Hypoxia Promotes Atrial Tachyarrhythmias via Opening of ATP-Sensitive Potassium Channels.

BACKGROUND: Hypoxia-ischemia predisposes to atrial arrhythmia. Atrial ATP-sensitive potassium channel (KATP) modulation during hypoxia has not been explored. We investigated the effects of hypoxia on atrial electrophysiology in mice with global deletion of KATP pore-forming subunits. METHODS: Whole heart KATP RNA expression was probed. Whole-cell KATP current and action potentials were recorded in isolated wild-type (WT), Kir6.1 global knockout (6.1-gKO), and Kir6.2 global knockout (6.2-gKO) murine atrial myocytes. Langendorff-perfused hearts were assessed for atrial effective refractory period (ERP), conduction velocity, wavefront path length (WFPL), and arrhymogenicity under normoxia/hypoxia using a microelectrode array and programmed electrical stimulation. Heart histology was assessed. RESULTS: Expression patterns were essentially identical for all KATP subunit RNA across human heart, whereas in mouse, Kir6.1 and SUR2 (sulphonylurea receptor subunit) were higher in ventricle than atrium, and Kir6.2 and SUR1 were higher in atrium. Compared with WT, 6.2-gKO atrial myocytes had reduced tolbutamide-sensitive current and action potentials were more depolarized with slower upstroke and reduced peak amplitude. Action potential duration was prolonged in 6.1-gKO atrial myocytes, absent of changes in other ion channel gene expression or atrial myocyte hypertrophy. In Langendorff-perfused hearts, baseline atrial ERP was prolonged and conduction velocity reduced in both KATP knockout mice compared with WT, without histological fibrosis. Compared with baseline, hypoxia led to conduction velocity slowing, stable ERP, and WFPL shortening in WT and 6.1-gKO hearts, whereas WFPL was stable in 6.2-gKO hearts due to ERP prolongation with conduction velocity slowing. Tolbutamide reversed hypoxia-induced WFPL shortening in WT and 6.1-gKO hearts through ERP prolongation. Atrial tachyarrhythmias inducible with programmed electrical stimulation during hypoxia in WT and 6.1-gKO mice correlated with WFPL shortening. Spontaneous arrhythmia was not seen. CONCLUSIONS: KATP block/absence leads to cellular and tissue level atrial electrophysiological modification. Kir6.2 global knockout prevents hypoxia-induced atrial WFPL shortening and atrial arrhythmogenicity to programmed electrical stimulation. This mechanism could be explored translationally to treat ischemically driven atrial arrhythmia.

BET Inhibition Sensitizes Immunologically Cold Rb-Deficient Prostate Cancer to Immune Checkpoint Blockade.

Non-T-cell-inflamed immunologically "cold" tumor microenvironments (TME) are associated with poor responsiveness to immune checkpoint blockade (ICB) and can be sculpted by tumor cell genomics. Here, we evaluated how retinoblastoma (Rb) tumor-suppressor loss-of-function (LOF), one of the most frequent alterations in human cancer and associated with lineage plasticity, poor prognosis, and therapeutic outcomes, alters the TME, and whether therapeutic strategies targeting the molecular consequences of Rb loss enhance ICB efficacy. We performed bioinformatics analysis to elucidate the impact of endogenous Rb LOF on the immune TME in human primary and metastatic tumors. Next, we used isogenic murine models of Rb-deficient prostate cancer for in vitro and in vivo mechanistic studies to examine how Rb loss and bromodomain and extraterminal (BET) domain inhibition (BETi) reprograms the immune landscape, and evaluated in vivo therapeutic efficacy of BETi, singly and in combination with ICB and androgen deprivation therapy. Rb loss was enriched in non-T-cell-inflamed tumors, and Rb-deficient murine tumors demonstrated decreased immune infiltration in vivo. The BETi JQ1 increased immune infiltration into the TME through enhanced tumor cell STING/NF-κB activation and type I IFN signaling within tumor cells, resulting in differential macrophage and T-cell-mediated tumor growth inhibition and sensitization of Rb-deficient prostate cancer to ICB. BETi can reprogram the immunologically cold Rb-deficient TME via STING/NF-κB/IFN signaling to sensitize Rb-deficient prostate cancer to ICB. These data provide the mechanistic rationale to test combinations of BETi and ICB in clinical trials of Rb-deficient prostate cancer.

Association of Primary Versus Rotating Nephrologist Model of Care in Hemodialysis Programs with Patient Outcomes.

SIGNIFICANCE STATEMENT: Nephrologist staffing models for patients receiving hemodialysis vary widely. Patients may be cared for continuously by a single primary nephrologist or by a group of nephrologists on a rotating basis. It remains unclear whether these differing care models influence clinical outcomes. In this population-based cohort study of more than 14,000 incident patients on maintenance hemodialysis from Ontario, Canada, we found no difference in mortality, kidney transplantation, home dialysis initiation, hospitalizations, or emergency department visits when care was provided by a single primary nephrologist or a rotating group of nephrologists. These results suggest that primary nephrologist models do not necessarily improve objective clinical outcomes, providing reassurance to patients, providers, and administrators that both models are acceptable options.

Changes in suspected adverse drug reaction reporting via the yellow card scheme in Wales following the introduction of a National Reporting Indicator.

AIMS: This study aimed to assess the impact of a National Reporting Indicator (NRI) on rates of reporting of suspected adverse drug reactions using the Yellow Card scheme following the introduction of the NRI in Wales (UK) in April 2014. METHODS: Yellow Card reporting data for general practitioners and other reporting groups in Wales and England for the financial years 2014-15 (study period 1) and 2015-16 (study period 2) were obtained from the Medicines and Healthcare Products Regulatory Agency and compared with those for 2013-14 (pre-NRI control period). RESULTS: The numbers of Yellow Cards submitted by general practitioners in Wales were 271, 665 and 870 in the control period, study period 1 and study period 2, respectively. This is equivalent to an increase of 145% in study period 1 and 221% in study period 2 compared with the 12-month control period (2013-14). Corresponding increases in England were 17% and 37%, respectively (P < .001 chi-squared test). The numbers of Yellow Cards submitted by other groups in Wales were 906, 795 and 947 in each of the study periods. CONCLUSIONS: Introduction of the NRI corresponded with a significant increase in the number of Yellow Cards submitted by general practitioners in Wales. General practitioner reporting rates continued to increase year on year through to 2018-19 with the NRI still in place. No concomitant change was found in reporting rates by other groups in the health boards in Wales.

Development and validation of a constipation treatment toolkit for patients on hemodialysis.

INTRODUCTION: The cause of constipation is multifactorial and common problem for patients on hemodialysis. A lack of strong evidence on suitable treatment strategies means there is an unorganized approach to selecting therapies, which can exacerbate constipation or worsen symptoms. Clinicians and patients would benefit from a content and face validated treatment algorithm for treating constipation. In this study, our objective was to develop and content and face validate a constipation treatment toolkit for patients on hemodialysis, consisting of treatment algorithm, and patient information tools (pamphlet and video). METHODS: Literature searches were performed to develop an initial toolkit using Lynn's method for developing content-valid clinical tools. Content and face validity were evaluated as per Lynn's method for determining content validity; the algorithm was evaluated by Canadian nephrology clinicians, while patient information tools were evaluated by clinicians and patients. Components were rated on a Likert scale for content relevance and on a 5-point scale for face validity. After each round, the content validity index (CVI) score was calculated and revisions were made based on feedback. FINDINGS: A total of 23 clinicians and 15 patients were interviewed across three validation rounds. After three rounds, the treatment algorithm achieved content (overall CVI = 0.93) and face (91% agreement) validity. Our patient information tools achieved content and face validity (pamphlet overall CVI = 0.99, 85.5% agreement; video overall CVI = 0.99, 90.5% agreement). DISCUSSION: A treatment algorithm and patient information toolkit for the treatment of constipation in patients on hemodialysis were content and face validated via expert review. Further research will be needed to ascertain the effectiveness and implementation of this toolkit.

Public awareness in Wales of the UK Yellow Card scheme for reporting suspected adverse drug reactions.

We used the HealthWise Wales (HWW) platform to explore public knowledge about the UK Yellow Card scheme (YCS), the spontaneous reporting scheme for suspected adverse drug reactions (ADRs) and whether a short information video could improve awareness. Members of the public in Wales (n = 1606) completed a questionnaire about the YCS, watched the information video and then completed a follow-up questionnaire. Almost half (46.5%) of respondents said they had previously experienced an ADR (>90% of the ADRs involving prescribed medicines). Before the video, 18% of respondents knew how to report an ADR via the YCS and of these, 34% were from allied-health professions. Immediately after watching it, 71% participants reported knowing how to report and 82% reported being confident to report. If this awareness were maintained, such an approach could contribute to improved reporting of suspected ADRs by the public.

Fit for Dialysis: a prospective 2-site parallel intervention trial of a filmed research-based drama to increase exercise amongst older hemodialysis patients.

PURPOSE: The present study aimed to evaluate the impact of a filmed research-based drama-Fit for Dialysis-and an exercise program on patients' physical activity and fitness outcomes. METHODS: Nineteen (10 at the intervention site, 9 at the control site) older patients with a medical diagnosis of hemodialysis-dependent end-stage renal disease were recruited from two acute care hospitals in urban central Canada where they were receiving out-patient hemodialysis care. Participants at the intervention site viewed Fit for Dialysis prior to participating in a 16-week exercise program. Participants at the control site participated only in the 16-week exercise program. Physical activity, measured by total intradialytic exercise time (TIDE), and physical fitness, measured by the Two-Minute Walk Test (2MWT). Secondary measures included: Timed Up and Go (TUG), Grip Strength, Duke Activity Status Index (DASI), Godin Leisure-Time Exerciser Questionnaire (GLTEQ), and pedometer step count. RESULTS: TIDE, TUG, and GLTEQ were better at the intervention site compared to the control site at all time points measured. However, the change over time was not different between the sites. The 2MWT improved over time at the intervention site for those who exercised consistently. No significant differences between sites, or over time were found for any of the other measures. CONCLUSIONS: Further research is needed to determine the effectiveness of this intervention to facilitate the incorporation of exercise into the care and treatment of HD patients.

An Environmental Scan of Canadian Quality Metrics for Patients on In-Center Hemodialysis.

BACKGROUND: Quality metrics or indicators help guide quality improvement work by reporting on measurable aspects of health care upon which improvement efforts can focus. For recipients of in-center hemodialysis (ICHD) in Canada, it is unclear what ICHD quality indicators exist and whether they adequately cover different domains of health care quality. OBJECTIVES: To identify and evaluate current Canadian ICHD quality metrics to document a starting point for future collaborations and standardization of quality improvement in Canada. DESIGN: Environmental scan of quality metrics in ICHD, and subsequent indicator evaluation using a modified Delphi approach. SETTING: Canadian ICHD units. PARTICIPANTS: Sixteen-member pan-Canadian working group with expertise in ICHD and quality improvement. MEASUREMENTS: We classified the existing indicators based on the Institute of Medicine (IOM) and Donabedian frameworks. METHODS: Each metric was rated by a 5-person subcommittee using a modified Delphi approach based on the American College of Physicians/Agency for Healthcare Research and Quality criteria. We shared these consensus ratings with the entire 16-member panel for additional comments. RESULTS: We identified 27 metrics that are tracked across 8 provinces, with only 9 (33%) tracked by multiple provinces (ie, more than 1 province). We rated 9 metrics (33%) as "necessary" to distinguish high-quality from low-quality care, of which only 2 were tracked by multiple provinces (proportion of patients by primary access and rate of vascular access-related bloodstream infections). Most (16/27, 59%) indicators assessed the IOM domains of safe or effective care, and none of the "necessary" indicators measured the IOM domains of timely, patient-centered, or equitable care. LIMITATIONS: The environmental scan is a nonexhaustive list of quality indicators in Canada. The panel also lacked representation from patients, administrators, and allied health professionals, with more representation from academic sites. CONCLUSIONS: Quality indicators in Canada mainly focus on safe and effective care, with little provincial overlap. These results highlight current gaps in quality of care measurement for ICHD, and this initial work should provide programs with a starting point to combine highly rated indicators with newly developed indicators into a concise balanced scorecard that supports quality improvement initiatives across all aspects of ICHD care. TRIAL REGISTRATION: not applicable.

CONTEXTE: Les mesures ou indicateurs de la qualité contribuent à guider les travaux d'amélioration de la qualité des soins de santé en indiquant les aspects mesurables sur lesquels les efforts peuvent se concentrer. On connait peu les indicateurs de la qualité existant au Canada pour les bénéficiaires de l'hémodialyse en centre (HDC). On ignore également si ces indicateurs couvrent adéquatement les différents domaines de la qualité des soins de santé. OBJECTIFS: Définir et évaluer les mesures actuelles de la qualité des soins d'HDC au Canada. Ces travaux serviront à documenter le point de départ de futures collaborations et la normalisation de l'amélioration de la qualité au Canada. TYPE D'ÉTUDE: Analyse contextuelle des mesures de la qualité en HDC, suivie de leur évaluation par une méthode Delphi modifiée. CADRE: Des unités d'HDC au Canada. SUJETS: Un groupe de travail pancanadien constitué de 16 membres ayant une expertise en HDC et en amélioration de la qualité. MESURES: Les indicateurs existants ont été évalués à l'aide des modèles de l'IOM (Institute of Medicine) et de Donabedian. MÉTHODOLOGIE: Chaque indicateur a été évalué par un sous-comité de cinq personnes à l'aide d'une méthode Delphi modifiée basée sur les critères de l'American College of Physicians/Agency for Healthcare Research and Quality. Les évaluations consensuelles ont été partagées avec l'ensemble des 16 membres pour recueillir des commentaires supplémentaires. RÉSULTATS: Nous avons répertorié 27 indicateurs suivis dans 8 provinces, dont 9 (33 %) sont suivis dans plus d'une province. Neuf indicateurs (33 %) ont été classés comme « nécessaires ¼ pour départager les soins de haute qualité des soins de faible qualité, dont seulement deux (la proportion de patients selon l'accès primaire et le taux de bactériémies liées à l'accès vasculaire) sont suivis par plusieurs provinces. La majorité des indicateurs (16/27; 59 %) a évalué les domaines de l'IOM relatifs aux soins sûrs ou efficaces; aucun des indicateurs « nécessaires ¼ n'a mesuré les domaines de l'IOM relatifs aux soins opportuns, centrés sur le patient ou équitables. LIMITES: Au Canada, l'analyse contextuelle consiste en une liste non exhaustive d'indicateurs de la qualité. Le groupe de travail manquait de représentants des patients, des administrateurs et des professionnels paramédicaux, les sites universitaires étant mieux représentés. CONCLUSION: Au Canada, les indicateurs de la qualité se concentrent principalement sur la prestation de soins sûrs et efficaces, et les chevauchements entre les provinces sont rares. Ces résultats mettent en évidence les lacunes actuelles dans l'évaluation de la qualité des soins d'HDC. Ces travaux préliminaires devraient fournir aux programmes un point de départ pour combiner des indicateurs bien cotés à d'autres nouvellement développés dans une fiche d'évaluation concise destinée à soutenir les initiatives d'amélioration de la qualité dans tous les aspects des soins entourant l'HDC. ENREGISTREMENT DE L'ESSAI: Sans objet.

Anatomical Variations of the Recurrent Laryngeal Nerve and Implications for Injury Prevention during Surgical Procedures of the Neck.

Accurate knowledge of anatomical variations of the recurrent laryngeal nerve (RLN) provides information to prevent inadvertent intraoperative injury and ultimately guide best clinical and surgical practices. The present study aims to assess the potential anatomical variability of RLN pertaining to its course, branching pattern, and relationship to the inferior thyroid artery, which makes it vulnerable during surgical procedures of the neck. Fifty-five formalin-fixed cadavers were carefully dissected and examined, with the course of the RLN carefully evaluated and documented bilaterally. Our findings indicate that extra-laryngeal branches coming off the RLN on both the right and left side innervate the esophagus, trachea, and mainly intrinsic laryngeal muscles. On the right side, 89.1% of the cadavers demonstrated 2-5 extra-laryngeal branches. On the left, 74.6% of the cadavers demonstrated 2-3 extra-laryngeal branches. In relation to the inferior thyroid artery (ITA), 67.9% of right RLNs were located anteriorly, while 32.1% were located posteriorly. On the other hand, 32.1% of left RLNs were anterior to the ITA, while 67.9% were related posteriorly. On both sides, 3-5% of RLN crossed in between the branches of the ITA. Anatomical consideration of the variations in the course, branching pattern, and relationship of the RLNs is essential to minimize complications associated with surgical procedures of the neck, especially thyroidectomy and anterior cervical discectomy and fusion (ACDF) surgery. The information gained in this study emphasizes the need to preferentially utilize left-sided approaches for ACDF surgery whenever possible.

COVID-19 Outbreak in an Urban Hemodialysis Unit.

RATIONALE & OBJECTIVE: Hemodialysis patients are at increased risk for coronavirus disease 2019 (COVID-19) transmission due in part to difficulty maintaining physical distancing. Our hemodialysis unit experienced a COVID-19 outbreak despite following symptom-based screening guidelines. We describe the course of the COVID-19 outbreak and the infection control measures taken for mitigation. STUDY DESIGN: Retrospective cohort study. SETTING & PARTICIPANTS: 237 maintenance hemodialysis patients and 93 hemodialysis staff at a single hemodialysis center in Toronto, Canada. EXPOSURE: Universal screening of patients and staff for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). OUTCOMES: The primary outcome was detection of SARS-CoV-2 in nasopharyngeal samples from patients and staff using reverse transcriptase-polymerase chain reaction (RT-PCR). ANALYTICAL APPROACH: Descriptive statistics were used for clinical characteristics and the primary outcome. RESULTS: 11 of 237 (4.6%) hemodialysis patients and 11 of 93 (12%) staff members had a positive RT-PCR test result for SARS-CoV-2. Among individuals testing positive, 12 of 22 (55%) were asymptomatic at time of testing and 7 of 22 (32%) were asymptomatic for the duration of follow-up. One patient was hospitalized at the time of SARS-CoV-2 infection and 4 additional patients with positive test results were subsequently hospitalized. 2 (18%) patients required admission to the intensive care unit. After 30 days' follow-up, no patients had died or required mechanical ventilation. No hemodialysis staff required hospitalization. Universal droplet and contact precautions were implemented during the outbreak. Hemodialysis staff with SARS-CoV-2 infection were placed on home quarantine regardless of symptom status. Patients with SARS-CoV-2 infection, including asymptomatic individuals, were treated with droplet and contact precautions until confirmation of negative SARS-CoV-2 RT-PCR test results. Analysis of the outbreak identified 2 index cases with subsequent nosocomial transmission within the dialysis unit and in shared shuttle buses to the hemodialysis unit. LIMITATIONS: Single-center study. CONCLUSIONS: Universal SARS-CoV-2 testing and universal droplet and contact precautions in the setting of an outbreak appeared to be effective in preventing further transmission.

The Frequency of Routine Blood Sampling and Patient Outcomes Among Maintenance Hemodialysis Recipients.

RATIONALE & OBJECTIVE: Surveillance blood work is routinely performed in maintenance hemodialysis (HD) recipients. Although more frequent blood testing may confer better outcomes, there is little evidence to support any particular monitoring interval. STUDY DESIGN: Retrospective population-based cohort study. SETTING & PARTICIPANTS: All prevalent HD recipients in Ontario, Canada, as of April 1, 2011, and a cohort of incident patients commencing maintenance HD in Ontario, Canada, between April 1, 2011, and March 31, 2016. EXPOSURE: Frequency of surveillance blood work, monthly versus every 6 weeks. OUTCOMES: The primary outcome was all-cause mortality. Secondary outcomes were major adverse cardiovascular events, all-cause hospitalization, and episodes of hyperkalemia. ANALYTICAL APPROACH: Cox proportional hazards with adjustment for demographic and clinical characteristics was used to evaluate the association between blood testing frequency and all-cause mortality. Secondary outcomes were evaluated using the Andersen-Gill extension of the Cox model to allow for potential recurrent events. RESULTS: 7,454 prevalent patients received care at 17 HD programs with monthly blood sampling protocols (n=5,335 patients) and at 8 programs with blood sampling every 6 weeks (n=2,119 patients). More frequent monitoring was not associated with a lower risk for all-cause mortality compared to blood sampling every 6 weeks (adjusted HR, 1.16; 95% CI, 0.99-1.38). Monthly monitoring was not associated with a lower risk for any of the secondary outcomes. Results were consistent among incident HD recipients. LIMITATIONS: Unmeasured confounding; limited data for center practices unrelated to blood sampling frequency; no information on frequency of unscheduled blood work performed outside the prescribed sampling interval. CONCLUSIONS: Monthly routine blood testing in HD recipients was not associated with a lower risk for death, cardiovascular events, or hospitalizations as compared with testing every 6 weeks. Given the health resource implications, the frequency of routine blood sampling in HD recipients deserves careful reassessment.

Differentially expressed genes for atrial fibrillation identified by RNA sequencing from paired human left and right atrial appendages.

Atrial fibrillation is a significant worldwide contributor to cardiovascular morbidity and mortality. Few studies have investigated the differences in gene expression between the left and right atrial appendages, leaving their characterization largely unexplored. In this study, differential gene expression was investigated in atrial fibrillation and sinus rhythm using left and right atrial appendages from the same patients. RNA sequencing was performed on the left and right atrial appendages from five sinus rhythm (SR) control patients and five permanent AF case patients. Differential gene expression in both the left and right atrial appendages was analyzed using the Bioconductor package edgeR. A selection of differentially expressed genes, with relevance to atrial fibrillation, were further validated using quantitative RT-PCR. The distribution of the samples assessed through principal component analysis showed distinct grouping between left and right atrial appendages and between SR controls and AF cases. Overall 157 differentially expressed genes were identified to be downregulated and 90 genes upregulated in AF. Pathway enrichment analysis indicated a greater involvement of left atrial genes in the Wnt signaling pathway whereas right atrial genes were involved in clathrin-coated vesicle and collagen formation. The differing expression of genes in both left and right atrial appendages indicate that there are different mechanisms for development, support and remodeling of AF within the left and right atria.

Splice variant in ARX leading to loss of C-terminal region in a boy with intellectual disability and infantile onset developmental and epileptic encephalopathy.

Pathogenic variants in the X-chromosome Aristaless-related homeobox (ARX) gene contribute to intellectual disability, epilepsy, and associated comorbidities in affected males. Here, we report a novel splice variant in ARX in a family with three affected individuals. The proband had early onset developmental and epileptic encephalopathy, his brother and mother had severe and mild intellectual disability, respectively. Massively parallel sequencing identified a novel c.1449-1G>C in intron 4 of the ARX gene, predicted to abolish the splice acceptor site, retaining intron 4 and leading to a premature termination codon immediately after exon 4. As exon 5 is the last exon of the ARX gene, the premature termination codon at position p.L484* would be predicted to escape nonsense-mediated mRNA decay, potentially producing at least some C-terminally truncated protein. Analysis of cDNA from patient lymphoblastoid cells confirmed retention of intron 4 and loss of detectable expression of ARX mRNA across exon 4 to exon 5. We review published cases of variants that lead to altered or early termination of the ARX protein, but not complete loss of function, and are associated with phenotypes of intellectual disability and infantile onset developmental and epileptic encephalopathies, including Ohtahara and West syndromes. Taken together, this novel splice variant retaining intron 4 is likely to be the cause of the early onset developmental and epileptic encephalopathy in the proband.

Elevated circulating TGFß1 during acute liver failure activates TGFßR2 on cortical neurons and exacerbates neuroinflammation and hepatic encephalopathy in mice.

BACKGROUND: Acute liver failure resulting from drug-induced liver injury can lead to the development of neurological complications called hepatic encephalopathy (HE). Hepatic transforming growth factor beta 1 (TGFß1) is upregulated due to liver failure in mice and inhibiting circulating TGFß reduced HE progression. However, the specific contributions of TGFß1 on brain cell populations and neuroinflammation during HE are not known. Therefore, the aim of this study was to characterize hepatic and brain TGFß1 signaling during acute liver failure and its contribution to HE progression using a combination of pharmacological and genetic approaches. METHODS: C57Bl/6 or neuron-specific transforming growth factor beta receptor 2 (TGFßR2) null mice (TGFßR2ΔNeu) were treated with azoxymethane (AOM) to induce acute liver failure and HE. The activity of circulating TGFß1 was inhibited in C57Bl/6 mice via injection of a neutralizing antibody against TGFß1 (anti-TGFß1) prior to AOM injection. In all mouse treatment groups, liver damage, neuroinflammation, and neurological deficits were assessed. Inflammatory signaling between neurons and microglia were investigated in in vitro studies through the use of pharmacological inhibitors of TGFß1 signaling in HT-22 and EOC-20 cells. RESULTS: TGFß1 was expressed and upregulated in the liver following AOM injection. Pharmacological inhibition of TGFß1 after AOM injection attenuated neurological decline, microglia activation, and neuroinflammation with no significant changes in liver damage. TGFßR2ΔNeu mice administered AOM showed no effect on liver pathology but significantly reduced neurological decline compared to control mice. Microglia activation and neuroinflammation were attenuated in mice with pharmacological inhibition of TGFß1 or in TGFßR2ΔNeu mice. TGFß1 increased chemokine ligand 2 (CCL2) and decreased C-X3-C motif ligand 1 (CX3CL1) expression in HT-22 cells and reduced interleukin-1 beta (IL-1ß) expression, tumor necrosis factor alpha (TNFα) expression, and phagocytosis activity in EOC-20 cells. CONCLUSION: Increased circulating TGFß1 following acute liver failure results in activation of neuronal TGFßR2 signaling, driving neuroinflammation and neurological decline during AOM-induced HE.

Stand-Alone Balloon Kyphoplasty for Treatment of Traumatic Burst Fracture in Pediatric Patient.

BACKGROUND: Kyphoplasty is commonly employed in the treatment of compression fractures in the elderly and is increasingly used in the treatment of adult trauma along with concomitant instrumentation. Although kyphoplasty with instrumentation has been reported in pediatric patients, concerns regarding retardation of spinal growth and iatrogenic spinal deformity have been raised. The utilization of kyphoplasty without instrumentation has yet to be reported in the case of pediatric patients. CASE DESCRIPTION: A 13-year-old male presented to the emergency department with a traumatic L2 burst fracture with 50% loss of height, which continued to cause severe pain after a trial of bracing. He was subsequently treated with a kyphoplasty without instrumentation. He experienced a rapid and excellent recovery and resumed all previous activity. CONCLUSIONS: Kyphoplasty alone without instrumentation is a less invasive means to treat these patients and also prevents iatrogenic deformity or retardation of growth in the pediatric spine.

A scoping review of 'big data', 'informatics', and 'bioinformatics' in the animal health and veterinary medical literature.

Research in big data, informatics, and bioinformatics has grown dramatically (Andreu-Perez J, et al., 2015, IEEE Journal of Biomedical and Health Informatics 19, 1193-1208). Advances in gene sequencing technologies, surveillance systems, and electronic medical records have increased the amount of health data available. Unconventional data sources such as social media, wearable sensors, and internet search engine activity have also contributed to the influx of health data. The purpose of this study was to describe how 'big data', 'informatics', and 'bioinformatics' have been used in the animal health and veterinary medical literature and to map and chart publications using these terms through time. A scoping review methodology was used. A literature search of the terms 'big data', 'informatics', and 'bioinformatics' was conducted in the context of animal health and veterinary medicine. Relevance screening on abstract and full-text was conducted sequentially. In order for articles to be relevant, they must have used the words 'big data', 'informatics', or 'bioinformatics' in the title or abstract and full-text and have dealt with one of the major animal species encountered in veterinary medicine. Data items collected for all relevant articles included species, geographic region, first author affiliation, and journal of publication. The study level, study type, and data sources were collected for primary studies. After relevance screening, 1093 were classified. While there was a steady increase in 'bioinformatics' articles between 1995 and the end of the study period, 'informatics' articles reached their peak in 2012, then declined. The first 'big data' publication in animal health and veterinary medicine was in 2012. While few articles used the term 'big data' (n = 14), recent growth in 'big data' articles was observed. All geographic regions produced publications in 'informatics' and 'bioinformatics' while only North America, Europe, Asia, and Australia/Oceania produced publications about 'big data'. 'Bioinformatics' primary studies tended to use genetic data and tended to be conducted at the genetic level. In contrast, 'informatics' primary studies tended to use non-genetic data sources and conducted at an organismal level. The rapidly evolving definition of 'big data' may lead to avoidance of the term.