Perceptions of High-Intensity Interval Training Among People With Spinal Cord Injury: A Mixed-Methods Analysis.

This mixed-method project investigated how people with spinal cord injury perceive high-intensity interval training (HIIT). Using a recumbent hand cycle, 11 active men and 9 active women with spinal cord injury or related disease participated in a single HIIT and moderate-intensity continuous training (MICT) session. Following exercise, participants completed surveys assessing enjoyment, self-efficacy, and outcome expectations. Ten participants were randomly selected to participate in a semistructured interview to assess perceptions toward HIIT. Quantitative survey data revealed that participants trended toward enjoying HIIT over MICT (p = .06) with similar levels of self-efficacy and outcome expectations toward HIIT and MICT (p > .05). Qualitative data revealed that participants believed HIIT would enhance long-term physical and self-evaluative outcomes; several barriers emerged that could prevent widespread adoption among the general population with spinal cord injury. Results support HIIT as a viable exercise option, although research should begin exploring ways to remove HIIT-related barriers that people with spinal cord injury may encounter.

A Rare Case of Late-Onset Ertapenem-Induced Encephalopathy.

Encephalopathy is a rare side effect associated with carbapenem antibiotics, typically presenting within one week of initiating treatment. It is almost exclusively seen in patients with poor renal function. We present a case of a middle-aged male with a history of cerebral vascular accident and normal renal function admitted for agitation, delirium, and insomnia more than two weeks after starting ertapenem to treat osteomyelitis. He was empirically treated for meningitis on admission, and ertapenem was discontinued. After an extensive negative workup for infectious and neurological etiologies of encephalopathy, a presumptive diagnosis of ertapenem-induced encephalopathy was made. The patient returned to his baseline mental status five days after discontinuing ertapenem. The nature of his neurological symptoms and timely resolution after stopping ertapenem is consistent with ertapenem-induced encephalopathy and represents a notably delayed symptom onset compared to previously described cases.

Moving forward: A review of continuous kinetics and kinematics during handcycling propulsion.

Wheelchair users (WCUs) face high rates of shoulder overuse injuries. As exercise is recommended to reduce cardiovascular disease prevalent among WCUs, it is becoming increasingly important to understand the mechanisms behind shoulder soft-tissue injury in WCUs. Understanding the kinetics and kinematics during upper-limb propulsion is the first step toward evaluating soft-tissue injury risk in WCUs. This paper examines continuous kinetic and kinematic data available in the literature. Attach-unit and recumbent handcycling are examined and compared. Athletic modes of propulsion such as recumbent handcycling are important considering the higher contact forces, speed, and power outputs experienced during these activities that could put users at increased risk of injury. Understanding the underlying kinetics and kinematics during various propulsion modes can lend insight into shoulder loading, and therefore injury risk, during these activities and inform future exercise guidelines for WCUs.

A polycistronic transgene design for combinatorial genetic perturbations from a single transcript in Drosophila.

Experimental models that capture the genetic complexity of human disease and allow mechanistic explorations of the underlying cell, tissue, and organ interactions are crucial to furthering our understanding of disease biology. Such models require combinatorial manipulations of multiple genes, often in more than one tissue at once. The ability to perform complex genetic manipulations in vivo is a key strength of Drosophila, where many tools for sophisticated and orthogonal genetic perturbations exist. However, combining the large number of transgenes required to establish more representative disease models and conducting mechanistic studies in these already complex genetic backgrounds is challenging. Here we present a design that pushes the limits of Drosophila genetics by allowing targeted combinatorial ectopic expression and knockdown of multiple genes from a single inducible transgene. The polycistronic transcript encoded by this transgene includes a synthetic short hairpin cluster cloned within an intron placed at the 5' end of the transcript, followed by two protein-coding sequences separated by the T2A sequence that mediates ribosome skipping. This technology is particularly useful for modeling genetically complex diseases like cancer, which typically involve concurrent activation of multiple oncogenes and loss of multiple tumor suppressors. Furthermore, consolidating multiple genetic perturbations into a single transgene further streamlines the ability to perform combinatorial genetic manipulations and makes it readily adaptable to a broad palette of transgenic systems. This flexible design for combinatorial genetic perturbations will also be a valuable tool for functionally exploring multigenic gene signatures identified from omics studies of human disease and creating humanized Drosophila models to characterize disease-associated variants in human genes. It can also be adapted for studying biological processes underlying normal tissue homeostasis and development that require simultaneous manipulation of many genes.

The influence of gender on shoulder kinematics and head-hip technique during non-level transfers in full-time wheelchair users.

BACKGROUND: Non-level transfers are some of the most demanding tasks for manual wheelchair users. Safely performing these transfer tasks may be needed for maintaining long-term upper limb health. This cross-sectional study aimed to examine the influence of gender on the head-hip technique and lead arm kinematics during multi-height transfers in manual wheelchair users. METHODS: Motion analysis was used to obtain lead-arm shoulder kinematics (flexion/extension and abduction/adduction) and trunk flexion during level, uphill, and floor-to-table transfers in full-time manual wheelchair users. FINDINGS: Twelve male (N = 12) and fifteen female (N = 15) manual wheelchair users with a mean age of 23 ± 5 years and no signs of shoulder pain participated in the study. Lead-arm shoulder flexion and abduction increased as vertical displacement requirements increased during the various transfer tasks (p < 0.01). Women displaced greater trunk flexion during level transfers at approaching significant levels (p = 0.07). During uphill transfers, women displayed significantly greater trunk flexion than men (p < 0.05). INTERPRETATION: Manual wheelchair users use unique kinematic requirements when using the head-hip during level and non-level transfers. Women may be at decreased risk of chronic shoulder pain due to a greater use of the head-hip technique during non-level transfers. Nonetheless, more research that integrates kinetics and strength assessments during non-level transfer biomechanical analyses is needed to better understand technical requirements of non-level transfers in manual wheelchair users.

Robotic external ventricular drain placement for acute neurosurgical care in low-resource settings: feasibility considerations and a prototype design.

OBJECTIVE: Emergency neurosurgical care in lower-middle-income countries faces pronounced shortages in neurosurgical personnel and infrastructure. In instances of traumatic brain injury (TBI), hydrocephalus, and subarachnoid hemorrhage, the timely placement of external ventricular drains (EVDs) strongly dictates prognosis and can provide necessary stabilization before transfer to a higher-level center of care that has access to neurosurgery. Accordingly, the authors have developed an inexpensive and portable robotic navigation tool to allow surgeons who do not have explicit neurosurgical training to place EVDs. In this article, the authors aimed to highlight income disparities in neurosurgical care, evaluate access to CT imaging around the world, and introduce a novel, inexpensive robotic navigation tool for EVD placement. METHODS: By combining the worldwide distribution of neurosurgeons, CT scanners, and gross domestic product with the incidence of TBI, meningitis, and hydrocephalus, the authors identified regions and countries where development of an inexpensive, passive robotic navigation system would be most beneficial and feasible. A prototype of the robotic navigation system was constructed using encoders, 3D-printed components, machined parts, and a printed circuit board. RESULTS: Global analysis showed Montenegro, Antigua and Barbuda, and Seychelles to be primary candidates for implementation and feasibility testing of the novel robotic navigation system. To validate the feasibility of the system for further development, its performance was analyzed through an accuracy study resulting in accuracy and repeatability within 1.53 ± 2.50 mm (mean ± 2 × SD, 95% CI). CONCLUSIONS: By considering regions of the world that have a shortage of neurosurgeons and a high incidence of EVD placement, the authors were able to provide an analysis of where to prioritize the development of a robotic navigation system. Subsequently, a proof-of-principle prototype has been provided, with sufficient accuracy to target the ventricles for EVD placement.

A Drosophila platform identifies a novel, personalized therapy for a patient with adenoid cystic carcinoma.

Adenoid cystic carcinoma (ACC) is a rare cancer type that originates in the salivary glands. Tumors commonly invade along nerve tracks in the head and neck, making surgery challenging. Follow-up treatments for recurrence or metastasis including chemotherapy and targeted therapies have shown limited efficacy, emphasizing the need for new therapies. Here, we report a Drosophila-based therapeutic approach for a patient with advanced ACC disease. A patient-specific Drosophila transgenic line was developed to model the five major variants associated with the patient's disease. Robotics-based screening identified a three-drug cocktail-vorinostat, pindolol, tofacitinib-that rescued transgene-mediated lethality in the Drosophila patient-specific line. Patient treatment led to a sustained stabilization and a partial metabolic response of 12 months. Subsequent resistance was associated with new genomic amplifications and deletions. Given the lack of options for patients with ACC, our data suggest that this approach may prove useful for identifying novel therapeutic candidates.

A personalized platform identifies trametinib plus zoledronate for a patient with KRAS-mutant metastatic colorectal cancer.

Colorectal cancer remains a leading source of cancer mortality worldwide. Initial response is often followed by emergent resistance that is poorly responsive to targeted therapies, reflecting currently undruggable cancer drivers such as KRAS and overall genomic complexity. Here, we report a novel approach to developing a personalized therapy for a patient with treatment-resistant metastatic KRAS-mutant colorectal cancer. An extensive genomic analysis of the tumor's genomic landscape identified nine key drivers. A transgenic model that altered orthologs of these nine genes in the Drosophila hindgut was developed; a robotics-based screen using this platform identified trametinib plus zoledronate as a candidate treatment combination. Treating the patient led to a significant response: Target and nontarget lesions displayed a strong partial response and remained stable for 11 months. By addressing a disease's genomic complexity, this personalized approach may provide an alternative treatment option for recalcitrant disease such as KRAS-mutant colorectal cancer.

Functional exploration of colorectal cancer genomes using Drosophila.

The multigenic nature of human tumours presents a fundamental challenge for cancer drug discovery. Here we use Drosophila to generate 32 multigenic models of colon cancer using patient data from The Cancer Genome Atlas. These models recapitulate key features of human cancer, often as emergent properties of multigenic combinations. Multigenic models such as ras p53 pten apc exhibit emergent resistance to a panel of cancer-relevant drugs. Exploring one drug in detail, we identify a mechanism of resistance for the PI3K pathway inhibitor BEZ235. We use this data to identify a combinatorial therapy that circumvents this resistance through a two-step process of emergent pathway dependence and sensitivity we term 'induced dependence'. This approach is effective in cultured human tumour cells, xenografts and mouse models of colorectal cancer. These data demonstrate how multigenic animal models that reference cancer genomes can provide an effective approach for developing novel targeted therapies.

Donor Lymphocyte Infusion-Mediated Graft-versus-Host Responses in a Preclinical Swine Model of Haploidentical Hematopoietic Cell Transplantation.

We previously described successful hematopoietic stem cell engraftment across MHC barriers in miniature swine without graft-versus-host disease (GVHD) using novel reduced-intensity conditioning regimens consisting of partial transient recipient T cell-depletion, thymic or low-dose total body irradiation, and a short course of cyclosporine A. Here we report that stable chimeric animals generated with these protocols are strongly resistant to donor leukocyte infusion (DLI)-mediated GVH effects. Of 33 total DLIs in tolerant chimeras at clinical doses, 21 failed to induce conversion to full donor hematopoietic chimerism or cause GVHD. We attempted to overcome this resistance to conversion through several mechanisms, including using sensitized donor lymphocytes, increasing the DLI dose, removing chimeric host peripheral blood cells through extensive recipient leukapheresis before DLI, and using fully mismatched lymphocytes. Despite our attempts, the resistance to conversion in our model was robust, and when conversion was achieved, it was associated with GVHD in most animals. Our studies suggest that delivery of unmodified hematopoietic stem cell doses under reduced-intensity conditioning can induce a potent, GVHD-free, immune tolerant state that is strongly resistant to DLI.

Myelogenous leukemia in adult inbred MHC-defined miniature swine: a model for human myeloid leukemias.

This manuscript reports on five cases of spontaneous myelogenous leukemia, similar to human disease, occurring within highly inbred, histocompatible sublines of Massachusetts General Hospital (MGH) MHC-defined miniature swine. In cases where a neoplasm was suspected based on clinical observations, samples were obtained for complete blood count, peripheral blood smear, and flow cytometric analysis. Animals confirmed to have neoplasms were euthanized and underwent necropsy. Histological samples were obtained from abnormal tissues and suspect lesions. The phenotype of the malignancies was assessed by flow cytometric analysis of processed peripheral blood mononuclear cells and affected tissues. Five cases of spontaneous myeloid leukemia were identified in adult animals older than 30 months of age. All animals presented with symptoms of weight loss, lethargy, and marked leukocytosis. At autopsy, all animals had systemic disease involvement and presented with severe hepatosplenomegaly. Three of the five myelogenous leukemias have successfully been expanded in vitro. The clustered incidence of disease in this closed herd suggests that genetic factors may be contributing to disease development. Myelogenous leukemia cell lines established from inbred sublines of MGH MHC-defined miniature swine have the potential to be utilized as a model to evaluate therapies of human leukemia.

Approaches to avoid immune responses induced by repeated subcutaneous injections of allogeneic umbilical cord tissue-derived cells.

BACKGROUND: Cellular treatments for repairing diseased tissues represent a promising clinical strategy. Umbilical cord tissue-derived cells (UTC) are a unique source of cells with a low immunogenic profile and potential for tissue repair. By using UTC from miniature swine, we previously demonstrated that despite their low immunogenic phenotype, UTC could induce an immune response under certain inflammatory conditions and after multiple subcutaneous (SC) injections. Given that repeat dosing of cells may be necessary to achieve a lasting therapeutic benefit, in this study, we examined approaches to avoid an immune response to multiple SC injections of UTC. METHODS: By using in vitro and in vivo measures of sensitization to SC cellular injections, we assessed the effects of varying the location of administration site, prolongation of timing between injections, and use of immunosuppressive treatments on repeated cellular injections in Massachusetts General Hospital major histocompatibility complex-defined miniature swine. RESULTS: Although under normal conditions, a single SC injection of major histocompatibility complex-mismatched UTC did not induce a detectable immune response, multiple SC injections of UTC demonstrated rapid humoral and cell-mediated immune responses. Avoidance of an immune response to repeat SC injection was achieved by concurrent immunosuppression with each dose of UTC. CONCLUSIONS: UTC and other similar cell types believed to be nonimmunogenic have the potential to induce immune responses under certain conditions. These studies provide important considerations and guidelines for preclinical studies investigating allogeneic cellular therapies.