loss. However, the traditional rehabilitation approach involves a period of rest and passive loading followed by gradual active loading. Extracellular matrix is a naturally occurring material consisting of structural proteins that provide mechanical strength, structural support, and functional molecules with diverse bioactive properties. There is evidence to suggest that the addition of aggressive regenerative rehabilitation protocols immediately after surgical implantation of an extracellular matrix scaffold to an area of volumetric muscle loss has significant benefits for extracellular matrix remodeling. Rehabilitation exercises likely provide the needed mechanical signals to encourage cell migration and site-specific differentiation in the temporal framework required for constructive remodeling. Herein, the authors review the literature and present an example of an aggressive rehabilitation program implemented immediately after extracellular matrix transplantation into a severely injured quadriceps muscle.

An acellular biologic scaffold promotes skeletal muscle formation in mice and humans with volumetric muscle loss.

Biologic scaffolds composed of naturally occurring extracellular matrix (ECM) can provide a microenvironmental niche that alters the default healing response toward a constructive and functional outcome. The present study showed similarities in the remodeling characteristics of xenogeneic ECM scaffolds when used as a surgical treatment for volumetric muscle loss in both a preclinical rodent model and five male patients. Porcine urinary bladder ECM scaffold implantation was associated with perivascular stem cell mobilization and accumulation within the site of injury, and de novo formation of skeletal muscle cells. The ECM-mediated constructive remodeling was associated with stimulus-responsive skeletal muscle in rodents and functional improvement in three of the five human patients.

Collaborative approach in the development of high-performance brain-computer interfaces for a neuroprosthetic arm: translation from animal models to human control.

Our research group recently demonstrated that a person with tetraplegia could use a brain-computer interface (BCI) to control a sophisticated anthropomorphic robotic arm with skill and speed approaching that of an able-bodied person. This multiyear study exemplifies important principles in translating research from foundational theory and animal experiments into a clinical study. We present a roadmap that may serve as an example for other areas of clinical device research as well as an update on study results. Prior to conducting a multiyear clinical trial, years of animal research preceded BCI testing in an epilepsy monitoring unit, and then in a short-term (28 days) clinical investigation. Scientists and engineers developed the necessary robotic and surgical hardware, software environment, data analysis techniques, and training paradigms. Coordination among researchers, funding institutes, and regulatory bodies ensured that the study would provide valuable scientific information in a safe environment for the study participant. Finally, clinicians from neurosurgery, anesthesiology, physiatry, psychology, and occupational therapy all worked in a multidisciplinary team along with the other researchers to conduct a multiyear BCI clinical study. This teamwork and coordination can be used as a model for others attempting to translate basic science into real-world clinical situations.

Biological basis of exercise-based treatments for musculoskeletal conditions.

Exercise-based therapies are the cornerstone of rehabilitation programs. While the benefits of exercise on systemic and tissue function are generally accepted, mechanisms underlying these benefits are sometimes poorly understood. An improved understanding of the effects of mechanical loading on molecular and cellular processes has the potential to lead to more disease-specific and efficacious exercise-based therapies. The purpose of this paper is to review the current literature examining the role of mechanical signaling on muscle and cartilage biology.