Incidence and Impact of Takotsubo Syndrome in Hospitalized Patients With COVID-19.

BACKGROUND: Takotsubo syndrome has been reported in patients with COVID-19, although minimal data are available. This investigation assessed the incidence and impact of takotsubo syndrome on patients hospitalized with COVID-19. METHODS: A retrospective cohort study was conducted using International Statistical Classification of Diseases, Tenth Revision, codes to identify patients with a primary diagnosis of COVID-19 with or without takotsubo syndrome in the National Inpatient Sample 2020 database. Outcomes between groups were compared after propensity score matching for patient and hospital demographics and comorbidities. RESULTS: A total of 211,448 patients with a primary diagnosis of COVID-19 were identified. Of these, 171 (0.08%) had a secondary diagnosis of takotsubo syndrome. Before matching, patients with COVID-19 and takotsubo syndrome, compared with patients without takotsubo syndrome, were older (68.95 vs 64.26 years; P < .001); more likely to be female (64.3% vs 47.2%; P < .001); and more likely to have anxiety (24.6% vs 12.8%; P < .001), depression (17.5% vs 11.4%; P = .02), and chronic obstructive pulmonary disease (24.6% vs 14.7%; P < .001). The takotsubo syndrome group had worse outcomes than the non-takotsubo syndrome group for death (30.4% vs 11.1%), cardiac arrest (7.6% vs 2.1%), cardiogenic shock (12.9% vs 0.4%), length of hospital stay (10.7 vs 7.5 days), and total charges ($152,685 vs $78,468) (all P < .001). After matching and compared with the non-takotsubo syndrome group (n = 508), the takotsubo syndrome group (n = 170) had a higher incidence of inpatient mortality (30% vs 14%; P < .001), cardiac arrest (7.6% vs 2.8%; P = .009), and cardiogenic shock (12.4% vs 0.4%; P < .001); a longer hospital stay (10.7 vs 7.6 days; P < .001); and higher total charges ($152,943 vs $79,523; P < .001). CONCLUSION: Takotsubo syndrome is a rare but severe in-hospital complication in patients with COVID-19.

Cellulitis in the Emergency Department: A prospective cohort study with patient-centred follow-up.

OBJECTIVE: There is substantial practice variation in the management of cellulitis with limited prospective studies describing the course of cellulitis after diagnosis. We aimed to describe the demographics, clinical features (erythema, warmth, swelling and pain), patient-reported disease trajectory and medium-term follow-up for ED patients with cellulitis. METHODS: Prospective observational cohort study of adults diagnosed with cellulitis in two EDs in Southeast Queensland, Australia. Patients with (peri)orbital cellulitis and abscess were excluded. Data were obtained from a baseline questionnaire, electronic medical records and follow-up questionnaires at 3, 7 and 14 days. Clinician adjudication of day 14 cellulitis cure was compared to patient assessment. Descriptive analyses were conducted. RESULTS: Three-hundred patients (mean age 50 years, SD 19.9) with cellulitis were enrolled, predominantly affecting the lower limb (75%). Cellulitis features showed greatest improvement between enrolment and day 3. Clinical improvement continued gradually at days 7 and 14 with persistent skin erythema (41%) and swelling (37%) at day 14. Skin warmth was the feature most likely to be resolved at each time point. There was a discrepancy in clinician and patient assessment of cellulitis cure at day 14 (85.8% vs. 52.8% cured). CONCLUSIONS: A clinical response of cellulitis features can be expected at day 3 with ongoing slower improvement over time. Over one third of patients had erythema or swelling at day 14. Patients are less likely than clinicians to deem their cellulitis cured at day 14. Future research should include parallel patient and clinician evaluation of cellulitis to help develop clearer definitions of treatment failure and cure.

The uni-directional association of atopic dermatitis and rheumatoid arthritis: a systematic review and meta-analysis.

Atopic dermatitis (AD) is a highly pruritic, inflammatory skin disease with a strong immune component. Rheumatoid arthritis (RA) is a systemic autoimmune disease that causes synovitis and destruction of small joints. Researchers have attempted to quantify an association between both diseases with mixed conclusions. This systematic review and meta-analysis will study the association between AD and RA. Additionally, we conducted a systematic review between AD and other arthritic conditions including osteoarthritis (OA), psoriatic arthritis (PsA), and juvenile idiopathic arthritis (JIA). Medline, Web of Science, Cochrane, and EMBASE databases were searched for relevant studies from inception to March 2021. Observational studies examining relationships between AD and arthritic conditions were selected. 2539 studies were screened; nine were found suitable for quantitative analysis, all of which examined AD and RA. All studies had low risk of bias as determined by the Newcastle-Ottawa Scale. Patients with RA did not have significantly increased odds of comorbid AD. These findings were consistent across multiple study designs. However, patients with AD had significantly increased odds of comorbid RA. There were not enough studies identified to perform quantitative analysis between AD and other arthritic conditions. Two studies, one on JIA and one PsA, found no association with AD. Two studies on AD and OA had conflicting results. The present study provides definitive evidence of increased odds of comorbid RA in AD patients. There were no such increased odds of comorbid AD in RA patients. No such association was found between AD and PsA, OA or JIA.

Therapeutic angiogenesis and tissue revascularization in ischemic vascular disease.

Ischemic vascular disease is a major healthcare problem. The keys to treatment lie in vascular regeneration and restoration of perfusion. However, current treatments cannot satisfy the need for vascular regeneration to restore blood circulation. As biomedical research has evolved rapidly, a variety of potential alternative therapeutics has been explored widely, such as growth factor-based therapy, cell-based therapy, and material-based therapy including nanomedicine and biomaterials. This review will comprehensively describe the main pathogenesis of vascular injury in ischemic vascular disease, the therapeutic function of the above three treatment strategies, the corresponding potential challenges, and future research directions.

Hippo pathway inhibition promotes metabolic adaptability and antioxidant response in myoblasts.

Metabolic plasticity in a hostile environment ensures cell survival. We investigated whether Hippo pathway inhibition contributed to cell adaptations under challenging conditions. We examined metabolic profiles and fuel substrate choices and preferences in C2C12 myoblasts after Hippo pathway inhibition via Salvador knockdown (SAV1 KD). SAV1 KD induced higher ATP production and a more energetic phenotype. Bioenergetic profiling showed enhanced key mitochondrial parameters including spare respiratory capacity. SAV1 KD cells showed markedly elevated glycolysis and glycolytic reserves; blocking other fuel-oxidation pathways enhanced mitochondrial flexibility of glucose oxidation. Under limited glucose, endogenous fatty acid oxidation increased to cope with bioenergetic stress. Gene expression patterns after SAV1 KD suggested transcriptional upregulation of key metabolic network regulators to promote energy production and free radical scavenging that may prevent impaired lipid and glucose metabolism. In SAV1 KD cells, sirtuin signaling was the top enriched canonical pathway linked with enhanced mitochondrial ATP production. Collectively, we demonstrated that Hippo pathway inhibition in SAV1 KD cells induces multiple metabolic properties, including enhancing mitochondrial spare respiratory capacity or glycolytic reserve to cope with stress and upregulating metabolic pathways supporting elevated ATP demand, bioenergetics, and glycolysis and counteracting oxidative stress. In response to metabolic challenges, SAV1 KD cells can increase fatty acid oxidation or glucose-coupled oxidative phosphorylation capacity to compensate for substrate limitations or alternative fuel oxidation pathway inhibition.

Association of atrial fibrillation burden with in-hospital outcomes in patients with Takotsubo cardiomyopathy.

BACKGROUND: The effects of atrial fibrillation (AF) and its burden on in-hospital mortality in patients with Takotsubo cardiomyopathy (TCM) are unclear. Here, we examined the effect of AF and paroxysmal AF on in-hospital outcomes in patients with TCM. METHODS: We used ICD-10 codes to retrospectively identify patients with a primary diagnosis of TCM in the National Inpatient Sample database 2016-2018. We compared in-hospital outcomes in TCM patients with and without AF before and after propensity score matching. The effect of AF burden on outcomes was assessed in patients with paroxysmal AF and no AF. RESULTS: Of the 4,733 patients with a primary diagnosis of TCM, 650 (13.7%) had AF, and 4,083 (86.3%) did not. Of TCM patients with AF, 368 (56.6%) had paroxysmal AF. In-hospital mortality was higher in patients with AF before (3.4% vs 1.2%, P <  0.001) and after propensity matching (3.4% vs 1.7%, P = 0.021) but did not differ between the paroxysmal AF and the no AF groups (P = 0.205). In the matched cohorts, both AF and paroxysmal AF groups were associated with a higher rate of cardiogenic shock (AF, P < 0.001; paroxysmal AF, P < 0.001), ventricular arrhythmia (AF, P = 0.002; paroxysmal AF, P = 0.02), acute kidney injury (AF, P = 0.007; paroxysmal AF, P = 0.008), and acute respiratory failure (AF, P < 0.001; paroxysmal AF, P < 0.001) compared with the no AF group. CONCLUSIONS: Although AF was associated with increased in-hospital mortality, paroxysmal AF did not affect in-hospital mortality, suggesting a higher AF burden is associated with worse clinical outcome in patients with TCM.

Contractile Adaptation of the Left Ventricle Post-myocardial Infarction: Predictions by Rodent-Specific Computational Modeling.

Myocardial infarction (MI) results in cardiac myocyte death and the formation of a fibrotic scar in the left ventricular free wall (LVFW). Following an acute MI, LVFW remodeling takes place consisting of several alterations in the structure and properties of cellular and extracellular components with a heterogeneous pattern across the LVFW. The normal function of the heart is strongly influenced by the passive and active biomechanical behavior of the LVFW, and progressive myocardial structural remodeling can have a detrimental effect on both diastolic and systolic functions of the LV leading to heart failure. Despite important advances in understanding LVFW passive remodeling in the setting of MI, heterogeneous remodeling in the LVFW active properties and its relationship to organ-level LV function remain understudied. To address these gaps, we developed high-fidelity finite-element (FE) rodent computational cardiac models (RCCMs) of MI using extensive datasets from MI rat hearts representing the heart remodeling from one-week (1-wk) to four-week (4-wk) post-MI timepoints. The rat-specific models (n = 2 for each timepoint) integrate detailed imaging data of the heart geometry, myocardial fiber architecture, and infarct zone determined using late gadolinium enhancement prior to terminal measurements. The computational models predicted a significantly higher level of active tension in remote myocardium in early post-MI hearts (1-wk post-MI) followed by a return to near the control level in late-stage MI (3- and 4-wk post-MI). The late-stage MI rats showed smaller myofiber ranges in the remote region and in-silico experiments using RCCMs suggested that the smaller fiber helicity is consistent with lower contractile forces needed to meet the measured ejection fractions in late-stage MI. In contrast, in-silico experiments predicted that collagen fiber transmural orientation in the infarct region has little influence on organ-level function. In addition, our MI RCCMs indicated that reduced and potentially positive circumferential strains in the infarct region at end-systole can be used to infer information about the time-varying properties of the infarct region. The detailed description of regional passive and active remodeling patterns can complement and enhance the traditional measures of LV anatomy and function that often lead to a gross and limited assessment of cardiac performance. The translation and implementation of our model in patient-specific organ-level simulations offer to advance the investigation of individualized prognosis and intervention for MI.

Cardiac Arrhythmia after COVID-19 Vaccination versus Non-COVID-19 Vaccination: A Systematic Review and Meta-Analysis

AimsCardiac arrhythmia is a rare complication after vaccination. Recently, reports of arrhythmia after COVID-19 vaccination have increased. Whether the risk for cardiac arrhythmia is higher with COVID-19 vaccines than with non-COVID-19 vaccines remains controversial. This meta-analysis explored the incidence of arrhythmia after COVID-19 vaccination and compared it with the incidence of arrhythmia after non-COVID-19 vaccination. MethodsWe searched the MEDLINE, Scopus, Cochrane Library, and Embase databases for English-language studies reporting the incidence of arrhythmia (the primary endpoint) after vaccination from January 1, 1947 to October 28, 2022. Secondary endpoints included incidence of tachyarrhythmia and all-cause mortality. Subgroup analyses were conducted to evaluate the incidence of arrhythmia by age (children [<18 years] versus adults [[≥]18 years]), vaccine type (mRNA COVID-19 vaccine versus non-mRNA COVID-19 vaccine; individual non-COVID-19 vaccines versus COVID-19 vaccine), and COVID-19 vaccine dose (first versus second versus third). Random-effects meta-analyses were performed, and the intrastudy risk for bias and the certainty of evidence were evaluated. This study was registered with PROSPERO (CRD42022365912). ResultsThe overall incidence of arrhythmia from 36 studies (1,528,459,662 vaccine doses) was 291.8 (95% CI 111.6-762.7) cases per million doses. The incidence of arrhythmia was significantly higher after COVID-19 vaccination (2263.4 [875.4-5839.2] cases per million doses; 830,585,553 doses, 23 studies) than after non-COVID-19 vaccination (9.9 [1.3-75.5] cases per million doses; 697,874,109 doses, 14 studies; P<0.01). Compared with COVID-19 vaccines, the influenza, pertussis, human papillomavirus, and acellular pertussis vaccines were associated with a significantly lower incidence of arrhythmia. The incidence of tachyarrhythmia was significantly higher after COVID-19 vaccination (4367.5 [1535.2-12,360.8] cases per million doses; 1,208,656 doses, 15 studies) than after non- COVID-19 vaccination (25.8 [4.5-149.4] cases per million doses; 179,822,553 doses, 11 studies; P<0.01). Arrhythmia was also more frequent after the third dose of COVID-19 vaccine (19,064.3 [5775.5-61,051.2] cases per million doses; 7968 doses, 3 studies) than after the first dose (3450.9 [988.2-11,977.6] cases per million doses; 41,714,762 doses, 12 studies; P=0.05) or second dose (2262.5 [2205.9-2320.7] cases per million doses; 34,540,749 doses, 10 studies; P<0.01). All-cause mortality was comparable between the COVID-19 and non-COVID-19 vaccination groups. ConclusionsThe overall risk for arrhythmia after COVID-19 vaccination was relatively low, although it was higher in COVID-19 vaccine recipients than in non-COVID-19 vaccine recipients. This increased risk should be evaluated along with other important factors, such as the incidence of local outbreaks and the risk for arrhythmia due to COVID infection itself, when weighing the safety and efficacy of COVID-19 vaccines.

Takotsubo syndrome and respiratory diseases: a systematic review.

Takotsubo syndrome (TTS) is a rare cardiovascular condition characterized by reversible ventricular dysfunction and a presentation resembling that of acute myocardial infarction. An increasing number of studies has shown the association of respiratory diseases with TTS. Here, we comprehensively reviewed the literature and examined the available evidence for this association. After searching PubMed, EMBASE, and Cochrane Library databases, two investigators independently reviewed 3117 studies published through May 2021. Of these studies, 99 met the inclusion criteria (n = 108 patients). In patients with coexisting respiratory disease and TTS, the most common TTS symptom was dyspnoea (70.48%), followed by chest pain (24.76%) and syncope (2.86%). The most common type of TTS was apical, accounting for 81.13% of cases, followed by the midventricular (8.49%), basal (8.49%), and biventricular (1.89%) types. Among the TTS cases, 39.82% were associated with obstructive lung disease and 38.89% were associated with pneumonia. Coronavirus disease 2019 (COVID-19), which has been increasingly reported in patients with TTS, was identified in 29 of 42 (69.05%) patients with pneumonia. The overall mortality rate for patients admitted for respiratory disease complicated by TTS was 12.50%. Obstructive lung disease and pneumonia are the most frequently identified respiratory triggers of TTS. Medications and invasive procedures utilized in managing respiratory diseases may also contribute to the development of TTS. Furthermore, the diagnosis of TTS triggered by these conditions can be challenging due to its atypical presentation. Future prospective studies are needed to establish appropriate guidelines for managing respiratory disease with concurrent TTS.

Impact of family history of coronary artery disease on clinical outcomes in Takotsubo cardiomyopathy.

Family history of coronary artery disease (FHxCAD) is a critical risk factor for CAD, underscoring the contribution of genetic factors to disease pathogenesis and susceptibility. Takotsubo cardiomyopathy (TCM) simulates the clinical features of and frequently coexists with CAD. However, the association between FHxCAD and TCM is unclear. Here, we retrospectively examined the impact of FHxCAD on in-hospital outcomes of patients with TCM. Using the National Inpatient Sample database (2016-2018), we identified 4733 patients admitted to hospital with a primary diagnosis of TCM. We compared in-hospital outcomes and complications between TCM patients with (n=646, 13.7%) and without FHxCAD (n=646) in the unmatched and in a propensity-score matched cohort (1:1 ratio). TCM with FHxCAD patients had a reduced incidence of cardiogenic shock, acute kidney injury (AKI), and acute respiratory failure (ARF); lower mortality rates; shorter length of stay (LOS); and decreased total charge compared with TCM without FHxCAD patients (p<0.05). In the matched cohort, TCM with FHxCAD patients (vs TCM without FHxCAD patients) had a lower incidence of cardiogenic shock (2.2% vs 6.3%, p<0.001; OR 0.33, 95% CI 0.18 to 0.61), AKI (5.1% vs 8.7%, p=0.016; OR 0.57, 95% CI 0.36 to 0.88), and ARF (5.7% vs 12.7%, p<0.001; OR 0.42, 95% CI 0.28 to 0.63); decreased in-hospital mortality (<11% vs 3.1%, p=0.002; OR 0.2, 95% CI 0.07 to 0.57); shorter LOS (2.66±1.96 days vs 3.40±3.05 days, p<0.001); and a reduced total charge (p=0.001), respectively. FHxCAD was associated with favorable outcomes in both unmatched and propensity-matched cohorts.

A machine learning model to estimate myocardial stiffness from EDPVR.

In-vivo estimation of mechanical properties of the myocardium is essential for patient-specific diagnosis and prognosis of cardiac disease involving myocardial remodeling, including myocardial infarction and heart failure with preserved ejection fraction. Current approaches use time-consuming finite-element (FE) inverse methods that involve reconstructing and meshing the heart geometry, imposing measured loading, and conducting computationally expensive iterative FE simulations. In this paper, we propose a machine learning (ML) model that feasibly and accurately predicts passive myocardial properties directly from select geometric, architectural, and hemodynamic measures, thus bypassing exhaustive steps commonly required in cardiac FE inverse problems. Geometric and fiber-orientation features were chosen to be readily obtainable from standard cardiac imaging protocols. The end-diastolic pressure-volume relationship (EDPVR), which can be obtained using a single-point pressure-volume measurement, was used as a hemodynamic (loading) feature. A comprehensive ML training dataset in the geometry-architecture-loading space was generated, including a wide variety of partially synthesized rodent heart geometry and myofiber helicity possibilities, and a broad range of EDPVRs obtained using forward FE simulations. Latin hypercube sampling was used to create 2500 examples for training, validation, and testing. A multi-layer feed-forward neural network (MFNN) was used as a deep learning agent to train the ML model. The model showed excellent performance in predicting stiffness parameters [Formula: see text] and [Formula: see text] associated with fiber direction ([Formula: see text] and [Formula: see text]). After conducting permutation feature importance analysis, the ML performance further improved for [Formula: see text] ([Formula: see text]), and the left ventricular volume and endocardial area were found to be the most critical geometric features for accurate predictions. The ML model predictions were evaluated further in two cases: (i) rat-specific stiffness data measured using ex-vivo mechanical testing, and (ii) patient-specific estimation using FE inverse modeling. Excellent agreements with ML predictions were found for both cases. The trained ML model offers a feasible technology to estimate patient-specific myocardial properties, thus, bridging the gap between EDPVR, as a confounded organ-level metric for tissue stiffness, and intrinsic tissue-level properties. These properties provide incremental information relative to traditional organ-level indices for cardiac function, improving the clinical assessment and prognosis of cardiac diseases.

The Headache in Emergency Departments study: Opioid prescribing in patients presenting with headache. A multicenter, cross-sectional, observational study.

OBJECTIVE: To describe the patterns of opioid use in patients presenting to the emergency department (ED) with nontraumatic headache by severity and geography. BACKGROUND: International guidelines recognize opioids are ineffective in treating primary headache disorders. Globally, many countries are experiencing an opioid crisis. The ED can be a point of initial exposure leading to tolerance for patients. More geographically diverse data are required to inform practice. METHODS: This was a planned, multicenter, cross-sectional, observational substudy of the international Headache in Emergency Departments (HEAD) study. Participants were prospectively identified throughout March 2019 from 67 hospitals in Europe, Asia, Australia, and New Zealand. Adult patients with nontraumatic headache were included as identified by the local site investigator. RESULTS: Overall, 4536 patients were enrolled in the HEAD study. Opioids were administered in 1072/4536 (23.6%) patients in the ED, and 386/3792 (10.2%) of discharged patients. High opioid use occurred prehospital in Australia (190/1777, 10.7%) and New Zealand (55/593, 9.3%). Opioid use in the ED was highest in these countries (Australia: 586/1777, 33.0%; New Zealand: 221/593, 37.3%). Opioid prescription on discharge was highest in Singapore (125/442, 28.3%) and Hong Kong (12/49, 24.5%). Independent predictors of ED opioid administration included the following: severe headache (OR 4.2, 95% CI 3.1-5.5), pre-ED opioid use (OR 1.42, 95% CI 1.11-1.82), and long-term opioid use (OR 1.80, 95% CI 1.26-2.58). ED opioid administration independently predicted opioid prescription at discharge (OR 8.4, 95% CI 6.3-11.0). CONCLUSION: Opioid prescription for nontraumatic headache in the ED and on discharge varies internationally. Severe headache, prehospital opioid use, and long-term opioid use predicted ED opioid administration. ED opioid administration was a strong predictor of opioid prescription at discharge. These findings support education around policy and guidelines to ensure adherence to evidence-based interventions for headache.

Identification of Phenotypes Among COVID-19 Patients in the United States Using Latent Class Analysis.

BACKGROUND: Coronavirus disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2 or COVID-19) is a heterogeneous disorder with a complex pathogenesis. Recent studies from Spain and France have indicated that underlying phenotypes may exist among patients admitted to the hospital with COVID-19. Whether those same phenotypes exist in the United States (US) remains unclear. Using latent class analysis (LCA), we sought to determine whether clinical phenotypes exist among patients admitted for COVID-19. METHODS: We reviewed the charts of adult patients who were hospitalized primarily for COVID-19 at Greenwich Hospital and performed LCA using variables based on patient demographics and comorbidities. To further examine the reliability and replicability of the clustering results, we repeated LCA on the cohort of patients who died during hospitalization for COVID-19. RESULTS: Two phenotypes were identified in patients admitted for COVID-19 (N = 483). According to phenotype, patients were designated as cluster 1 (C1) or cluster 2 (C2). C1 (n = 193) consisted of older individuals with more comorbidities and a higher mortality rate (25.4% vs 8.97%, p < 0.001) than patients in C2. C2 (n = 290) consisted of younger individuals who were more likely to be obese, male, and nonwhite, with higher levels of the inflammatory markers C-reactive protein and alanine aminotransferase. When we performed LCA on the cohort of patients who died during hospitalization for COVID-19 (n = 75), we found that the distribution of patient baseline characteristics and comorbidities was similar to that of the entire cohort of patients admitted for COVID-19. CONCLUSION: Using LCA, we identified two clinical phenotypes of patients who were admitted to our hospital for COVID-19. These findings may reflect different pathophysiologic processes that lead to moderate to severe COVID-19 and may be useful for identifying treatment targets and selecting patients with severe COVID-19 disease for future clinical trials.

Prognostic factors of Takotsubo cardiomyopathy: a systematic review.

Takotsubo cardiomyopathy (TCM), characterized by reversible ventricular dysfunction, has similar mortality to acute coronary syndrome. With the growing interest in the diagnosis of and interventions for TCM, many risk factors had been found to affect the prognosis of TCM patients, such as age, sex, and pre-existing diseases. Because of the incomplete understanding of the pathophysiologic mechanism in TCM, evidence-based medical therapy for this condition is lacking. Early intervention on risk factors may improve the outcomes of TCM. In this review, we sought to provide up-to-date evidence on risk factors and medical therapies that affect TCM outcome. We found that male sex, physical triggers, and certain comorbidities such as chronic kidney disease, malignant disease, higher body mass index, sepsis, chronic obstructive pulmonary disease, and anaemia were associated with poor TCM prognosis. In contrast, race, hyperlipidaemia, diabetes mellitus, and mood disorders were not clearly associated with TCM prognosis. We also reviewed the effect of medical therapies on TCM outcome, including angiotensin-converting enzyme inhibitors/angiotensin receptor blockers, ß-blockers, calcium channel blockers, and statins. The evidence that these medications confer a survival benefit on TCM patients is limited. Understanding these prognostic factors could help develop risk-stratification tools for TCM and establish effective prevention and interventions for this not-so-benign condition. Further multicentre clinical studies with large samples and meta-analyses of findings from previous studies are needed to address the inconsistent findings among the many potential risk factors for TCM.

Autoimmune Rheumatic Diseases: An Update on the Role of Atherogenic Electronegative LDL and Potential Therapeutic Strategies.

Atherosclerosis has been linked with an increased risk of atherosclerotic cardiovascular disease (ASCVD). Autoimmune rheumatic diseases (AIRDs) are associated with accelerated atherosclerosis and ASCVD. However, the mechanisms underlying the high ASCVD burden in patients with AIRDs cannot be explained only by conventional risk factors despite disease-specific factors and chronic inflammation. Nevertheless, the normal levels of plasma low-density lipoprotein (LDL) cholesterol observed in most patients with AIRDs do not exclude the possibility of increased LDL atherogenicity. By using anion-exchange chromatography, human LDL can be divided into five increasingly electronegative subfractions, L1 to L5, or into electropositive and electronegative counterparts, LDL (+) and LDL (-). Electronegative L5 and LDL (-) have similar chemical compositions and can induce adverse inflammatory reactions in vascular cells. Notably, the percentage of L5 or LDL (-) in total LDL is increased in normolipidemic patients with AIRDs. Electronegative L5 and LDL (-) are not recognized by the normal LDL receptor but instead signal through the lectin-like oxidized LDL receptor 1 (LOX-1) to activate inflammasomes involving interleukin 1ß (IL-1ß). Here, we describe the detailed mechanisms of AIRD-related ASCVD mediated by L5 or LDL (-) and discuss the potential targeting of LOX-1 or IL-1ß signaling as new therapeutic modalities for these diseases.

Rural and Remote Intubations in an Australian Air Medical Retrieval Service: A Retrospective Cohort Study.

OBJECTIVE: Critically unwell patients in rural and remote areas of Queensland, Australia, often require airway management with rapid sequence intubation before retrieval to a tertiary center. Retrieval Services Queensland coordinate retrievals and support rural hospitals, including via telehealth. This study compared the demographics of patients intubated by a retrieval team including a LifeFlight Retrieval Medicine doctor with those intubated by the local hospital team. METHODS: This was a retrospective cohort study of patients intubated in hospitals in Queensland, Australia, requiring subsequent air medical retrieval between January and December 2019. The data collected included the time of day, mission priority, geographic location, diagnosis, and failure/assistance with intubation. Descriptive statistics were complemented by regression analyses. RESULTS: In 2019, 684 patients were intubated in hospitals in Queensland, Australia, requiring air medical retrieval by a team including a LifeFlight Retrieval Medicine doctor. One hundred thirty-one (19.2%) were intubated by the retrieval team, and 553 (80.8%) were intubated by the hospital team. In the most rural and remote areas, 64 (43.2%) of the patients were intubated by the retrieval team compared with 84 (56.8%) by the hospital team. CONCLUSION: A retrieval team is more likely to intubate patients in remote hospitals in Queensland, Australia. Remote hospitals should be given preference for dispatch of the retrieval team for assistance with critical patients.

Suppressing Hippo signaling in the stem cell niche promotes skeletal muscle regeneration.

Lack of blood flow to the lower extremities in peripheral arterial disease causes oxygen and nutrient deprivation in ischemic skeletal muscles, leading to functional impairment. Treatment options for muscle regeneration in this scenario are lacking. Here, we selectively targeted the Hippo pathway in myofibers, which provide architectural support for muscle stem cell niches, to facilitate functional muscle recovery in ischemic extremities by promoting angiogenesis, neovascularization, and myogenesis. We knocked down the core Hippo pathway component, Salvador (SAV1), by using an adeno-associated virus 9 (AAV9) vector expressing a miR30-based triple short-hairpin RNA (shRNA), controlled by a muscle-specific promoter. In a mouse hindlimb-ischemia model, AAV9 SAV1 shRNA administration in ischemic muscles induced nuclear localization of the Hippo effector YAP, accelerated perfusion restoration, and increased exercise endurance. Intravascular lectin labeling of the vasculature revealed enhanced angiogenesis. Using 5-ethynyl-2'-deoxyuridine to label replicating cellular DNA in vivo, we found SAV1 knockdown concurrently increased paired box transcription factor Pax7+ muscle satellite cell and CD31+ endothelial cell proliferation in ischemic muscles. To further study Hippo suppression in skeletal muscle regeneration, we used a cardiotoxin-induced muscle damage model in adult (12-15 weeks old) and aged mice (26-month old). Two weeks after delivery of AAV9 SAV1 shRNA into injured muscles, the distribution of regenerative myofibers shifted toward a larger cross-sectional area and increased capillary density compared with mice receiving AAV9 control. Together, these findings suggest our approach may have clinical promise in regenerative therapy for leg ischemia and muscle injury.

Identifying different phenotypes in takotsubo cardiomyopathy by latent class analysis.

AIMS: This study sought to determine whether clinical clusters exist in takotsubo cardiomyopathy. Takotsubo cardiomyopathy (TCM) is a heterogeneous disorder with a complex, poorly understood pathogenesis. To better understand the heterogeneity of TCM, we identified different clinical phenotypes in a large sample of TCM patients by using latent class analysis (LCA). METHODS AND RESULTS: Using the National Inpatient Sample (NIS) database, we identified 3139 patients admitted to hospitals in 2016-2017 with a primary diagnosis of TCM. We performed LCA based on several patient demographics and comorbidities: age, sex, hypertension, hyperlipidaemia, diabetes mellitus, obesity, current smoking, asthma, chronic obstructive pulmonary disease (COPD), and anxiety and depressive disorders. We then repeated LCA separately with the NIS 2016 and 2017 data sets and performed a robust test to validate our results. We also compared in-hospital outcomes among the different clusters identified by LCA. Four patient clusters were identified. C1 (n = 1228, 39.4%) had the highest prevalence of hyperlipidaemia (93.4%), hypertension (61.6%), and diabetes (34.3%). In C2 (n = 440, 14.0%), all patients had COPD, and many were smokers (45.8%). C3 (n = 376, 11.8%) largely comprised patients with anxiety disorders (98.4%) and depressive disorders (80.1%). C4 (n = 1097, 34.8%) comprised patients with isolated TCM and few comorbidities. Among all clusters, C1 had the lowest in-hospital mortality (1.0%) and the shortest length of stay (3.2 ± 3.1 days), whereas C2 had the highest in-hospital mortality (3.4%). CONCLUSIONS: Using LCA, we identified four clinical phenotypes of TCM. These may reflect different pathophysiological processes in TCM. Our findings may help identify treatment targets and select patients for future clinical trials.

Cardiopulmonary Bypass Induces Acute Lung Injury via the High-Mobility Group Box 1/Toll-Like Receptor 4 Pathway.

During cardiopulmonary bypass (CPB), pulmonary ischemia/reperfusion (I/R) injury can cause acute lung injury (ALI). Our previous research confirmed that abnormal high-mobility group box 1 (HMGB1) release after CPB was closely related to ALI. However, the mechanism underlying the HMGB1-mediated induction of ALI after CPB is unclear. Our previous study found that HMGB1 binds Toll-like receptor 4 (TLR4), leading to lung injury, but direct evidence of a role for these proteins in the mechanism of CPB-induced lung injury has not been shown. We examined the effects of inhibiting HMGB1 or reducing TLR4 expression on CPB-induced lung injury in rats administered anti-HMBG1 antibody or TLR4 short-hairpin RNA (shTLR4), respectively. In these rat lungs, we studied the histologic changes and levels of interleukin- (IL-) 1ß, tumour necrosis factor- (TNF-) α, HMGB1, and TLR4 after CPB. After CPB, the lung tissues from untreated rats showed histologic features of injury and significantly elevated levels of IL-1ß, TNF-α, HMGB1, and TLR4. Treatment with anti-HMGB1 attenuated the CPB-induced morphological inflammatory response and protein levels of IL-1ß, TNF-α, HMGB1, and TLR4 in the lung tissues and eventually alleviated the ALI after CPB. Treatment with shTLR4 attenuated the CPB-induced morphological inflammatory response and protein levels of IL-1ß, TNF-α, and TLR4 in the lung tissues and eventually alleviated the ALI after CPB, but could not alleviate the HMGB1 protein levels induced by CPB. In summary, the present study demonstrated that the HMGB1/TLR4 pathway mediated the development of ALI induced by CPB.