The Diagnostic Utility of Biochemical Markers and Intestinal Ultrasound Compared with Endoscopy in Patients with Crohn's Disease and Ulcerative Colitis: A Systemic Review and Meta-Analysis.

Background: Inflammatory bowel disease (IBD) consists of Crohn's disease (CD) and Ulcerative colitis (UC). The main goal of treatment is to obtain mucosal healing via endoscopy. More recently, intestinal ultrasounds, along with biochemical markers, have been increasingly popular as point-of-care testing to monitor treatment response. This systemic review and meta-analysis aimed to assess the diagnostic test performance of ultrasonography and biochemical markers (C-reactive protein and fecal calprotectin) compared with endoscopy for detecting inflammation in IBD. Methods: A comprehensive literature search was conducted using PubMed Medline, EMBASE, ScienceDirect, and CINAHL from 1 January 2018 to 1 January 2024. The included studies were prospective and retrospective observational studies, clinical trials, and cross-sectional studies investigating the diagnostic sensitivity and specificity of ultrasonography, biochemical markers, and endoscopy. Studies were selected based on the Preferred Reporting Items for Systematic Review and Meta-analysis Statement (PRISMA). Results: Of the 1035 studies retrieved, 16 met the inclusion criteria, and most of the included studies were prospective observational studies. Diagnostic test accuracy was conducted, and the pooled sensitivity and specificity of all the studies revealed that ultrasonography has the highest pooled sensitivity, at 85% (95% CI, 78 to 91%), and specificity, at 92% (95% CI, 86 to 96%), as compared with biochemical markers and endoscopy. More specifically, biochemical markers had a pooled sensitivity and specificity of 85% (95% CI, 81 to 87%) and 61% (95% CI, 58 to 64%), respectively, and endoscopy had 60% (95% CI, 52 to 68%) and 82% (95% CI, 76 to 87%), respectively. However, the results also show substantial heterogeneity in the studies because of various populations, protocols, and outcomes in the studies included. This was especially noted in the assessment of biochemical markers, in which a metaregression was performed showing a nonsignificant p-value of 0.8856 for the coefficient. Conclusions: IUS was found to have the highest pooled sensitivity and specificity of all the included studies for diagnosing inflammation in patients with CD and UC, and this, coupled with biochemical markers, can improve diagnostic utility.

Efficacy of Biologics in the Treatment of Primary Sclerosing Cholangitis Associated With Inflammatory Bowel Disease: A Systematic Review and Meta-Analysis.

This is the first systematic review and meta-analysis that aims to address the scarcity of research on the use of biological therapy in primary sclerosing cholangitis-inflammatory bowel disease (PSC-IBD) and the historical inadequacy of therapeutic options. Its purpose is to investigate this matter comprehensively and furnish guidance for clinical practice. Utilizing Embase, PubMed, Medline, and clinicaltrials.gov studies investigating the roles of biologics and antibiotics in PSC-IBD were identified. The systematic literature review encompassed articles published from inception through September 2023. Two independent reviewers assessed the articles, and methodological quality was gauged using Review Manager 5.4.2. Nine studies were included in the systematic review and meta-analysis. However, only four met the criteria for inclusion in the meta-analysis due to variability and availability of data; the remaining studies underwent descriptive analysis. Notably, infliximab, adalimumab, vedolizumab, and tofacitinib showed ineffectiveness in reducing cholestatic markers. This review underscores the limited impact of biological and small-molecule therapies on disease progression in PSC-IBD patients, signifying the need for further exploration and development of treatment modalities in this domain.

Pharmacological targeting of the hyper-inflammatory response to SARS-CoV-2-infected K18-hACE2 mice using a cluster of differentiation 36 receptor modulator.

The scientific and medical community faced an unprecedented global health hazard that led to nearly 7 million deaths attributable to the rapid spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. In spite of the development of efficient vaccines against SARS-CoV-2, many people remain at risk of developing severe symptoms as the virus continues to spread without beneficial patient therapy. The hyper-inflammatory response to SARS-CoV-2 infection progressing to acute respiratory distress syndrome remains an unmet medical need for improving patient care. The viral infection stimulates alveolar macrophages to adopt an inflammatory phenotype regulated, at least in part, by the cluster of differentiation 36 receptor (CD36) to produce unrestrained inflammatory cytokine secretions. We suggest herein that the modulation of the macrophage response using the synthetic CD36 ligand hexarelin offers potential as therapy for halting respiratory failure in SARS-CoV-2-infected patients.

Exploring the Interconnections of Functional Gut Disorders and Inflammatory Bowel Disease: A Narrative Review Article.

This review reveals details of the interaction between disorders of gut-brain interaction (DGBI) and inflammatory bowel disease (IBD) by providing an in-depth review of that relationship. The review provides a nuanced understanding of this multifaceted dynamic by spanning shared symptomatology, the impact of inflammation on functional aspects, and addressing diagnostic challenges, psychological influences, treatment strategies, and emerging research directions. By synthesizing current knowledge and identifying gaps in understanding, this article aims to contribute to the evolving discourse surrounding the interplay between IBD and DGBI, offering valuable insights for clinicians, researchers, and healthcare professionals navigating the complexities of gastrointestinal health.

Pericoronary adipose tissue attenuation on coronary computed tomography angiography associates with male sex and Indigenous Australian status.

To evaluate if Indigenous Australians have higher coronary inflammation demonstrated non-invasively using pericoronary adipose tissue attenuation on coronary computed tomography angiography (CCTA). We retrospectively obtained a cohort 54 Indigenous patients age- and sex-matched to 54 non-Indigenous controls (age: 46.5 ± 13.1 years; male: n = 66) undergoing CCTA at the Royal Darwin Hospital and Monash Medical Centre. Patient groups were defined to investigate the interaction of ethnicity and sex: Indigenous + male, Indigenous + female, control + male, control + female. Semi-automated software was used to assess pericoronary adipose tissue attenuation (PCAT-a) and volume (PCAT-v). Males had significantly higher PCAT-a (- 86.7 ± 7.8 HU vs. - 91.3 ± 7.1 HU, p = 0.003) than females. Indigenous patients had significantly higher PCAT-v (1.5 ± 0.5cm3 vs. 1.3 ± 0.4cm3, p = 0.032), but only numerically higher PCAT-a (p = 0.133) than controls. There was a significant difference in PCAT-a and PCAT-v across groups defined by Indigenous status and sex (p = 0.010 and p = 0.030, respectively). Among patients with matching CCTA contrast density, multivariable linear regression analysis showed an independent association between Indigenous status and PCAT-a. Indigenous men have increased PCAT-a in an age- and sex-matched cohort. Male sex is strongly associated with increased PCAT-a. Coronary inflammation may contribute to adverse cardiovascular outcomes in Indigenous Australians, but larger studies are required to validate these findings.

CD98hc is a target for brain delivery of biotherapeutics.

Brain exposure of systemically administered biotherapeutics is highly restricted by the blood-brain barrier (BBB). Here, we report the engineering and characterization of a BBB transport vehicle targeting the CD98 heavy chain (CD98hc or SLC3A2) of heterodimeric amino acid transporters (TVCD98hc). The pharmacokinetic and biodistribution properties of a CD98hc antibody transport vehicle (ATVCD98hc) are assessed in humanized CD98hc knock-in mice and cynomolgus monkeys. Compared to most existing BBB platforms targeting the transferrin receptor, peripherally administered ATVCD98hc demonstrates differentiated brain delivery with markedly slower and more prolonged kinetic properties. Specific biodistribution profiles within the brain parenchyma can be modulated by introducing Fc mutations on ATVCD98hc that impact FcγR engagement, changing the valency of CD98hc binding, and by altering the extent of target engagement with Fabs. Our study establishes TVCD98hc as a modular brain delivery platform with favorable kinetic, biodistribution, and safety properties distinct from previously reported BBB platforms.

A cyclic azapeptide ligand of the scavenger receptor CD36/SR-B2 reduces the atherosclerotic lesion progression and enhances plaque stability in apolipoprotein E-deficient mice.

Atherosclerosis is a chronic inflammatory disease of the arterial walls that develops at predisposed sites. As a major risk factor for adverse cardiovascular pathology, atherosclerosis can progress to myocardial infarction and stroke, due to the rupture of unstable atherosclerotic lesions. Macrophage uptake of modified lipoproteins and metabolic dysfunction contributes significantly to the initiation and development of atherosclerotic lesions. The cluster of differentiation 36 receptor [CD36 (SR-B2)] plays a key role in atherosclerotic lesion progression and acts as an efferocytic molecule in the resolution of advanced plaque. In previous studies, linear azapeptide CD36 ligands were shown to exhibit anti-atherosclerotic properties. In the present study, a novel potent and selective macrocyclic azapeptide CD36 ligand, MPE-298, has proven effective in protecting against atherosclerosis progression. Features of greater plaque stability were observed after 8 weeks of daily injections with the cyclic azapeptide in apolipoprotein E-deficient mice fed a high-fat high-cholesterol diet.

Comparison of mRNA vaccine effectiveness against COVID-19-associated hospitalization by vaccination source: Immunization information systems, electronic medical records, and self-report-IVY Network, February 1-August 31, 2022.

BACKGROUND: Accurate determination of COVID-19 vaccination status is necessary to produce reliable COVID-19 vaccine effectiveness (VE) estimates. Data comparing differences in COVID-19 VE by vaccination sources (i.e., immunization information systems [IIS], electronic medical records [EMR], and self-report) are limited. We compared the number of mRNA COVID-19 vaccine doses identified by each of these sources to assess agreement as well as differences in VE estimates using vaccination data from each individual source and vaccination data adjudicated from all sources combined. METHODS: Adults aged ≥18 years who were hospitalized with COVID-like illness at 21 hospitals in 18 U.S. states participating in the IVY Network during February 1-August 31, 2022, were enrolled. Numbers of COVID-19 vaccine doses identified by IIS, EMR, and self-report were compared in kappa agreement analyses. Effectiveness of mRNA COVID-19 vaccines against COVID-19-associated hospitalization was estimated using multivariable logistic regression models to compare the odds of COVID-19 vaccination between SARS-CoV-2-positive case-patients and SARS-CoV-2-negative control-patients. VE was estimated using each source of vaccination data separately and all sources combined. RESULTS: A total of 4499 patients were included. Patients with ≥1 mRNA COVID-19 vaccine dose were identified most frequently by self-report (n = 3570, 79 %), followed by IIS (n = 3272, 73 %) and EMR (n = 3057, 68 %). Agreement was highest between IIS and self-report for 4 doses with a kappa of 0.77 (95 % CI = 0.73-0.81). VE point estimates of 3 doses against COVID-19 hospitalization were substantially lower when using vaccination data from EMR only (VE = 31 %, 95 % CI = 16 %-43 %) than when using all sources combined (VE = 53 %, 95 % CI = 41 %-62%). CONCLUSION: Vaccination data from EMR only may substantially underestimate COVID-19 VE.

Daily changes in ambient air pollution concentrations and temperature and suicide mortality in Canada: Findings from a national time-stratified case-crossover study.

INTRODUCTION: Worldwide, approximately 1900 people die by suicide daily. Daily elevations in air pollution and temperature have previously been linked to a higher risk of death from suicide. To date, there have been relatively few studies of air pollution and suicide, particularly at a national level. National analyses play an important role in shaping health policy to mitigate against adverse health outcomes. METHODS: We used a time-stratified case-crossover study design to investigate the influence of short-term (i.e., day to day) interquartile range (IQR) increases in air pollutants (nitrogen dioxide [NO2], ozone [O3], and fine particulate matter [PM2.5]) and temperature on suicide mortality in Canada between 2002 and 2015. For air pollution models, odds ratios (ORs) derived from conditional logistic regression models were adjusted for average daily temperature, and holidays. For temperature models, ORs were adjusted for holidays. Stratified analyses were undertaken by suicide type (non-violent and violent), sex, age, and season. RESULTS: Analyses are based on 50,800 suicide deaths. Overall, temperature effects were stronger than those for air pollution. A same day IQR increase in temperature (9.6 °C) was associated with a 10.1% increase (95% confidence interval (CI): 9.0%-11.2%) of death from suicide. For 3-day average increase of O3 (IQR = 14.1 ppb), PM2.5 (IQR = 5.6 µg/m3) and NO2 (IQR = 9.7 ppb) the corresponding risks were 4.7% (95% CI: 3.9, 5.6), 3.4% (95% CI: 3.0, 3.8), and 2.0% (95% CI: 1.1, 2.8), respectively. All pollutants showed stronger associations with suicide during the warmer season (April-September). Stratified analyses revealed stronger associations for both temperature and air pollution in women. CONCLUSIONS: Daily increases in air pollution and temperature were found to increase the risk of death from suicide. Females, particularly during warmer season, were most vulnerable to these exposures. Policy decisions related to air pollution and climate change should consider effects on mental health.

Ventral tegmental area glutamate neurons mediate nonassociative consequences of stress.

Exposure to trauma is a risk factor for the development of a number of mood disorders, and may enhance vulnerability to future adverse life events. Recent data demonstrate that ventral tegmental area (VTA) neurons expressing the vesicular glutamate transporter 2 (VGluT2) signal and causally contribute to behaviors that involve aversive or threatening stimuli. However, it is unknown whether VTA VGluT2 neurons regulate transsituational outcomes of stress and whether these neurons are sensitive to stressor controllability. This work adapted an operant mouse paradigm to examine the impact of stressor controllability on VTA VGluT2 neuron function as well as the role of VTA VGluT2 neurons in mediating transsituational stressor outcomes. Uncontrollable (inescapable) stress, but not physically identical controllable (escapable) stress, produced social avoidance and exaggerated fear in male mice. Uncontrollable stress in females led to exploratory avoidance of a novel brightly lit environment. Both controllable and uncontrollable stressors increased VTA VGluT2 neuronal activity, and chemogenetic silencing of VTA VGluT2 neurons prevented the behavioral sequelae of uncontrollable stress in male and female mice. Further, we show that stress activates multiple genetically-distinct subtypes of VTA VGluT2 neurons, especially those that are VGluT2+VGaT+, as well as lateral habenula neurons receiving synaptic input from VTA VGluT2 neurons. Our results provide causal evidence that mice can be used for identifying stressor controllability circuitry and that VTA VGluT2 neurons contribute to transsituational stressor outcomes, such as social avoidance, exaggerated fear, or anxiety-like behavior that are observed within trauma-related disorders.

Vaccine Effectiveness of Primary Series and Booster Doses against Omicron Variant COVID-19-Associated Hospitalization in the United States.

Objectives: To compare the effectiveness of a primary COVID-19 vaccine series plus a booster dose with a primary series alone for the prevention of Omicron variant COVID-19 hospitalization. Design: Multicenter observational case-control study using the test-negative design to evaluate vaccine effectiveness (VE). Setting: Twenty-one hospitals in the United States (US). Participants: 3,181 adults hospitalized with an acute respiratory illness between December 26, 2021 and April 30, 2022, a period of SARS-CoV-2 Omicron variant (BA.1, BA.2) predominance. Participants included 1,572 (49%) case-patients with laboratory confirmed COVID-19 and 1,609 (51%) control patients who tested negative for SARS-CoV-2. Median age was 64 years, 48% were female, and 21% were immunocompromised; 798 (25%) were vaccinated with a primary series plus booster, 1,326 (42%) were vaccinated with a primary series alone, and 1,057 (33%) were unvaccinated. Main Outcome Measures: VE against COVID-19 hospitalization was calculated for a primary series plus a booster and a primary series alone by comparing the odds of being vaccinated with each of these regimens versus being unvaccinated among cases versus controls. VE analyses were stratified by immune status (immunocompetent; immunocompromised) because the recommended vaccine schedules are different for these groups. The primary analysis evaluated all COVID-19 vaccine types combined and secondary analyses evaluated specific vaccine products. Results: Among immunocompetent patients, VE against Omicron COVID-19 hospitalization for a primary series plus one booster of any vaccine product dose was 77% (95% CI: 71-82%), and for a primary series alone was 44% (95% CI: 31-54%) (p<0.001). VE was higher for a boosted regimen than a primary series alone for both mRNA vaccines used in the US (BNT162b2: primary series plus booster VE 80% (95% CI: 73-85%), primary series alone VE 46% (95% CI: 30-58%) [p<0.001]; mRNA-1273: primary series plus booster VE 77% (95% CI: 67-83%), primary series alone VE 47% (95% CI: 30-60%) [p<0.001]). Among immunocompromised patients, VE for a primary series of any vaccine product against Omicron COVID-19 hospitalization was 60% (95% CI: 41-73%). Insufficient sample size has accumulated to calculate effectiveness of boosted regimens for immunocompromised patients. Conclusions: Among immunocompetent people, a booster dose of COVID-19 vaccine provided additional benefit beyond a primary vaccine series alone for preventing COVID-19 hospitalization due to the Omicron variant.

Optimization of a Liposomal DNase I Formulation with an Extended Circulating Half-Life.

Drug delivery systems such as liposomes are widely used to stabilize and increase the plasma half-life of therapeutics. In this article, we have investigated two strategies to increase the half-life of deoxyribonuclease I, an FDA-approved enzyme used for the treatment of cystic fibrosis, and a potential candidate for the reduction of uncontrolled inflammation induced by neutrophil extracellular traps. We demonstrate that our optimized preparation procedure resulted in nanoparticles with improved plasma half-life and total exposure relative to native protein, while maintaining enzymatic activity.

Distinctive Roles of Furin and TMPRSS2 in SARS-CoV-2 Infectivity.

The spike protein (S) of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) directs infection of the lungs and other tissues following its binding to the angiotensin-converting enzyme 2 (ACE2) receptor. For effective infection, the S protein is cleaved at two sites: S1/S2 and S2'. The "priming" of the surface S protein at S1/S2 (PRRAR685↓) [the underlined basic amino acids refer to critical residues needed for the furin recognition] by furin has been shown to be important for SARS-CoV-2 infectivity in cells and small-animal models. In this study, for the first time we unambiguously identified by proteomics the fusion activation site S2' as KPSKR815↓ (the underlined basic amino acids refer to critical residues needed for the furin recognition) and demonstrated that this cleavage was strongly enhanced by ACE2 engagement with the S protein. Novel pharmacological furin inhibitors (BOS inhibitors) effectively blocked endogenous S protein processing at both sites in HeLa cells, and SARS-CoV-2 infection of lung-derived Calu-3 cells was completely prevented by combined inhibitors of furin (BOS) and type II transmembrane serine protease 2 (TMPRSS2) (camostat). Quantitative analyses of cell-to-cell fusion and S protein processing revealed that ACE2 shedding by TMPRSS2 was required for TMPRSS2-mediated enhancement of fusion in the absence of S1/S2 priming. We further demonstrated that the collectrin dimerization domain of ACE2 was essential for the effect of TMPRSS2 on cell-to-cell fusion. Overall, our results indicate that furin and TMPRSS2 act synergistically in viral entry and infectivity, supporting the combination of furin and TMPRSS2 inhibitors as potent antivirals against SARS-CoV-2. IMPORTANCE SARS-CoV-2, the etiological agent of COVID-19, has so far resulted in >6.1 million deaths worldwide. The spike protein (S) of the virus directs infection of the lungs and other tissues by binding the angiotensin-converting enzyme 2 (ACE2) receptor. For effective infection, the S protein is cleaved at two sites: S1/S2 and S2'. Cleavage at S1/S2 induces a conformational change favoring the S protein recognition by ACE2. The S2' cleavage is critical for triggering membrane fusion and virus entry into host cells. Our study highlights the complex dynamics of interaction between the S protein, ACE2, and the host proteases furin and TMPRSS2 during SARS-CoV-2 entry and suggests that the combination of a nontoxic furin inhibitor with a TMPRSS2 inhibitor significantly reduces viral entry in lung cells, as evidenced by an average synergistic ∼95% reduction of viral infection. This represents a powerful novel antiviral approach to reduce viral spread in individuals infected by SARS-CoV-2 or future related coronaviruses.

Oxidative stress-induced senescence mediates inflammatory and fibrotic phenotypes in fibroblasts from systemic sclerosis patients.

OBJECTIVE: SSc is an autoimmune connective tissue disorder characterized by inflammation and fibrosis. Although constitutive activation of fibroblasts is proposed to be responsible for the fibrotic and inflammatory features of the disease, the underlying mechanism remains elusive, and effective therapeutic targets are still lacking. The aim of this study was to evaluate the role of oxidative stress-induced senescence and its contribution to the pro-fibrotic and pro-inflammatory phenotypes of fibroblasts from SSc patients. METHODS: Dermal fibroblasts were isolated from SSc (n = 13) and healthy (n = 10) donors. Fibroblasts' intracellular and mitochondrial reactive oxygen species (ROS) were determined by flow cytometry. Mitochondrial function was measured by Seahorse XF24 analyser. Fibrotic and inflammatory gene expressions were assessed by qPCR and key pro-inflammatory components of the fibroblasts' secretome (IL-6 and IL-8) were quantified by ELISA. RESULTS: Compared with healthy fibroblasts, SSc fibroblasts displayed higher levels of both intracellular and mitochondrial ROS. Oxidative stress in SSc fibroblasts induced the expression of fibrotic genes and activated the TGF-ß-activated kinase 1 (TAK1)-IκB kinase ß (IKKß)-IFN regulatory factor 5 (IRF5) inflammatory signalling cascade. These cellular responses paralleled the presence of a DNA damage response, a senescence-associated secretory phenotype and a fibrotic response. Treatment of SSc fibroblasts with ROS scavengers reduced their pro-inflammatory secretome production and fibrotic gene expression. CONCLUSIONS: Oxidative stress-induced cellular senescence in SSc fibroblasts underlies their pro-inflammatory and pro-fibrotic phenotypes. Targeting redox imbalance of SSc fibroblasts enhances their in vitro functions and could be of relevance for SSc therapy.

Associations between meteorological factors and emergency department visits for unintentional falls during Ontario winters. / Associations entre facteurs météorologiques et nombre de visites aux services d'urgence en raison de chutes accidentelles pendant les hivers ontariens.

INTRODUCTION: Unintentional falls are a leading cause of injury-related hospital visits among Canadians, especially seniors. While certain meteorological conditions are suspected risk factors for fall-related injuries, few studies have quantified these associations across a wider range of age groups and with population-based datasets. METHODS: We applied a time-stratified case-crossover study design to characterize associations of highly-spatially-resolved meteorological factors and emergency department (ED) visits for falls, in Ontario, among those aged 5 years and older during the winter months (November to March) between 2011 and 2015. Conditional logistic models were used to estimate the odds ratios (ORs) and their 95% confidence intervals (CIs) for these visits in relation to daily snowfall accumulation, including single-day lags of up to one week before the visit, and daily mean temperature on the day of the visit. Analyses were stratified by age and sex. RESULTS: We identified 761 853 fall-related ED visits. The odds for these visits was increased for most days up to a week after a snowfall of 0.2 cm or greater (OR = 1.05-1.08) compared to days with no snowfall. This association was strongest among adults aged 30 to 64 years (OR = 1.16-1.19). The OR for fall-related ED visits on cold days (less than -9.4 °C) was reduced by 0.05 relative to days with an average daily temperature of 3.0 °C or higher (OR = 0.95; 95% CI: 0.94, 0.96), and this pattern was evident across all ages. There were no substantive differences in the strength of this association by sex. CONCLUSION: Snowfall and warmer winter temperatures were associated with an increased risk of fall-related ED visits during Ontario winters. These findings are relevant for developing falls prevention strategies and ensuring timely treatment.

Ex vivo Ikkß ablation rescues the immunopotency of mesenchymal stromal cells from diabetics with advanced atherosclerosis.

AIMS: Diabetes is a conventional risk factor for atherosclerotic cardiovascular disease and myocardial infarction (MI) is the most common cause of death among these patients. Mesenchymal stromal cells (MSCs) in patients with type 2 diabetes mellitus (T2DM) and atherosclerosis have impaired ability to suppress activated T-cells (i.e. reduced immunopotency). This is mediated by an inflammatory shift in MSC-secreted soluble factors (i.e. pro-inflammatory secretome) and can contribute to the reduced therapeutic effects of autologous T2DM and atherosclerosis-MSC post-MI. The signalling pathways driving the altered secretome of atherosclerosis- and T2DM-MSC are unknown. Specifically, the effect of IκB kinase ß (IKKß) modulation, a key regulator of inflammatory responses, on the immunopotency of MSCs from T2DM patients with advanced atherosclerosis has not been studied. METHODS AND RESULTS: MSCs were isolated from adipose tissue obtained from patients with (i) atherosclerosis and T2DM (atherosclerosis+T2DM MSCs, n = 17) and (ii) atherosclerosis without T2DM (atherosclerosis MSCs, n = 17). MSCs from atherosclerosis+T2DM individuals displayed an inflammatory senescent phenotype and constitutively expressed active forms of effectors of the canonical IKKß nuclear factor-κB transcription factors inflammatory pathway. Importantly, this constitutive pro-inflammatory IKKß signature resulted in an altered secretome and impaired in vitro immunopotency and in vivo healing capacity in an acute MI model. Notably, treatment with a selective IKKß inhibitor or IKKß knockdown (KD) (clustered regularly interspaced short palindromic repeats/Cas9-mediated IKKß KD) in atherosclerosis+T2DM MSCs reduced the production of pro-inflammatory secretome, increased survival, and rescued their immunopotency both in vitro and in vivo. CONCLUSIONS: Constitutively active IKKß reduces the immunopotency of atherosclerosis+T2DM MSC by changing their secretome composition. Modulation of IKKß in atherosclerosis+T2DM MSCs enhances their myocardial repair ability.

Bedrails and Falls in Nursing Homes: A Systematic Review.

Bedrail use for fall prevention in elderly clients (>65 years) is controversial. Some healthcare providers believe bedrails prevent falls, while others think they are ineffective and dangerous. A systematic review was conducted to address: "For older adults living in nursing homes, does more or less bedrail use reduce the incidence of falls?" We searched HealthStar, MEDLINE, CINAHL, Academic Search complete ProQuest and Canadian Health Research Collection using "elder*," "bedrail*," "fall*," and "assisted-living*." After filtering for primary data, English records, older adult population, relationship between bedrails and falls, fourteen studies remained. Results suggest using alternative fall prevention measures, and bedrails are either beneficial, harmful, or do not influence falls. Bedrail reduction with fall prevention interventions led to no changes in fall frequency. Ambiguity persists regarding fall frequencies and bedrail use without using other fall prevention strategies. Educating health care providers on fall prevention is key to patient safety.

Do statutory holidays impact the number of opioid-related hospitalizations among Canadian adults? Findings from a national case-crossover study.

OBJECTIVE: In Canada, emergency department visits, hospitalizations, and deaths due to opioid use have risen substantially in recent years. While these events have exhibited seasonal and day of week patterns, there have been no attempts to investigate the extent to which statutory holidays influence these patterns, particularly opioid-related hospitalizations. METHODS: We applied a time-stratified case-crossover study design to investigate whether statutory holidays were predictive of opioid-related hospitalizations using the Canadian Discharge Abstract Database (excluding Quebec) for fiscal years 2011/2012 to 2016/2017. This design controls for day of week effects. We restricted analyses to opioid hospitalizations (ICD-10 codes: F11.x, T40.0-T40.4, and T40.6) among individuals 15 years and older. Conditional logistic regression models were fit to estimate the odds of opioid-related hospitalization on holidays relative to non-holidays. We examined these patterns across different holiday types, namely social gathering holidays (e.g., Canada Day) and family holidays (e.g., Christmas). Stratified analyses were done to identify whether these associations varied by age group and sex. RESULTS: We identified a total of 59,965 opioid-related hospitalizations. Overall, we found a 12% reduced odds in opioid hospitalizations on holidays (odds ratio [OR] = 0.88, 95% CI 0.83, 0.93) relative to non-holidays. Similar reductions were observed for both family (OR = 0.86, 95% CI 0.79, 0.93) and social gathering holidays (OR = 0.90, 95% CI 0.84, 0.96). No substantive differences were noted by age group or sex. CONCLUSIONS: Our findings support the hypothesis that opioid-related hospitalizations occur less frequently on statutory holidays. This knowledge may help inform healthcare resources and health promotion activities to reduce the impacts of opioid use.

RéSUMé: OBJECTIVES: Au Canada, les visites aux urgences, les hospitalisations ou les décès liés aux opioïdes ont augmenté considérablement dans les dernières années. Bien que ces événements présentent des tendances saisonnières et des tendances dépendant du jour de la semaine, aucun essai n'a été fait pour déterminer dans quelle manière les jours de fêtes influencent ces tendances, particulièrement pour les hospitalisations liées aux opioïdes. MéTHODES: Nous avons appliqué une étude cas croisés stratifiée dans le temps pour déterminer si les jours de fêtes étaient prédictifs des hospitalisations liées aux opioïdes enregistrées dans la Base de données canadienne sur les congés des patients (à l'exclusion du Québec) durant les années 2011/2012 à 2016/2017. Ce modèle d'étude contrôle pour les effets du jour de la semaine. Nous avons limité les analyses aux hospitalisations liées aux opioïdes (codes CIM-10 : F11.x, T40.0-T40.4 et T40.6) chez les personnes de 15 ans et plus. Des modèles de régression logistique conditionnelle ont été ajustés pour estimer la probabilité d'une hospitalisation liée aux opioïdes pendant les jours de fêtes par rapport aux jours non-fêtes. Nous avons ensuite examiné ces tendances pour de différents types de fêtes, par exemple les fêtes de rassemblement social (p. ex., la fête du Canada) ou les fêtes familiales (p. ex., Noël). Des analyses stratifiées ont été réalisées pour déterminer si ces associations variaient en fonction de l'âge et du sexe. RéSULTATS: Nous avons identifié un total de 59 965 hospitalisations liées aux opioïdes. Nous avons vu une réduction de 12 % des risques d'hospitalisation pendant les jours de fêtes (OR = 0,88, 95 % CI : 0,83, 0,93) par rapport aux jours non-fêtes. Des réductions similaires ont été observées pour les fêtes familiales (OR = 0,86, CI 95 % : 0,79, 0,93) et les fêtes de rassemblement social (OR = 0,90, CI 95 % : 0,84, 0,96). Aucune différence n'a été observée selon l'âge et le sexe. CONCLUSIONS: Nos résultats confirment l'hypothèse selon laquelle les hospitalisations liées aux opioïdes sont réduites durant les jours de fêtes. Ces connaissances peuvent aider à informer les ressources de soins de santé et les activités de promotion de la santé afin de réduire les impacts de l'utilisation des opioïdes.