COVID-19 in a rural intensive care unit in Northern British Columbia: Descriptive analysis of outcomes and demands on rural resources.

INTRODUCTION: This descriptive study reviews clinical outcomes of individuals admitted to a northern Canadian, rural intensive care unit (ICU) with severe COVID-19. It reports our site-specific data that is part of an ongoing global effort to gather data and guide therapy; the aims of this study were to describe participants admitted to our ICU with COVID-19 and illuminate challenges faced by rural and remote centres. METHODS: This retrospective study examined data from participants admitted to the ICU with COVID-19 pneumonia between 24th November 2020 and 28th February 2022. Using data from electronic and hardcopy health records, data were obtained according to standardised forms developed for the Short Period Incidence Study of Severe Acute Respiratory Infection. RESULTS: Eighty-five adult participants were admitted to our ICU with COVID-19. The median age of participants was 57 years old (range: 23-83 years); 49.4% were males and 50.6% were females. Of our cohort, 58.9% required mechanical ventilation at some point during their stay and the median duration of stay in our ICU was 5 days (range: 1-36 days). Amongst individuals included, 25.9% were discharged alive from our hospital on their index admission, 57.6% were transferred to another facility and 16.5% died in our facility. CONCLUSION: COVID-19 significantly strained our local ICU resources, necessitating high numbers of patient transfers. However, despite limited resources, patients at our site received contemporary guideline-based care for COVID-19 pneumonia. Future pandemic and surge capacity planning must ensure that rural and remote communities receive adequate additional resources to meet the anticipated needs of their local populations. INTRODUCTION: Cette étude descriptive examine les résultats cliniques des personnes admises dans une unité de soins intensifs rurale du nord du Canada avec une COVID-19 sévère. Elle rapporte des données spécifiques à notre site qui font partie d'un effort global en cours pour rassembler des données et guider la thérapie. Les objectifs de cette étude étaient de décrire les participants admis dans notre unité de soins intensifs avec la COVID-19 et d'éclairer les défis auxquels sont confrontés les centres ruraux et éloignés. MTHODES: Cette étude rétrospective a examiné les données des participants admis à l'unité de soins intensifs pour une pneumonie due à la COIVD-19 entre le 24 novembre 2020 et le 28 février 2022. Les données ont été obtenues à partir de dossiers médicaux électroniques et papier, selon des formulaires standardisés développés pour l'étude d'incidence à court terme des infections respiratoires aiguës sévères (SPRINT-SARI). RSULTATS: 85 participants adultes ont été admis dans notre unité de soins intensifs avec la COVID-19. L'âge médian des participants était de 57 ans (intervalle: 23-83 ans); 49,4% étaient des hommes et 50,6% des femmes. Dans notre cohorte, 58,9% ont eu besoin d'une ventilation mécanique à un moment ou à un autre de leur séjour et la durée médiane du séjour dans notre unité de soins intensifs était de 5 jours (intervalle: 1-36 jours). Parmi les personnes incluses, 25,9% sont sorties vivantes de notre hôpital lors de leur admission initiale, 57,6% ont été transférées dans un autre établissement et 16,5% sont décédées dans notre établissement. CONCLUSION: La COVID-19 a mis à rude épreuve les ressources de notre unité locale de soins intensifs, nécessitant un grand nombre de transferts de patients. Cependant, malgré des ressources limitées, les patients de notre site ont reçu des soins fondés sur des lignes directrices contemporaines pour la pneumonie due à la COVID-19. À l'avenir, la planification de la pandémie et de la capacité de pointe doit garantir que les communautés rurales et éloignées reçoivent des ressources supplémentaires adéquates pour répondre aux besoins anticipés de leurs populations locales.

Effect of manual hyperinflation on recurrent atelectasis in a ventilator-dependent C3 complete spinal cord injury patient: A case report.

CLINICAL CASE: We present here the case of a ventilator-dependent 76-year-old man with C3 complete spinal cord injury (SCI) who presented with recurrent left lung atelectasis managed with manual hyperinflation (MH). Atelectasis was primarily assessed with chest X-ray (CXR). Additional monitoring included blood gas analysis, serum procalcitonin, and the Modified Borg Dyspnea Scale (MBS), as an objective measure of reported dyspnea. We found that MH successfully reversed the radiographic appearance of atelectasis after the first treatment and maintained this effect for the duration of the 2-week intervention period as well as at 2 weeks of follow-up post-intervention. Furthermore, MH decreased the patient's oxygen requirements and was associated with a decrease in serum procalcitonin. Clinically, the patient reported reduced subjective dyspnea post-MH, which was reflected as an improvement on the MBS. We conclude that MH may represent a therapeutic modality for consideration in the routine management of recurrent atelectasis in mechanically ventilated patients.

Diversity of Reactive Astrogliosis in CNS Pathology: Heterogeneity or Plasticity?

Astrocytes are essential for the development and homeostatic maintenance of the central nervous system (CNS). They are also critical players in the CNS injury response during which they undergo a process referred to as "reactive astrogliosis." Diversity in astrocyte morphology and gene expression, as revealed by transcriptional analysis, is well-recognized and has been reported in several CNS pathologies, including ischemic stroke, CNS demyelination, and traumatic injury. This diversity appears unique to the specific pathology, with significant variance across temporal, topographical, age, and sex-specific variables. Despite this, there is limited functional data corroborating this diversity. Furthermore, as reactive astrocytes display significant environmental-dependent plasticity and fate-mapping data on astrocyte subsets in the adult CNS is limited, it remains unclear whether this diversity represents heterogeneity or plasticity. As astrocytes are important for neuronal survival and CNS function post-injury, establishing to what extent this diversity reflects distinct established heterogeneous astrocyte subpopulations vs. environmentally dependent plasticity within established astrocyte subsets will be critical for guiding therapeutic development. To that end, we review the current state of knowledge on astrocyte diversity in the context of three representative CNS pathologies: ischemic stroke, demyelination, and traumatic injury, with the goal of identifying key limitations in our current knowledge and suggesting future areas of research needed to address them. We suggest that the majority of identified astrocyte diversity in CNS pathologies to date represents plasticity in response to dynamically changing post-injury environments as opposed to heterogeneity, an important consideration for the understanding of disease pathogenesis and the development of therapeutic interventions.

BCG immunomodulation: From the 'hygiene hypothesis' to COVID-19.

The century-old tuberculosis vaccine BCG has been the focus of renewed interest due to its well-documented ability to protect against various non-TB pathogens. Much of these broad spectrum protective effects are attributed to trained immunity, the epigenetic and metabolic reprogramming of innate immune cells. As BCG vaccine is safe, cheap, widely available, amendable to use as a recombinant vector, and immunogenic, it has immense potential for use as an immunotherapeutic agent for various conditions including autoimmune, allergic, neurodegenerative, and neoplastic diseases as well as a preventive measure against infectious agents. Of particular interest is the use of BCG vaccination to counteract the increasing prevalence of autoimmune and allergic conditions in industrialized countries attributable to reduced infectious burden as described by the 'hygiene hypothesis.' Furthermore, BCG vaccination has been proposed as a potential therapy to mitigate spread and disease burden of COVID-19 as a bridge to development of a specific vaccine and recombinant BCG expression vectors may prove useful for the introduction of SARS-CoV-2 antigens (rBCG-SARS-CoV-2) to induce long-term immunity. Understanding the immunomodulatory effects of BCG vaccine in these disease contexts is therefore critical. To that end, we review here BCG-induced immunomodulation focusing specifically on BCG-induced trained immunity and how it relates to the 'hygiene hypothesis' and COVID-19.

Neuroprotective effects of a ketogenic diet in combination with exogenous ketone salts following acute spinal cord injury.

We have previously shown that induction of ketosis by ketogenic diet (KD) conveyed neuroprotection following spinal cord injury in rodent models, however, clinical translation may be limited by the slow raise of ketone levels when applying KD in the acute post-injury period. Thus we investigated the use of exogenous ketone supplementation (ketone sodium, KS) combined with ketogenic diet as a means rapidly inducing a metabolic state of ketosis following spinal cord injury in adult rats. In uninjured rats, ketone levels increased more rapidly than those in rats with KD alone and peaked at higher levels than we previously demonstrated for the KD in models of spinal cord injury. However, ketone levels in KD + KS treated rats with SCI did not exceed the previously observed levels in rats treated with KD alone. We still demonstrated neuroprotective effects of KD + KS treatment that extend our previous neuroprotective observations with KD only. The results showed increased neuronal and axonal sparing in the dorsal corticospinal tract. Also, better performance of forelimb motor abilities were observed on the Montoya staircase (for testing food pellets reaching) at 4 and 6 weeks post-injury and rearing in a cylinder (for testing forelimb usage) at 6 and 8 weeks post-injury. Taken together, the findings of this study add to the growing body of work demonstrating the potential benefits of inducing ketosis following neurotrauma. Ketone salt combined with a ketogenic diet gavage in rats with acute spinal cord injury can rapidly increase ketone body levels in the blood and promote motor function recovery. This study was approved by the Animal Care Committee of the University of British Columbia (protocol No. A14-350) on August 31, 2015.

Factors Within the Endoneurial Microenvironment Act to Suppress Tumorigenesis of MPNST.

Background: Deciphering avenues to adequately control malignancies in the peripheral nerve will reduce the need for current, largely-ineffective, standards of care which includes the use of invasive, nerve-damaging, resection surgery. By avoiding the need for en bloc resection surgery, the likelihood of retained function or efficient nerve regeneration following the control of tumor growth is greater, which has several implications for long-term health and well-being of cancer survivors. Nerve tumors can arise as malignant peripheral nerve sheath tumors (MPNST) that result in a highly-aggressive form of soft tissue sarcoma. Although the precise cause of MPNST remains unknown, studies suggest that dysregulation of Schwann cells, mediated by the microenvironment, plays a key role in tumor progression. This study aimed to further characterize the role of local microenvironment on tumor progression, with an emphasis on identifying factors within tumor suppressive environments that have potential for therapeutic application. Methods: We created GFP-tagged adult induced tumorigenic Schwann cell lines (iSCs) and transplanted them into various in vivo microenvironments. We used immunohistochemistry to document the response of iSCs and performed proteomics analysis to identify local factors that might modulate divergent iSC behaviors. Results: Following transplant into the skin, spinal cord or epineurial compartment of the nerve, iSCs formed tumors closely resembling MPNST. In contrast, transplantation into the endoneurial compartment of the nerve significantly suppressed iSC proliferation. Proteomics analysis revealed a battery of factors enriched within the endoneurial compartment, of which one growth factor of interest, ciliary neurotrophic factor (CNTF) was capable of preventing iSCs proliferation in vitro. Conclusions: This dataset describes a novel approach for identifying biologically relevant therapeutic targets, such as CNTF, and highlights the complex relationship that tumor cells have with their local microenvironment. This study has significant implications for the development of future therapeutic strategies to fight MPNSTs, and, consequently, improve peripheral nerve regeneration and nerve function.

Locomotor recovery following contusive spinal cord injury does not require oligodendrocyte remyelination.

Remyelination occurs after spinal cord injury (SCI) but its functional relevance is unclear. We assessed the necessity of myelin regulatory factor (Myrf) in remyelination after contusive SCI by deleting the gene from platelet-derived growth factor receptor alpha positive (PDGFRα-positive) oligodendrocyte progenitor cells (OPCs) in mice prior to SCI. While OPC proliferation and density are not altered by Myrf inducible knockout after SCI, the accumulation of new oligodendrocytes is largely prevented. This greatly inhibits myelin regeneration, resulting in a 44% reduction in myelinated axons at the lesion epicenter. However, spontaneous locomotor recovery after SCI is not altered by remyelination failure. In controls with functional MYRF, locomotor recovery precedes the onset of most oligodendrocyte myelin regeneration. Collectively, these data demonstrate that MYRF expression in PDGFRα-positive cell derived oligodendrocytes is indispensable for myelin regeneration following contusive SCI but that oligodendrocyte remyelination is not required for spontaneous recovery of stepping.

Adult skin-derived precursor Schwann cell grafts form growths in the injured spinal cord of Fischer rats.

In this study, GFP+ skin-derived precursor Schwann cells (SKP-SCs) from adult rats were grafted into the injured spinal cord of immunosuppressed rats. Our goal was to improve grafted cell survival in the injured spinal cord, which is typically low. Cells were grafted in hyaluronan-methylcellulose hydrogel (HAMC) or hyaluronan-methylcellulose modified with laminin- and fibronectin-derived peptide sequences (eHAMC). The criteria for selection of hyaluronan was for its shear-thinning properties, making the hydrogel easy to inject, methylcellulose for its inverse thermal gelation, helping to keep grafted cells in situ, and fibronectin and laminin to improve cell attachment and, thus, prevent cell death due to dissociation from substrate molecules (i.e., anoikis). Post-mortem examination revealed large masses of GFP+ SKP-SCs in the spinal cords of rats that received cells in HAMC (5 out of n = 8) and eHAMC (6 out of n = 8). Cell transplantation in eHAMC caused significantly greater spinal lesions compared to lesion and eHAMC only control groups. A parallel study showed similar masses in the contused spinal cord of rats after transplantation of adult GFP+ SKP-SCs without a hydrogel or immunosuppression. These findings suggest that adult GFP+ SKP-SCs, cultured/transplanted under the conditions described here, have a capacity for uncontrolled proliferation. Growth-formation in pre-clinical research has also been documented after transplantation of: human induced pluripotent stem cell-derived neural stem cells (Itakura et al 2015 PLoS One 10 e0116413), embryonic stem cells and embryonic stem cell-derived neurons (Brederlau et al 2006 Stem Cells 24 1433-40; Dressel et al 2008 PLoS One 3 e2622), bone marrow derived mesenchymal stem cells (Jeong et al 2011 Circ. Res. 108 1340-47) and rat nerve-derived SCs following in vitro expansion for >11 passages (Funk et al 2007 Eur. J. Cell Biol. 86 207-19; Langford et al 1988 J. Neurocytology 17 521-9; Morrissey et al 1991 J. Neurosci. 11 2433-42). It is of upmost importance to define the precise culture/transplantation parameters for maintenance of normal cell function and safe and effective use of cell therapy.

Neuroprotection and secondary damage following spinal cord injury: concepts and methods.

Neuroprotection refers to the attenuation of pathophysiological processes triggered by acute injury to minimize secondary damage. The development of neuroprotective treatments represents a major goal in the field of spinal cord injury (SCI) research. In this review, we discuss the strengths and limitations of the methodologies employed to assess secondary damage and neuroprotection in preclinical models of traumatic SCI. We also discuss modelling issues and how new tools might be exploited to study secondary damage and neuroprotection.