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Studies conducted in psychotic disorders have shown that DNA-methylation (DNAm) is sensitive to the impact of Childhood Adversity (CA). However, whether it mediates the association between CA and psychosis is yet to be explored. Epigenome-wide association studies (EWAS) using the Illumina Infinium-Methylation EPIC array in peripheral blood tissue from 366 First-episode of psychosis and 517 healthy controls was performed. Polyvictimization scores were created for abuse, neglect, and composite adversity with the Childhood Trauma Questionnaire (CTQ). Regressions examining (I) CTQ scores with psychosis; (II) with DNAm EWAS level and (III), then between DNAm and caseness, adjusted for a variety of confounders were conducted. Divide-Aggregate Composite-null Test for the composite null hypothesis of no mediation effect was conducted. Enrichment analyses were conducted with missMethyl package and the KEGG database. Our results show that CA was associated with psychosis (Composite: OR = 3.09; p =

Introduction: Motor deficit is common following anterior cerebral artery (ACA) stroke. This study aimed to determine the impact on the motor outcome, given the location of descending corticofugal fiber tracts (from the primary motor cortex [M1], dorsal and ventral premotor area [PMdv], and supplementary motor area [SMA]) and the regional variations in collateral support of the ACA territory. Methods: Patients with ACA vessel occlusion were included. Disruption to corticofugal fibers was inferred by overlap of tracts with a lesion on computed tomography perfusion at the onset and on magnetic resonance imaging (MRI) poststroke. The motor outcome was defined by dichotomized and combined National Institute of Health Stroke Scale (NIHSS) sub-scores for the arm and leg. Multivariate hierarchical partitioning was used to analyze the proportional contribution of the corticofugal fibers to the motor outcome. Results: Forty-seven patients with a median age of 77.5 (interquartile range 68.0–84.5) years were studied. At the stroke onset, 96% of patients showed evidence of motor deficit on the NIHSS, and the proportional contribution of the corticofugal fibers to motor deficit was M1-33%, SMA-33%, and PMdv-33%. By day 7, motor deficit was present in Conclusion: Improvements in the motor outcome seen in ACA stroke may be due to the relative sparing of M1 fiber tracts from infarction. This may occur as a consequence of the posterior location of M1 fiber tracts and the evolving topography of ACA stroke due to the compensatory capacity of leptomeningeal anastomoses.

Background and Purpose: The circle of Willis (CoW) and leptomeningeal anastomoses play an important role in transforming infarct topography following middle cerebral artery occlusion. Their role in infarct topography following anterior cerebral artery occlusion is not well understood. The aim of this study was to evaluate the role of the CoW and leptomeningeal anastomoses in modifying regional variation in infarct topography following occlusion of the anterior cerebral artery and its branches. Methods: Perfusion and magnetic resonance imaging of patients with anterior cerebral artery stroke and evidence of vessel occlusion were segmented and manually registered to standard brain template for voxel-wise comparison. Next, a computer model of the cerebral arteries was formulated as network of nodes connected by cylindrical pipes. The experiments included occlusion of successive branches of the anterior cerebral artery while the configurations of the CoW were varied. Results: Forty-seven patients with a median age of 77.5 years (interquartile range, 68.0–84.5 years) were studied. The regions with the highest probabilities of infarction were the superior frontal gyrus (probability =0.26) and anterior cingulate gyrus (probability =0.24). The regions around the posterior cingulate gyrus (probability =0.08), paracentral lobule (probability =0.05), precuneus and superior parietal lobule (probability =0.03) had a low probability of infarction. Following occlusions distal to the anterior communicating artery, the computer model demonstrated an increase in flow (>30%) in neighboring cortical arteries with leptomeningeal anastomoses. Conclusions: Traditionally the CoW has been regarded as the primary collateral system. However, our computer model shows that the CoW is only helpful in redirecting flow following proximal vessel occlusions (pre-anterior communicating artery). More important are leptomeningeal anastomoses, which play an essential role in distal vessel occlusions, influencing motor outcome by modifying the posterolateral extent of infarct topography.

Summary Background/Introduction Cardio-cerebral infarction (CCI), which involves the simultaneous occurrence of acute ischaemic stroke and acute myocardial infarction, has a reported incidence of 0.0009%. Treatment of CCI presents a dilemma to physicians as both conditions are time critical. Despite the need for standardized treatment protocols, published data are sparse. Aim We aimed to summarize the reported cardio-cerebral infarction cases in the literature. Design Meta-analysis. Methods Four databases, Pubmed, Embase, Scopus and Google Scholar were searched until 25 August 2020. A title and abstract sieve, full-text review and extraction of data were conducted independently by three authors. Results A total of 44 cases of CCI were identified from 37 case reports and series; 15 patients (34.1%) were treated using percutaneous coronary intervention (PCI) with stent, 8 patients (18.2%) were treated with a PCI without stent, 10 patients (22.7%) were treated via a cerebral vessel thrombectomy and 8 patients (18.2%) were treated via a thrombectomy of a coronary vessel. For medications, 20 patients (45.5%) were treated with thrombolytics, 10 patients (22.7%) were treated with anticoagulants, 8 patients (18.2%) were treated with antiplatelets and 11 patients (25.0%) were treated with anticoagulants and antiplatelets. Of 44 patients, 10 patients died, and 9 of those were due to cardiac causes. Among the 44 patients, days to death was observed to be a median of 2.0 days (interquartile range (IQR): 1.5, 4.0). The modified Rankin Score was measured in nine patients, with a median score of 2.0 (IQR: 1.0, 2.5) being reported. Discussion/Conclusion The condition of CCI has substantial morbidity and mortality, and further studies are needed to examine the optimal diagnostic and treatment strategies of these patients.

Transcatheter aortic valve replacement (TAVR) is increasingly carried out in patients with aortic valvular conditions. Atrial fibrillation (AF) is a common comorbidity among patients undergoing TAVR. Despite this, there remains a paucity of data and established guidelines regarding anticoagulation use post-TAVR in patients with AF.Four databases were searched from inception until 12 October 2021. A title and abstract sieve, full-text review and data extraction were conducted by independent authors, and articles including patients without AF were excluded. The Review Manager (Version 5.4) was utilised in data analysis.A total of 25,199 post-TAVR patients with AF were included from seven articles, with 9764 patients on non-vitamin K antagonist oral anticoagulants (NOAC) and 15,435 patients on vitamin K antagonists (VKA). In this analysis, there was a significantly lower risk of all-cause mortality at 1 year (RR: 0.75, CI: 0.58-0.97, p = 0.04, IWhile the results of this analysis reveal NOAC as a potential alternate treatment modality to VKA in post-TAVR patients with AF, further research is needed to determine the full safety and efficacy profile of NOAC (PROSPERO: CRD42021283548).

Background: Cardiac arrhythmias, heart failure, and myocarditis are common symptoms associated with coronavirus 2 (SARS-CoV-2) infection. The cytopathic effect of SARS-CoV-2 is initiated by spike protein (S-protein) binding to the ACE2 receptor. However, cellular mechanisms of SARS-CoV-2 causing cardiac complications, particularly in a subset of the population such as diabetic patients, remain unclear. Aims: To determine electrophysiological cytopathic effects of SARS-CoV-2 S-protein in human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs). Methods and Results: CMs were differentiated from WTC-11, then re-plated on 48-well microelectrode array (MEA) plates and cultured under normal or hyperglycemic conditions (Glucose 5 mM (NG), and Glucose 20 mM (HG)) for three days. These HiPSC-CMs were treated with recombinant S-protein with or without insulin supplementation. Cardiac modules in AxIS MEA program were used to acquire and analyze electric and contractile functions. Beat period and field potential duration were significantly prolonged, while conductance velocity and spike slope were accelerated in HG without insulin compared to that in HG with insulin (p Conclusion: These results demonstrate SARS-CoV-2 viral structural protein can induce acute electrophysiological dysfunctions in hiPSC-CMs, which is influenced by glucose level. This establishes a new model for dissecting the mechanism of cardiac complications in viral infection.

Introduction Gender discrimination remains pervasive in surgery, significantly impacting current and future surgeons and population health. This study analyses the gender barriers and critical retention factors for female surgeons and trainees in surgery. Method Five electronic databases were searched till May 2020. Titles and abstracts were sieved, followed by a full text review. Data synthesis and inductive thematic analysis were conducted using the Thomas and Harden methodology. Result 14 articles were included, involving 528 participants. Four themes were generated–unfavourable working environment, male-dominated culture, societal pressures and progress towards gender equality. Females in surgery often faced harassment, disrespect and perceptions of incompetence, resulting in hostile work conditions, which were aggravated by the inadequate support and mentorship. The persistence of male-dominated cultures was observed, with females facing prejudice and exclusion from professional and social circles. Differential treatment and higher expectations of female surgeons also arose from entrenched societal pressures. Despite these, increased acceptance of motherhood and greater recognition of contributions by female surgeons were reported, indicating some progress in gendered culture. Conclusions There is a need to increase female surgical leadership and allocate resources to address the deep-rooted causes of biased surgical culture and ingrained perceptions, to achieve greater gender equality in surgery.

This paper examines the security partnership of the United States-Philippines during the presidency of Rodrigo Duterte. Using the theoretical framework of alliance institutionalisation, we identified several factors that can determine the strength of alliances and security partnerships. Applying this framework, we suggest that because of deep alliance institutionalisation, the security partnership between the Philippines and the United States is actually quite resilient despite President Duterte’s position on this issue.

It remains a major challenge to achieve efficient oral delivery and controlled intestinal release of ions using hydrogels. Herein, we report a novel, pH/redox-dual responsive, nanoemulsion-embedded composite hydrogel to address this issue. The hydrogel was first synthesized by crosslinking a biocompatible, pH-responsive pseudopeptide, poly(L-lysine isophthalamide) (PLP), and redox-sensitive L-cystine dimethyl ester dihydrochloride (CDE). A suitable amount of magnesium acetate was encapsulated into oil-in-water nanoemulsions, which were then embedded into the lysine-based hydrogel. The resulting composite hydrogel collapsed into a compact structure at acidic gastric pH, but became highly swollen or degraded in the neutral and reducing intestinal environment. The ion release profiles indicated that the nanoemulsion-embedded composite hydrogel could well retain and protect magnesium ions in the simulated gastric fluid (SGF) buffer at pH 1.2, but efficiently release them in the simulated intestinal fluid (SIF) buffer at pH 6.8 in the presence of 1,4-dithiothreitol (DTT) as a reducing agent. Moreover, this composite hydrogel system displayed good biocompatibility. These results suggested that the pH/redox-dual responsive, nanoemulsion-embedded composite hydrogel could be a promising candidate for efficient oral delivery and controlled intestinal release of magnesium and other ions.

ObjectiveThis study was conducted to better understand the pervasive gender barriers obstructing the progression of women in surgery by synthesising the perspectives of both female surgical trainees and surgeons.MethodsFive electronic databases, including Medline, Embase, PsycINFO, CINAHL and Web of Science Core Collection, were searched for relevant articles. Following a full-text review by three authors, qualitative data was synthesized thematically according to the Thomas and Harden methodology and quality assessment was conducted by two authors reaching a consensus.ResultsFourteen articles were included, with unfavorable work environments, male-dominated culture and societal pressures being major themes. Females in surgery lacked support, faced harassment, and had unequal opportunities, which were often exacerbated by sex-blindness by their male counterparts. Mothers were especially affected, struggling to achieve a work-life balance while facing strong criticism. However, with increasing recognition of the unique professional traits of female surgeons, there is progress towards gender quality which requires continued and sustained efforts.ConclusionThis systematic review sheds light on the numerous gender barriers that continue to stand in the way of female surgeons despite progress towards gender equality over the years. As the global agenda towards equality progresses, this review serves as a call-to-action to increase collective effort towards gender inclusivity which will significantly improve future health outcomes.

Hepatocellular carcinoma (HCC) recurrence after liver transplant is associated with a poor prognosis and significantly increases morbidity and mortality among liver transplant patients. Therefore, this meta-analysis aims to evaluate the overall prevalence of HCC recurrence following liver transplant. Medline and Embase databases were searched, and a meta-analysis of proportions was conducted. Observational studies reporting the prevalence of recurrent hepatocellular carcinoma (HCC) after liver transplant were included, with the analysis being stratified by adherence to Milan criteria, ethnicity, socio-economic status, alpha fetoprotein (AFP) levels, living donor vs. deceased donor, and the underlying aetiology of the liver disease. A meta-regression on the date of the study completion was also performed. Of a total 40,495 patients, 3888 developed an HCC recurrence. The overall prevalence of recurrent HCC was 13% (CI: 0.12–0.15). Patients beyond the Milan criteria (MC) were more likely to recur than patients within MC. Asian populations had the greatest prevalence of HCC recurrence (19%; CI: 0.15–0.24) when compared to Western (12%; CI: 0.11–0.13) and Latin American populations (11%; CI: 0.09–0.14). The prevalence of recurrent HCC was the highest in patients infected with hepatitis B virus (HBV) (18%; CI: 0.11–0.27) compared to other aetiologies. A higher AFP also resulted in an increased recurrence. This highlights interesting differences based on ethnicity, income, and aetiology, and further studies are needed to determine the reasons for the disparity.

Leader-driven Change from Aquino to Duterte: Towards a Redirection or Restructuring in Philippine Foreign Policy? Andrea Chloe Wong Abstract The global perceptions of leaders have significant influence in a state’s foreign policy. In the Philippines’ case, the striking contrast between Presidents Benigno Aquino III, who possesses a moralist and liberalist views, and Duterte, who holds a legalist and realist global perceptions, led to significant changes in their foreign policies. These are evident in their conflicting stance on two cases involving the death penalty of a Filipino worker in Indonesia in 2013; and the country’s maritime arbitration case with China filed in 2013 and eventually won in 2016. Their divergence caused important leader-driven changes, which may result in either a redirection or a restructuring in the country’s foreign policy.

Aims Previous studies have examined risk factors for the development of heart failure (HF) subsequent to acute coronary syndrome (ACS). Our study seeks to clarify the clinical variables that best characterize patients who remain free from HF after coronary artery bypass grafting (CABG) surgery for ACS to determine novel biological factors favouring freedom from HF in prospective translational studies. Methods and results Nova Scotia residents (1995–2012) undergoing CABG within 3 weeks of ACS were included. The primary outcome was freedom from readmission to hospital due to HF. Descriptive statistics were generated, and a Cox proportional hazards model assessed outcome with adjustment for clinical characteristics. Of 11 936 Nova Scotians who underwent isolated CABG, 3264 (27%) had a recent ACS and were included. Deaths occurred in 210 (6%) of subjects prior to discharge. A total of 3054 patients were included in the long-term analysis. During follow-up, HF necessitating readmission occurred in 688 (21%) subjects with a hazard ratio of 12% at 2 years. The adjusted Cox model demonstrated significantly better freedom from HF for younger, male subjects without metabolic syndrome and no history of chronic obstructive pulmonary disease, renal insufficiency, atrial fibrillation, or HF. Conclusions Our findings have outlined important clinical variables that predict freedom from HF. Furthermore, we have shown that 12% of patients undergoing CABG after ACS develop HF (2 years). Our findings support our next phase in which we plan to prospectively collect blood and tissue specimens from ACS patients undergoing CABG in order to determine novel biological mechanism(s) that favour resolution of post-ACS inflammation.

Background Macrophages (MΦ) are functionally diverse and dynamic. Until recently, cardiac MΦ were assumed to be monocyte derived; however, resident cardiac MΦ (rCMΦ), present at baseline, were identified in myocardia and have been implicated in cardiac healing. Previously, we demonstrated that CCR2−/− mice are protected from myocardial fibrosis — an observation initially attributed to changes in infiltrating monocytes. Here, we reexplored this observation in the context of our new understanding of rCMΦ. Methods Male CCR2−/− and C57BL/6 hearts were digested and purified to a single cell suspension, incubated with fluorophore-linked antibodies (CCR2, CX3CR1, CD11b, Ly6C, TNF-α, and IL-10), and assessed by flow cytometry. Differentiated MΦ were cocultured with fibroblasts in order to characterize how MΦ phenotype influences fibroblast activation. Fibroblasts were characterized for their expression of smooth muscle cell actin (SMA). Results A significant decrease in Ly6C expression was observed in the CCR2−/− cardiac MΦ population relative to WT, which corresponded with significantly lower TNF-α expression and significantly higher IL-10 expression. Using in vitro coculture system, classical MΦ promoted fibroblast activation relative to nonclassical MΦ. Conclusion CCR2−/− rCMΦ favor a more antiinflammatory phenotype relative to WT controls. Moreover, a shift toward the antiinflammatory promotes proliferation, but not activation in vitro. Together, these observations suggest that antiinflammatory cardiac MΦ populations may inhibit myocardial fibrosis in a pathological setting by preventing the activation of fibroblasts. News and noteworthy Here, we provide novel evidence for baseline differences in rCMΦ phenotypes (i.e. classical vs. nonclassical) and how these differences could modulate cardiac healing. Importantly, we observed differences in how classical vs. nonclassical MΦ influenced fibroblast activation, which could, in turn, affect fibrosis.

Background The characteristics of circulating inflammatory cells (leukocytes) in patients undergoing heart surgery remains poorly understood. Recently, neutrophil-to-lymphocyte ratio (NLR) and specific monocyte subsets (based on CD14/CD16 expression) have been suggested as markers of inflammation and predictors of outcomes. The present study aims to characterize the influence cardiac surgery with cardiopulmonary bypass has on specific circulating leukocytes. Methods All enrolled patients had blood samples taken pre- (0 days), early post- (5 days), and late post- (90 days) surgery. Complete blood counts were performed and whole leukocyte isolations were obtained from blood samples and analyzed with flow cytometry. Fluorophore-linked antibodies (CD45, CD11b, CD14, and CD16) were added to the blood cell isolations and later assessed by flow cytometry. Results Seventeen patients were enrolled and samples obtained at 0, 5, and 90 days. We demonstrated a significant increase in NLR (2.2-fold; p = 0.0028) and CD16 mean fluorescence index (MFI-measure fluorescence intensity shift of CD16 in a gated cell population) early at day 5 (2.0-fold; p = 0.0051). Both NLR and CD16 MFI levels generally returned to normal by day 90. There was a significant positive correlation between NLR and CD16 MFI (r2 = 0.29; p = 0.0064). Adverse cardiovascular event (AE) was defined as prolonged length of hospitalization or readmission to hospital for cardiac reasons after discharge was seen in 59% of patients (no deaths occurred). In an unadjusted analysis of AE, we identified NLR as a likely predictor of AE, which meant that patients developing AE had a significantly higher baseline NLR (p = 0.0065), something that was not observed with CD16 MFI (p = 0.2541). Conclusion Cardiac surgery is associated with a significant increase in NLR and CD16 MFI (non-classical monocytes) early after surgery corresponding to the early inflammatory phase after surgery. Furthermore, we have, for the first time, identified a significant correlation between NLR and CD16 MFI. While the mechanism for this relationship remains unclear, our findings support the use of a simple test of NLR as a biomarker of inflammation for predicting outcomes in cardiac surgery patients.

Aims Previous studies have examined risk factors for the development of heart failure (HF) subsequent to acute coronary syndrome (ACS). Our study seeks to clarify the clinical variables that best characterize patients who remain free from HF after coronary artery bypass grafting (CABG) surgery for ACS to determine novel biological factors favouring freedom from HF in prospective translational studies. Methods and results Nova Scotia residents (1995–2012) undergoing CABG within 3 weeks of ACS were included. The primary outcome was freedom from readmission to hospital due to HF. Descriptive statistics were generated, and a Cox proportional hazards model assessed outcome with adjustment for clinical characteristics. Of 11 936 Nova Scotians who underwent isolated CABG, 3264 (27%) had a recent ACS and were included. Deaths occurred in 210 (6%) of subjects prior to discharge. A total of 3054 patients were included in the long‐term analysis. During follow‐up, HF necessitating readmission occurred in 688 (21%) subjects with a hazard ratio of 12% at 2 years. The adjusted Cox model demonstrated significantly better freedom from HF for younger, male subjects without metabolic syndrome and no history of chronic obstructive pulmonary disease, renal insufficiency, atrial fibrillation, or HF. Conclusions Our findings have outlined important clinical variables that predict freedom from HF. Furthermore, we have shown that 12% of patients undergoing CABG after ACS develop HF (2 years). Our findings support our next phase in which we plan to prospectively collect blood and tissue specimens from ACS patients undergoing CABG in order to determine novel biological mechanism(s) that favour resolution of post‐ACS inflammation.

Introduction: Transforming growth factor-β (TGF-β) and connective tissue growth factor (CTGF) are often described as the initial pro-fibrotic mediators upregulated early in fibrosis models dependent on angiotensin II (Ang-II). In the present study, we explore the mechanistic link between TGF-β and CTGF expression by using a novel TGF-β trap. Materials and methods: NIH/3T3 fibroblasts were subjected to TGF-β with or without TGF-β trap or 1D11 antibody, CTGF or CTGF plus TGF-β for six or 24 hours, and then used for quantitative real-time polymerase chain reaction (qRT-PCR) or immunocytochemistry. Male C57BL/6 mice were infused with Ang-II and randomly assigned TGF-β trap for six or 24 hours. Hearts were harvested for histological analyses, qRT-PCR and western blotting. Results: Exogenous TGF-β-induced fibroblasts resulted in significant upregulation of CTGF, TGF-β and type I collagen transcript levels in vitro. Additionally, TGF-β promoted the differentiation of fibroblasts into α-SMA+ myofibroblasts. CTGF expression was reduced by the addition of TGF-β trap or neutralizing antibody, confirming that its expression is dependent on TGF-β signaling. In contrast, exogenous CTGF did not appear to have an effect on fibroblast production of pro-fibrotic transcripts or fibroblast differentiation. Ang-II infusion in vivo led to a significant increase in TGF-β and CTGF mRNA expression at six and 24 hours with corresponding changes in Smad2 phosphorylation (pSmad2), indicative of increased TGF-β signaling. Ang-II animals that received the TGF-β trap demonstrated reduced CTGF mRNA levels and pSmad2 at six hours, suggesting that early CTGF expression is dependent on TGF-β signaling. Conclusions: We demonstrated that CTGF expression is dependent on TGF-β signaling both in vitro and in vivo in a model of myocardial fibrosis. This also suggests that early myocardial CTGF mRNA expression (six hours) after Ang-II exposure is likely dependent on latent TGF-β activation via the canonical Smad-dependent pathway in resident cardiac cells.

Surface-bound molecular rotation can occur with the rotational axis either perpendicular (azimuthal) or parallel (altitudinal) to the surface. The majority of molecular rotor studies involve azimuthal rotors, whereas very few altitudinal rotors have been reported. In this work, altitudinal rotors are formed by means of coupling aryl halides through a surface-mediated Ullmann coupling reaction, producing a reaction state-dependent altitudinal molecular rotor/stator. All steps in the reaction on a Cu(111) surface are visualized by low-temperature scanning tunneling microscopy. The intermediate stage of the coupling reaction is a metal-organic complex consisting of two aryl groups attached to a single copper atom with the aryl rings angled away from the surface. This conformation leads to nearly unhindered rotational motion of ethyl groups at the para positions of the aryl rings. Rotational events of the ethyl group are both induced and quantified by electron tunneling current versus time measurements and are only observed for the intermediate structure of the Ullmann coupling reaction, not the starting material or finished product in which the ethyl groups are static. We perform an extensive set of inelastic electron tunneling driven rotation experiments that reveal that torsional motion around the ethyl group is stimulated by tunneling electrons in a one-electron process with an excitation energy threshold of 45 meV. This chemically tunable system offers an ideal platform for examining many fundamental aspects of the dynamics of chemically tunable molecular rotor and motors.

Anxiety disorders that are the most commonly occurring psychiatric disorders in childhood, are associated with a range of social and educational impairments and often continue into adulthood. Cognitive behaviour therapy (CBT) is an effective treatment option for the majority of cases, although up to 35–45% of children do not achieve remission. Recent research suggests that some genetic variants may be associated with a more beneficial response to psychological therapy. Epigenetic mechanisms such as DNA methylation work at the interface between genetic and environmental influences. Furthermore, epigenetic alterations at the serotonin transporter (SERT) promoter region have been associated with environmental influences such as stressful life experiences. In this study, we measured DNA methylation upstream of SERT in 116 children with an anxiety disorder, before and after receiving CBT. Change during treatment in percentage DNA methylation was significantly different in treatment responders vs nonresponders. This effect was driven by one CpG site in particular, at which responders increased in methylation, whereas nonresponders showed a decrease in DNA methylation. This is the first study to demonstrate differences in SERT methylation change in association with response to a purely psychological therapy. These findings confirm that biological changes occur alongside changes in symptomatology following a psychological therapy such as CBT.