Reducing the burden of preventable deaths from sepsis in Canada: A need for a national sepsis action plan.

Sepsis is a global health threat with significant morbidity and mortality. Despite clinical practice guidelines and developed health systems, sepsis is often unrecognized or misdiagnosed, leading to preventable harm. In Canada, sepsis is responsible for 1 in 20 deaths and is a significant driver of health system costs. Despite being a signatory to the World Health Organization's Resolution WHA 70.7, adopted in 2017, Canada has not lived up to its commitment. Many existing sepsis policies were developed in response to a specific tragedy, and there is no national sepsis action plan. In this article, we describe the burden of sepsis, provide examples of existing, context-specific, reactionary sepsis policies, and urge a coordinated, proactive Canadian sepsis action plan to reduce the burden of sepsis.

Short-term outcomes of 43 dogs treated with arthroscopic suturing for meniscal tears associated with cranial cruciate ligament disease.

OBJECTIVE: To describe short-term outcomes and complications in dogs receiving meniscal suturing and concurrent tibial plateau leveling osteotomy (TPLO) with or without augmentation with an extracapsular suture. STUDY DESIGN: Retrospective case series. ANIMALS: Forty-three client-owned dogs submitted for cruciate ligament disease. METHODS: Dogs were included if meniscal suturing was performed during or after a TPLO procedure. Criteria included an unstable medial meniscus without evidence of a tear, a caudal vertical longitudinal tear with or without displacement, or if a bucket-handle tear was debrided and the remaining rim was unstable. Stifle stabilization was performed by either a standard TPLO or an augmented TPLO (TPLO + internal brace [IB]). Outcome measures included physical examination findings, radiographs, subjective gait examination, Liverpool Osteoarthritis in Dogs (LOAD) scores, and second-look arthroscopy. RESULTS: Forty-four meniscal repairs were performed in 43 dogs. Five types of meniscal tears were treated employing eight suture materials. Complications were documented in 15 cases (34%). The stabilization technique had a significant impact on the outcome (p = .049): TPLO + IB had a 93.3% success rate and the success rate was 71.4% in the TPLO-only group. CONCLUSION: Five types of meniscal pathology were addressed successfully in the study, indicating that currently accepted criteria for meniscal suturing in dogs may be overly conservative. The majority of complications were not related to the meniscal suturing itself and did not compromise the outcome. The stifle stabilization technique had an impact on outcome. CLINICAL SIGNIFICANCE: The authors found arthroscopic meniscal suturing to be practical and successful in this patient population. Postoperative stifle stability had an impact on successful treatment.

A retinoid analogue, TTNPB, promotes clonal expansion of human pluripotent stem cells by upregulating CLDN2 and HoxA1.

Enzymatic dissociation of human pluripotent stem cells (hPSCs) into single cells during routine passage leads to massive cell death. Although the Rho-associated protein kinase inhibitor, Y-27632 can enhance hPSC survival and proliferation at high seeding density, dissociated single cells undergo apoptosis at clonal density. This presents a major hurdle when deriving genetically modified hPSC lines since transfection and genome editing efficiencies are not satisfactory. As a result, colonies tend to contain heterogeneous mixtures of both modified and unmodified cells, making it difficult to isolate the desired clone buried within the colony. In this study, we report improved clonal expansion of hPSCs using a retinoic acid analogue, TTNPB. When combined with Y-27632, TTNPB synergistically increased hPSC cloning efficiency by more than 2 orders of magnitude (0.2% to 20%), whereas TTNPB itself increased more than double cell number expansion compared to Y-27632. Furthermore, TTNPB-treated cells showed two times higher aggregate formation and cell proliferation compared to Y-27632 in suspension culture. TTNPB-treated cells displayed a normal karyotype, pluripotency and were able to stochastically differentiate into all three germ layers both in vitro and in vivo. TTNBP acts, in part, by promoting cellular adhesion and self-renewal through the upregulation of Claudin 2 and HoxA1. By promoting clonal expansion, TTNPB provides a new approach for isolating and expanding pure hPSCs for future cell therapy applications.

Subcutaneous therapy for portal hypertension: PHIN-214, a partial vasopressin receptor 1A agonist.

Cirrhosis is a liver disease that leads to increased intrahepatic resistance, portal hypertension (PH), and splanchnic hyperemia resulting in ascites, variceal bleeding, and hepatorenal syndrome. Terlipressin, a prodrug that converts to a short half-life vasopressin receptor 1 A (V1a) full agonist [8-Lys]-Vasopressin (LVP), is an intravenous treatment for PH complications, but hyponatremia and ischemic side effects require close monitoring. We developed PHIN-214 which converts into PHIN-156, a more biologically stable V1a partial agonist. PHIN-214 enables once-daily subcutaneous administration without causing ischemia or tissue necrosis and has a 10-fold higher therapeutic index than terlipressin in healthy rats. As V1a partial agonists, PHIN-214 and PHIN-156 exhibited maximum activities of 28 % and 42 % of Arginine vasopressin (AVP), respectively. The potency of PHIN-156 and LVP relative to AVP is comparable for V1a (5.20 and 1.65 nM, respectively) and V1b (102 and 115 nM, respectively) receptors. However, the EC50 of PHIN-156 to the V2 receptor was 26-fold higher than that of LVP, indicating reduced potential for dilutional hyponatremia via V2 agonism compared to terlipressin/LVP. No significant off-target binding to 87 toxicologically relevant receptors were observed when evaluated in vitro at 10 µM concentration. In bile duct ligated rats with PH, subcutaneous PHIN-214 reduced portal pressure by 13.4 % ± 3.4 in 4 h. These collective findings suggest that PHIN-214 could be a novel pharmacological treatment for patients with PH, potentially administered outside of hospital settings, providing a safe and convenient alternative for managing PH and its complications.

Transition of care in CHD: a single-centre experience: an enigma remains.

Transition of care refers to the continuity of health care during the movement from one healthcare setting to another as care needs change during a chronic illness. We sought to describe social, demographic, and clinical factors related to successful transition in a tertiary urban care facility in patients with CHD. Patients were identified utilising the electronic medical record. Inclusion criteria were patients with CHDs aged ≥15 years seen in the paediatric cardiology clinic between 2013 and 2014. Deceased patients were excluded. Clinical and demographic variables were collected. Patient charts were reviewed in 2015-2021 to determine if included patients were a) still in paediatric cardiology care, b) transitioned to adult cardiology/adult CHD, or were c) lost to follow-up. A total of 322 patients, 53% male (N:172), 46% female (N:149) were included. Majority had moderately complex lesions (N:132, 41%). Most patients had public insurance (N:172, 53%), followed by private insurance (N:67, 21%), while 15% of patients (N:47) were uninsured. Only 49% (N = 159) had successful transition, while 22% (N = 70) continued in care with paediatric cardiology, and 29% (N = 93) were lost to follow-up. Severity of CHD (p = 0.0002), having healthcare insurance (p < .0001), presence of a defibrillator (p = 0.0028), and frequency of paediatric cardiology visits (p = 0.0005) were significantly associated with successful transition. Most patients lost to follow-up (N:42,62%) were either uninsured or had public insurance. Lack of successful transition is multifactorial, and further efforts are needed to improve the process in patients with CHD.

Distance Traveled by Patients Globally to Access Radiation Therapy: A Systematic Review.

PURPOSE: This study aimed to systematically review the literature on the travel patterns of patients seeking radiation therapy globally. It examined the distance patients travel for radiation therapy as well as secondary outcomes, including travel time. METHODS AND MATERIALS: A comprehensive search of 4 databases was conducted from June 2022 to August 2022. Studies were included in the review if they were observational, retrospective, randomized/nonrandomized, published between June 2000 and June 2022, and if they reported on the global distance traveled for radiation therapy in the treatment of malignant or benign disease. Studies were excluded if they did not report travel distance or were not written in English. RESULTS: Of the 168 studies, most were conducted in North America (76.3%), with 90.7% based in the United States. Radiation therapy studies for treating patients with breast cancer were the most common (26.6%), while external beam radiation therapy was the most prevalent treatment modality (16.6%). Forty-six studies reported the mean distance traveled for radiation therapy, with the shortest being 4.8 miles in the United States and the longest being 276.5 miles in Iran. It was observed that patients outside of the United States traveled greater distances than those living within the United States. Geographic location, urban versus rural residence, and patient population characteristics affected the distance patients traveled for radiation therapy. CONCLUSIONS: This systematic review provides the most extensive summary to date of the travel patterns of patients seeking radiation therapy globally. The results suggest that various factors may contribute to the variability in travel distance patterns, including treatment center location, patient residence, and treatment modality. Overall, the study highlights the need for more research to explore these factors and to develop effective strategies for improving radiation therapy access and reducing travel burden.

A Case of Thoracic Epidural Angiolipoma Causing Severe Spinal Cord Compression With Neurologic Manifestations.

A spinal epidural angiolipoma is a rare, benign tumor of adipocytes and blood vessels that accounts only for a small percentage of all spinal axis tumors. We report a case of a 44-year-old male who presented with three months of progressive decreased sensation and strength from about six cm above the umbilicus down to his feet bilaterally. He presented to the emergency room when he could no longer walk. He also had neurogenic urinary retention and likely neurogenic constipation. Physical exam was notable for decreased sensation, decreased strength, and increased patellar reflexes bilaterally. MRI of the thoracic spine showed a posterior epidural mass that spanned from T2 to T3, measuring 1.2 x 1.7 x 4.3 cm, and severely compressed the spinal cord posteriorly. The patient underwent an urgent laminectomy for decompression and mass resection. Pathology was consistent with an angiolipoma. Postoperatively, he experienced a drastic improvement in strength and gross motor skills. The sensation had a partial return following surgery and continued to improve over the hospital stay. In general, the literature reports significant symptomatic improvement in patients with spinal epidural angiolipomas after surgical resection.

Quantitative proteomics and phosphoproteomics of PP2A-PPP2R5D variants reveal deregulation of RPS6 phosphorylation via converging signaling cascades.

Genetic germline variants of PPP2R5D (encoding: phosphoprotein phosphatase 2 regulatory protein 5D) result in PPP2R5D-related disorder (Jordan's Syndrome), which is characterized by intellectual disability, hypotonia, seizures, macrocephaly, autism spectrum disorder, and delayed motor skill development. The disorder originates from de novo single nucleotide mutations, generating missense variants that act in a dominant manner. Pathogenic mutations altering 13 different amino acids have been identified, with the E198K variant accounting for ∼40% of reported cases. However, the generation of a heterozygous E198K variant cell line to study the molecular effects of the pathogenic mutation has been challenging. Here, we use CRISPR-PRIME genomic editing to introduce a transition (c.592G>A) in a single PPP2R5D allele in HEK293 cells, generating E198K-heterozygous lines to complement existing E420K variant lines. We generate global protein and phosphorylation profiles of WT, E198K, and E420K cell lines and find unique and shared changes between variants and WT cells in kinase- and phosphatase-controlled signaling cascades. We observed ribosomal protein S6 (RPS6) hyperphosphorylation as a shared signaling alteration, indicative of increased ribosomal protein S6-kinase activity. Treatment with rapamycin or an RPS6-kinase inhibitor (LY2584702) suppressed RPS6 phosphorylation in both, suggesting upstream activation of mTORC1/p70S6K. Intriguingly, our data suggests ERK-dependent activation of mTORC1 in both E198K and E420K variant cells, with additional AKT-mediated mTORC1 activation in the E420K variant. Thus, although upstream activation of mTORC1 differs between PPP2R5D-related disorder genotypes, inhibition of mTORC1 or RPS6 kinases warrants further investigation as potential therapeutic strategies for patients.

Diagnosis and Management of Aortic Dissection in a Pediatric Patient With Turner Syndrome: A Simulation.

Aortic dissection is exceedingly rare in the pediatric population. However, it is much more common among children and adolescents with certain underlying syndromes, including Turner syndrome. Furthermore, aortic dissection carries significant mortality without prompt diagnosis and management. Therefore, pediatric emergency providers should know how to recognize and treat pediatric aortic dissection in a patient with Turner syndrome. We designed this simulation for pediatric emergency medicine fellows. A simulated adolescent female patient with a known history of Turner syndrome presents with chest pain, tachycardia, and hypertension. Participants must order and interpret the appropriate diagnostics, diagnose aortic dissection, and manage aortic dissection adequately. This simulation was completed by six pediatric emergency medicine fellows and one pediatric resident. After completing the simulation, six participants (85.7%) provided anonymous feedback on a five-point Likert scale (one = strongly disagree, five = strongly agree). Feedback was positive, and participants agreed that the case content was relevant to their clinical practice and that the event will improve their clinical practice. This simulation encourages participants to recognize and manage pediatric aortic dissection in patients with Turner syndrome. Participants felt that the simulation was relevant and will improve their clinical practice.

Ex vivo evaluation of arthroscopically assisted shoulder stabilization in dogs using an intra-articular aiming device.

OBJECTIVE: To evaluate the use of an intra-articular aiming device (IAD) for medial shoulder stabilization with a suture-toggle repair or an interference screw repair using bone anchors in dogs. STUDY DESIGN: Ex-vivo Study METHODS: Specimens were randomly divided into 2 groups (anchor and suture-toggle) with 10 shoulders each. Abduction angles were measured by goniometry prior to and following medial glenerohumeral ligament transection and after receiving arthroscopically assisted stabilization with either bone anchors or suture-toggle constructs. Bone stock and insertion angles were measured with computed tomography scans. All specimens were inspected by dissection. RESULTS: Abduction angles increased post-transection in both groups, and were restored to normal in the anchor group, but 2° smaller than normal in the suture-toggle group following stabilization. Median magnitude of bone stock surrounding all tunnels ranged between 5.9 and 12.9 mm in the anchor group and 8.8 and 15.6 mm in the suture-toggle group (p = .002). Median insertion angles at the cranial glenoid, caudal glenoid, and humerus were 17.3°, 36.8 ° and 43.4° in the anchor group, respectively, and median insertion angles at the glenoid and humerus were 38.2° and 35.6° in the suture-toggle group, respectively (p = .91). Placement of anchors were not feasible in 3 specimens in the anchor group, and mild violations of the articular surfaces were detected in 3 specimens overall. CONCLUSION: Arthroscopically assisted shoulder stabilization with an IAD was feasible in canine cadavers. CLINICAL SIGNIFICANCE: An IAD may facilitate arthroscopic shoulder stabilization in dogs. Further studies are warranted to evaluate safety and efficacy in a clinical setting.

Intralesional application of ribavirin in two American flamingos (Phoenicopterus ruber) with poxvirus infection.

We report the successful treatment of poxvirus lesions in two juvenile American flamingos (Phoenicopterus ruber) with experimental low-dose intralesional ribavirin injection. In the first flamingo, the size and location of a beak verrucosity interfered with feeding, and after multiple surgical interventions, an experimental therapy of low-dose intralesional ribavirin was implemented with close blood parameter monitoring to minimize any potential side effects due to systemic antiviral administration. The second flamingo had a poxvirus lesion on the tibiotarsus, which recurred after unsuccessful conservative medical treatment and surgical intervention and a course of intralesional ribavirin therapy was implemented. Regression of the lesions in both flamingos commenced within 3 days of ribavirin treatment resulting in complete resolution within 6 weeks of onset of ribavirin treatment.

A Mass Spectrometry-Based Approach to Identify Phosphoprotein Phosphatases and their Interactors.

Most cellular processes are regulated by dynamic protein phosphorylation. More than three-quarters of proteins are phosphorylated, and phosphoprotein phosphatases (PPPs) coordinate over 90% of all cellular serine/threonine dephosphorylation. Deregulation of protein phosphorylation has been implicated in the pathophysiology of various diseases, including cancer and neurodegeneration. Despite their widespread activity, the molecular mechanisms controlling PPPs and those controlled by PPPs are poorly characterized. Here, a proteomic approach termed phosphatase inhibitor beads and mass spectrometry (PIB-MS) is described to identify and quantify PPPs, their posttranslational modifications, and their interactors in as little as 12 h using any cell line or tissue. PIB-MS utilizes a non-selective PPP inhibitor, microcystin-LR (MCLR), immobilized on sepharose beads to capture and enrich endogenous PPPs and their associated proteins (termed the PPPome). This method does not require the exogenous expression of tagged versions of PPPs or the use of specific antibodies. PIB-MS offers an innovative way to study the evolutionarily conserved PPPs and expand our current understanding of dephosphorylation signaling.

European LeukemiaNet-defined primary refractory acute myeloid leukemia: the value of allogeneic hematopoietic stem cell transplant and overall response.

We sought to appraise the value of overall response and salvage chemotherapy, inclusive of allogeneic hematopoietic stem cell transplant (AHSCT), in primary refractory acute myeloid leukemia (prAML). For establishing consistency in clinical practice, the 2017 European LeukemiaNet (ELN) defines prAML as failure to attain CR after at least 2 courses of intensive induction chemotherapy. Among 60 consecutive patients (median age 63 years) correspondent with ELN-criteria for prAML, salvage was documented in 48 cases, 30/48 (63%) being administered intensive chemotherapy regimens and 2/48 consolidated with AHSCT as first line salvage. 13/48 (27%) attained response: CR, 7/13 (54%), CRi, 2/13 (15%), MLFS, 4/13 (31%). The CR/CRi rate was 9/48 (19%), with CR rate of 7/48 (15%). On univariate analysis, intermediate-risk karyotype was the only predictor of response (44% vs 17% in unfavorable karyotype; P = 0.04). Administration of any higher-dose (>1 g/m2) cytarabine intensive induction (P = 0.50), intensive salvage chemotherapy (P = 0.72), targeted salvage (FLT3 or IDH inhibitors) (P = 0.42), greater than 1 salvage regimen (P = 0.89), age < 60 years (P = 0.30), and de novo AML (P = 0.10) did not enhance response achievement, nor a survival advantage. AHSCT was performed in 12 patients with (n = 8) or without (n = 4) CR/CRi/MLFS. 1/2/5-year overall survival (OS) rates were 63%/38%/33% in patients who received AHSCT (n = 12) vs 27%/0%/0% in those who achieved CR/CRi/MLFS but were not transplanted (n = 5), vs 14%/0%/0% who were neither transplanted nor achieved CR/CRi/MLFS (n = 43; P < 0.001); the median OS was 18.6, 12.6 and 5.6 months, respectively. Although CR/CRi/MLFS bridged to AHSCT (n = 8), appeared to manifest a longer median OS (20 months), vs (13.4 months) for those with no response consolidated with AHSCT (n = 4), the difference was not significant P = 0.47. We conclude AHSCT as indispensable for securing long-term survival in prAML (p = 0.03 on multivariate analysis), irrespective of response achievement.

PERINATAL CENTRILOBULAR HEPATIC NECROSIS IN GIANT PANDAS (AILUROPODA MELANOLEUCA): A RETROSPECTIVE STUDY.

Between 1983 and 2012, six giant panda cubs (Ailuropoda melanoleuca) born at a zoological institution were stillborn or died between the ages of 3 and 200 h. Two of the six cubs had panhepatic centrilobular hepatic necrosis (CHN), granulocytic extramedullary hematopoiesis (GEM), positive liver culture for Staphylococcus species, and terminal liver failure. Another low-weight cub was administered oxygen therapy immediately after birth and developed hyaline membranes in air spaces and hepatic necrosis restricted to the hilar region. A retrospective analysis of liver and lung lesions, pulmonary microanatomy, blood-gas barrier ultrastructure, and hepatic myofibroblast proliferation was conducted on the six cubs. Neonates with CHN had concurrent severe periportal GEM accompanied by severe myofibroblast proliferation. The pulmonary blood-gas barrier was markedly increased in one cub with CHN. Developmentally, the lungs of all but one cub were at the late saccular stage, and the lowest-weight cub was in early saccular stage, consistent with immaturity, and had pneumonia comparable to neonatal respiratory distress syndrome (RDS). Stage of lung development was eliminated as the primary factor leading to CHN. The pathogenesis of CHN in these neonates is proposed to be transformation of hepatic stellate cells to myofibroblasts initiating blockage and microvascular constriction of hepatic sinusoids, resulting in insufficient perfusion and cellular hypoxia of hepatocytes surrounding central veins in acinar zone 3.

Overview of the Therapeutic Applications of Stem Cell-Derived Exosomes: A Research and Commercial Perspective.

Progress in extracellular vesicle (EV) research over the past two decades has generated significant interest in using EVs in the biomedical field. Exosomes are a subgroup of EVs that comprise endocytic membrane-bound nanovesicles of 40 to 160 nm diameter. These vesicles have been shown to facilitate intercellular communication via the delivery of cellular molecules. There are currently several exciting applications for exosomes being developed in therapeutics, diagnostics, drug delivery, and cellular reprogramming. Stem cell-derived exosomes present the opportunity to harness the power of stem cells while circumventing several of the risks associated with their use. This review summarizes the recent developments in exosome technology and lends a prospective view to the future of exosome use and application in research and medicine. Through a review of relevant patent filings, recent literature, and ongoing clinical trials, a valuable overview of the field of exosomes is provided. © 2021 Wiley Periodicals LLC.

White-nose syndrome: A novel dermatomycosis of biologic interest and epidemiologic consequence.

Over the past 10 years, the environmental and veterinary communities have sounded alarms over an insidious keratinophilous fungus, Pseudogymnoascus destructans, that has decimated populations of bats (yes, bats, chiropterans) throughout North America and, most recently, Northern China and Siberia. We as dermatologists may find this invasive keratinophilous fungus of particular interest, as its method of destruction is disruption of the homeostatic mechanism of the bat wing integument. Although it is unlikely that this pathogen will become an infectious threat to humans, its environmental impact will likely affect us all, especially as recent data have shown upregulation of naturally occurring coronaviruses in coinfected bats. Dermatologists are familiar with keratinophilous dermatophyte infections, but these rarely cause serious morbidity in individual patients and never cause crisis on a population basis. This contribution describes the effects of P destructans on both the individual and the population basis. Bringing the white-nose syndrome to the attention of human dermatologists and skin scientists may invite transfer of expertise in understanding the disease, its pathophysiology, epidemiology, treatment, and prevention.

SPINAL NEMATODIASIS IN A LINED FLAT-TAIL GECKO (UROPLATUS LINEATUS).

A 5-y-old female lined flat-tail gecko (Uroplatus lineatus) presented for acute onset of lethargy and paraplegia and was subsequently euthanized. Histologic examination of the spinal cord revealed a verminous myelitis comprising moderate, multifocal, necrotizing myelitis with intramedullary adult and larval nematodes. Molecular data and morphology indicate a cosmocercid nematode, most likely of the genus Raillietnema, a diverse taxon reported to parasitize reptiles, amphibians, and teleost fish. To the authors' knowledge this is the first report of spinal nematodiasis in a reptile species, and the first report of spinal parasitism causing hind-limb paraplegia in a reptile.

Aberrated supraventricular tachycardia associated with neonatal fever and COVID-19 infection.

A 9-day-old girl presented during the 2020 SARS-CoV-2 pandemic in wide-complex tachycardia with acute, symptomatic COVID-19 infection. Because the potential cardiac complications of COVID-19 were unknown at the time of her presentation, we chose to avoid the potential risks of haemodynamic collapse associated with afterload reduction from adenosine. Instead, a transoesophageal pacing catheter was placed. Supraventricular tachycardia (SVT) with an aberrated QRS morphology was diagnosed and the catheter was used to pace-terminate tachycardia. This presentation illustrates that the haemodynamic consequences of a concurrent infection with largely unknown neonatal sequelae present a potentially high-risk situation for pharmacologic conversion. Oesophageal cannulation can be used to diagnose and terminate infantile SVT.