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Motivation The advent of long-read DNA sequencing is allowing complete assembly of highly repetitive genomic regions for the first time, including the megabase-scale satellite repeat arrays found in many eukaryotic centromeres. The assembly of such repetitive regions creates a need for their de novo annotation, including patterns of higher order repetition. To annotate tandem repeats, methods are required that can be widely applied to diverse genome sequences, without prior knowledge of monomer sequences. Results Tandem Repeat Annotation and Structural Hierarchy (TRASH) is a tool that identifies and maps tandem repeats in nucleotide sequence, without prior knowledge of repeat composition. TRASH analyses a fasta assembly file, identifies regions occupied by repeats and then precisely maps them and their higher order structures. To demonstrate the applicability and scalability of TRASH for centromere research, we apply our method to the recently published Col-CEN genome of Arabidopsis thaliana and the complete human CHM13 genome. Availability and implementation TRASH is freely available at:https://github.com/vlothec/TRASH and supported on Linux.

Autologous stem cell transplantation (ASCT) remains a key therapeutic strategy for treating patients with relapsed or refractory non-Hodgkin and Hodgkin lymphoma. Clonal hematopoiesis (CH) has been proposed as a major contributor not only to the development of therapy-related myeloid neoplasms but also to inferior overall survival (OS) in patients who had undergone ASCT. Herein, we aimed to investigate the prognostic implications of CH after ASCT in a cohort of 420 lymphoma patients using ultra-deep, highly sensitive error-correction sequencing. CH was identified in the stem cell product samples of 181 patients (43.1%) and was most common in those with T-cell lymphoma (72.2%). The presence of CH was associated with a longer time to neutrophil and platelet recovery. Moreover, patients with evidence of CH had inferior 5-year OS from the time of first relapse (39.4% vs. 45.8%, p = .043) and from the time of ASCT (51.8% vs. 59.3%, p = .018). The adverse prognostic impact of CH was not due to therapy-related myeloid neoplasms, the incidence of which was low in our cohort (10-year cumulative incidence of 3.3% vs. 3.0% in those with and without CH, p = .445). In terms of specific-gene mutations, adverse OS was mostly associated with PPM1D mutations (hazard ratio (HR) 1.74, 95% confidence interval (CI) 1.13-2.67, p = .011). In summary, we found that CH is associated with an increased risk of non-lymphoma-related death after ASCT, which suggests that lymphoma survivors with CH may need intensified surveillance strategies to prevent and treat late complications.

BACKGROUND: Access to primary care outside of regular working hours is limited in many countries. This study investigates the relation between the after-hours premium, an incentive for primary care physicians to provide services after hours, and less-urgent visits to the emergency department in Ontario, Canada. METHODS: We analyzed a retrospective cohort of a random sample of Ontario residents from April 2002 to March 2006, and a subcohort of patients followed from April 2005 to March 2016. We linked patient and primary care physician data with emergency department visit data. We used fixed-effects regression models to analyze the association between the introduction of the after-hours premium, as well as subsequent increases in the value of the premium, and the number of monthly emergency department visits. RESULTS: The sample consisted of 586 534 patients between 2002 and 2006, and 201 594 patients from 2005 to 2016. After controlling for patient and physician characteristics, seasonality and time-invariant patient confounding factors, introduction of the after-hours premium was associated with a reduction of 1.26 less-urgent visits to the emergency department per 1000 patients per month (95% confidence interval −1.48 to −1.04). Most of this reduction was observed in after-hours visits. Sensitivity analysis showed that the monthly reduction in less-urgent visits to the emergency department was in the range of −1.24 to −1.16 per 1000 patients. Subsequent increases in the after-hours premium were associated with a small reduction in less-urgent visits to the emergency department. INTERPRETATION: Ontario’s experience suggests that incentivizing physicians to improve access to after-hours primary care reduces some less-urgent visits to the emergency department. Other jurisdictions may consider incentives to limit less-urgent visits to the emergency department.

In this review paper, the most recent research on intracerebral hemorrhage (ICH) is summarized and novel perspectives are offered on the pathomechanisms of ICH. These underlying pathomechanisms of ICH provide clues for development of novel drugs or drug target screening. Specifically, recent research has provided evidence that iron chelators, lipid peroxidation/ferroptosis inhibitors, agonists or antagonists of prostaglandin E2 receptors (EP1/3 or EP2), and nonsteroidal anti-inflammatory drugs protect against ICH-induced brain edema, secondary brain tissue damage as well as inhibition of the toxicity in related tissue damage products. This review will provide a theoretical basis for testing new compounds that may have potential for future clinical trials.

ImportanceInferior vena cava filters are commonly implanted and infrequently retrieved. Nonretrieval contributes to significant morbidity, motivating US Food and Drug Administration and multisociety communications emphasizing the need for improved device surveillance. Current guidelines suggest that implanting physicians and referring physicians should be responsible for device follow-up, but it is not known whether shared responsibility contributes to lower retrieval.ObjectiveTo determine if primary responsibility for follow-up care assumed by the implanting physician team is associated with increased device retrieval.Design, Setting, and ParticipantsThis retrospective cohort study examined a prospectively collected registry of patients with inferior vena cava filters implanted from June 2011 to September 2019. Medical record review and data analysis was completed in 2021. The study included 699 patients who underwent implantation of retrievable inferior vena cava filters at an academic quaternary care center.ExposuresPrior to 2016, implanting physicians had a passive surveillance strategy whereby letters highlighting indications for and the need for timely retrieval were mailed to patients and ordering clinicians. Starting in 2016, implanting physicians assumed active responsibility for surveillance, whereby candidacy for device retrieval was assessed periodically via phone calls and retrieval scheduled when appropriate.Main Outcomes and MeasuresThe main outcome was the odds of inferior vena cava filter nonretrieval. Within regression modeling of the association between the surveillance method and nonretrieval, additional covariates of patient demographics, concomitant malignant neoplasm, and presence of thromboembolic disease were included.ResultsOf the 699 patients who received retrievable filter implants, 386 (55.2%) were followed up with passive surveillance, 313 (44.8%) with active surveillance, 346 (49.5%) were female, 100 (14.3%) were Black individuals, and 502 (71.8%) were White individuals. The mean (SD) age at filter implantation was 57.1 (16.0) years. Mean (SD) yearly filter retrieval increased following the adoption of active surveillance, from 190 of 386 (48.7%) to 192 of 313 (61.3%) (P P Conclusions and RelevanceThe findings of this cohort study suggest that active surveillance by implanting physicians is associated with improved inferior vena cava filter retrieval. These findings support encouraging physicians who implant the filter to take primary responsibility for tracking and retrieval.

Autoimmune bullous diseases (AIBDs) are a group of skin-related disorders that involve damage to structures maintaining cell-cell adhesion, such as desmosomes and hemidesmosomes. Key autoimmune bullous diseases include pemphigus related diseases, pemphigoid related conditions, acquired epidermolysis bullosa (EBA), and dermatitis herpetiformis (DH). Each group of conditions exhibits characteristic clinical lesion patterns and is associated with specific autoantibodies targeting epidermal and dermal structures involved in cell-cell adhesion and skin integrity. Pemphigus diseases primarily target desmoglein (Dsg) 3 and Dsg1 proteins but several non-desmoglein autoantibodies have also been linked to pemphigus. Pemphigoid diseases typically target BP (bullous pemphigoid)180 and BP230; EBA is associated with antibodies directed against anti-type VII collagen; and DH by IgA autoantibodies against tissue transglutaminase and deaminated gliadin. Investigation into the serological biomarkers found in autoimmune bullous diseases have allowed the development of diagnostic assessments (ie. tissue antibody detection and serological testing) based on the unique autoantibody profiles of a particular disease group. The methods for the detection and quantification of disease-associated autoantibodies continue to evolve and improve.

Objective We investigated the diagnostic performance of semi-quantitative hyperintensity on T2-weighted short-tau-inversion-recovery black-blood (T2W-STIR-BB) images in identifying active cardiac sarcoidosis (CS) in patients, and compared it with that of18F-fluoro-2-deoxyglucose positron emission tomography (FDG-PET). Methods This retrospective study included 40 steroid-naive patients (age 63.1±12.9 years, 20 men) diagnosed with CS who underwent both cardiac MRI and FDG-PET imaging. Active CS cases were defined as satisfying at least one of the following criteria for conventional indices: exacerbation of ventricular arrhythmia, newly identified advanced atrioventricular block, greater than 5% decrease in left ventricular ejection fraction on echocardiography, positive finding on gallium-scintigraphy or elevated levels of sarcoidosis-related serum biomarkers. T2W-STIR-BB images were semi-quantitatively analysed using a myocardium-to-spleen ratio (MSR). The diagnostic performance of T2W-STIR-BB and FDG-PET imaging for detecting active CS was investigated. Results Thirty-three patients satisfied at least one criterion and were considered as having active CS. Thirty patients (75%) tested positive with T2W-STIR-BB imaging, and 25 patients (63%) tested positive with FDG-PET. The sensitivity, specificity, accuracy, and positive and negative predictive values for identifying active CS by semi-quantitative MSR on T2W-STIR-BB images were 79%, 43%, 73%, 87% and 30%, respectively. These results were statistically comparable to those of FDG-PET (70%, 71%, 70%, 92% and 33%, respectively). Conclusions When using conventional diagnostic indices for active CS as the gold standard, T2W-STIR-BB imaging demonstrated comparable diagnostic performance to that of FDG-PET. The semi-quantitative analysis of high signal intensity on T2W-STIR-BB images using MSR was useful for detection of active CS.

Whether aldosterone itself contributes directly to macro- or microcirculatory disease in man or to adverse cardiovascular outcomes is not fully known. We report our long-term single-practice experience in 5 patients with chronic hyperaldosteronism (HA, including 3 with glucocorticoid remediable aldosteronism, GRA) treated with low-dose amiloride (a specific epithelial sodium channel [ENaC] blocker) 5-10 (mean 7) mg daily for 14-28 (mean 20) years. Except for 1 GRA diagnosed in infancy, all had severe resistant hypertension. In each case, BP was normal or near-normal within 1-4 weeks after starting amiloride and office BP's were well controlled for 20 years thereafter. Vascular studies and 24-hour ambulatory BP monitoring with pulse wave analysis (cardiac output, vascular resistance, augmentation index, and reflection magnitude) were assessed after a mean of 18 years as were regional pulse wave velocities, pulse stiffening ratio, ankle-brachial index, serum creatinine, estimated glomerular filtration rate, and spot urinary albumin:creatinine ratio. All indicators were completely normal in all patients after 18 years of amiloride, and none had a cardiovascular event during the 20-year mean follow-up. We conclude that long-term ENaC blockade can normalize BP and protect macro- and microvascular function in patients with HA. This suggests that (a) any vasculopathic effects of aldosterone are mediated via ENaC, not MR activation itself, and are fully preventable or reversible with ENaC blockade or (b) aldosterone may not play a major BP-independent role in human macro- and microcirculatory diseases. These and other widely divergent results in the literature underscore the need for additional studies regarding aldosterone, ENaC, and vascular disease.

Significant transducer, embedded, and wireless advancements on a novel system, AbStats, has led to the first non-hospital commercialization of a new system called, Wireless AbStats. The architecture for the Wireless AbStats system is presented. This thesis will cover the hardware and software design and implementation of the system, which includes the transducer properties of the acoustic sensor, an embedded node for local storage and wireless communication, a powerful, intermediate smartphone node for data collection, and a server enterprise for further integration with internet services. Additionally, we see improvements made to various aspects of the system, like design, manufacture, and deployment since the previous iteration. Overall, the new capabilities offered by the Wireless AbStats system, which include wireless support, smaller form-factor, and improved signal-to-noise ratio, can lead to new insights and solutions in high-impact and far-reaching problems and applications, such as veterinary care, animal husbandry, neonatal intensive care unit monitoring, and optimal athlete nutrition.

BackgroundSurgical site infections (SSIs) are morbid and costly complications after elective colorectal surgery. SSI prevention bundles have been shown to reduce SSI in colorectal surgery, but their impact on organ space infections (OSI) is variable. Adoption of an evidence-based practice without an implementation strategy is often unsuccessful. Our aim was to successfully implement an OSI prevention bundle and to achieve a cost-effective reduction in OSI following elective left-sided colorectal operations.MethodsThe Translating Research into Practice model was used to implement an OSI prevention bundle in all patients undergoing elective left-sided colorectal resections by a single unit from November 2018 to September 2019. The new components included oral antibiotics with mechanical bowel preparation, when required, and use of impermeable surgical gowns. Other standardised components included alcoholic chlorhexidine skin preparation, glove change after bowel handling prior to wound closure with clean instruments. The primary outcome was OSI. Secondary outcomes included bundle compliance, unintended consequences and total patient costs. Outcomes were compared with all patients undergoing elective left-sided colorectal resections at the same institution in 2017.ResultsElective colorectal resections were performed in 173 patients across two cohorts. The compliance rate with bundle items was 63% for all items and 93% for one omitted item. There was a reduction in OSI from 12.9% (11 of 85) to 3.4% (3 of 88, pConclusionSuccessful implementation of an OSI prevention bundle was associated with a reduced rate of OSI after elective colorectal surgery. The OSI bundle and its implementation were cost-effective. Further study is required to investigate the sustainability of the OSI prevention bundle.

Objective. The objective of this study is to assess the effectiveness of erythropoietin (EPO) on mortality, neurological outcomes, and adverse event in the treatment of traumatic brain injury (TBI). Methods. We searched databases including PubMed, OVID, and the Cochrane Library from inception until October 18, 2019 for randomized controlled trials (RCTs) to compare EPO treatment group and placebo in patients with TBI. Two authors independently processed the data and evaluated the quality of inclusion studies. Statistical analysis was performed with heterogeneity test with I 2 and chi-square tests. We summarized the mortality, prognosis of neurological function, and deep vein thrombosis (DVT) outcomes and presented as risk ratio (RR) or risk difference (RD) with a 95% CI. Results. Seven RCTs accounting for 1180 patients were included after meeting the inclusion criteria. Compared with placebo, the overall mortality of EPO-treated patients was significantly reduced (RR 0.68 [95% CI 0.50-0.93]; p = 0.02 ). EPO therapy did not improve neurological prognosis (RR 1.21 [95% CI 0.93-1.15]; p = 0.16 ) or increase the occurrence of DVT (RR 0.83 [95% CI 0.61–1.13]; p = 0.242 ), which showed no significant difference. Conclusions. The results showed that the administration of EPO may reduce the risk of mortality without enhancing the occurrence of DVT in TBI patients. However, the effect of EPO on neurological outcome remains indistinct. Through subgroup analysis, we demonstrated that the dose of EPO may be a potential factor affecting the heterogeneity in neurological function and that the follow-up duration may influence the stability of the result.

To examine the effect of discontinuing hydroxyethyl starch (HES) solutions on length of hospital stay, transfusion, risk of death, acute kidney injury (AKI), and dialysis. We conducted a historical cohort study of linked administrative and clinical databases in patients undergoing coronary artery bypass surgery (CABG) on cardiopulmonary bypass. We used propensity scores to match patients who did not receive HES (after discontinuation) with patients exposed to HES (before discontinuation) and also controlled for albumin exposure. Hospital length of stay (the primary outcome) was analyzed using Fine-Gray proportional hazard regression, with hospital discharge as the outcome and death as a competing risk. Adverse outcomes were compared between matched patients using conditional logistic regression. We compared 1,085 propensity score-matched pairs (n = 2,170) from a pool of 2,757 patients. Discontinuation of HES was associated with shorter length of hospital stay, as evidenced by an increased probability of discharge (hazard ratio, 1.24; 95% confidence interval [CI], 1.14 to 1.35) and a reduced risk of red blood cell transfusion (odds ratio [OR], 0.68; 95% CI, 0.55 to 0.84), plasma transfusion (OR, 0.48; 95% CI, 0.34 to 0.66), and platelet transfusion (OR, 0.62; 95% CI, 0.44 to 0.87). Discontinuation of HES was not associated with in-hospital mortality (OR, 0.74; 95% CI, 0.36 to 1.54), AKI (OR, 0.84; 95% CI, 0.57 to 1.25), or dialysis (OR, 0.83; 95% CI, 0.25 to 2.73). For patients undergoing CABG on cardiopulmonary bypass, discontinuation of HES was associated with reduced hospital length of stay and reduced blood product transfusion, without measurable change in renal failure, dialysis rate, or in-hospital mortality. Our results should be interpreted with caution, though we found no evidence of harms associated with discontinuing HES. www.clinicaltrials.gov (NCT02329158); registered 31 December, 2014.

This study was designed to investigate whether functional and molecular MRI techniques are sensitive biomarkers for assessment of neuroinflammation and drug efficacy after traumatic brain injury (TBI) in rats. We subjected rats to a controlled cortical impact model and used behavioral tests, histology, and immunofluorescence to assess whether flavonoid pinocembrin provides cerebral protection and improves functional recovery. Most importantly, we used multiple noninvasive structural, functional, and molecular MRI techniques to examine whether the pinocembrin-related neuroprotection and attenuation of neuroinflammation can be detected in vivo . Significant increases in cerebral blood flow (CBF) and amide proton transfer-weighted (APTw) MRI signals were observed in the perilesional areas in untreated TBI rats at 3 days and could be attributed to increased glial response. In addition, increased apparent diffusion coefficient and decreased magnetization transfer ratio signals in untreated TBI rats over time were likely due to edema. Post-treatment with pinocembrin decreased microglial/macrophage activation at 3 days, consistent with the recovery of CBF and APTw MRI signals in regions of secondary injury. These findings suggest that pinocembrin provides cerebral protection for TBI and that multiple MRI signals, CBF and APTw in particular, are sensitive biomarkers for identification and assessment of neuroinflammation and drug efficacy in the TBI model.

In this review, we summarize recent research related to intracerebral hemorrhage (ICH) and offer new insight into its pathomechanisms. These underlying pathomechanisms of ICH provide clues for development of novel drugs or drug target screening. Specifically, recent research has provided evidence that iron chelators, lipid peroxidation/ferroptosis inhibitors, antagonists or agonists of prostaglandin E2 receptors (EP1/3 or EP2), and nonsteroidal anti-inflammatory drugs protect against ICH-induced brain edema and secondary brain tissue damage, and inhibit the toxicity of related tissue damage products. This review will provide a theoretical basis for testing new compounds that may have potential for future clinical trials.

Whether aldosterone itself contributes directly to macro- or microcirculatory disease in man or to adverse cardiovascular outcomes is not fully known. We report our long-term single-practice experience in an unusual group of five patients with chronic hyperaldosteronism (HA, including three with glucocorticoid-remediable aldosteronism, GRA) treated with low-dose amiloride (a specific epithelial sodium channel [ENaC] blocker) 5-10 (mean 7) mg daily for 14-28 (mean 20) years. Except for one GRA diagnosed in infancy, all had severe resistant hypertension. In each case, BP was normalized within 1-4 weeks after starting amiloride and office BP's remained well controlled throughout the next two decades. 24-hour ambulatory BP monitoring with pulse wave analysis (cardiac output, vascular resistance, augmentation index, reflection magnitude), regional pulse wave velocities, pulse stiffening ratio, ankle-brachial index, serum creatinine, estimated glomerular filtration rate, and spot urinary albumin:creatinine ratio were measured after a mean of 18 years; all of these indicators were essentially normal. Over two additional years of observation (100 patient-years total), no cardiovascular or renal event occurred. We conclude that long-term ENaC blockade with amiloride can normalize BP and protect macro- and microvascular function in patients with HA. This suggests that either (a) putative vasculopathic effects of aldosterone are mediated via ENaC or (b) aldosterone may not play a direct role in age-dependent vasculopathic changes in humans independent of blood pressure. These findings, coupled with our literature review in both animal and human results, underscore the need for additional studies.

Access to after-hours primary care is problematic in many developed countries, leading patients to instead visit the emergency department for non-urgent conditions. However, emergency department utilization for conditions treatable in primary care settings may contribute to emergency department overcrowding and increased health system costs. This systematic review examines the impact of various initiatives by developed countries to improve access to after-hours primary care on emergency department and primary care utilization. We performed a systematic review on the impact of improved access to after-hours primary and searched CINAHL, EMBASE, MEDLINE, and Scopus. We identified 20 studies that examined the impact of improved access to after-hours primary care on ED utilization and 6 studies that examined the impact on primary care utilization. Improved access to after-hours primary care was associated with increased primary care utilization, but had a mixed effect on emergency department utilization, with limited evidence of a reduction in non-urgent and semi-urgent emergency department visits. Although our review suggests that improved access to after-hours primary care may limit emergency department utilization by shifting patient care from the emergency department back to primary care, rigorous research in a given institutional context is required before introducing any initiative to improve access to after-hours primary care.

Medical imaging examination on patients usually involves more than one imaging modalities, such as Computed Tomography (CT), Magnetic Resonance (MR) and Positron Emission Tomography(PET) imaging. Multimodal imaging allows examiners to benefit from the advantage of each modalities. For example, for Abdominal Aortic Aneurysm, CT imaging shows calcium deposits in the aorta clearly while MR imaging distinguishes thrombus and soft tissues better.1 Analysing and segmenting both CT and MR images to combine the results will greatly help radiologists and doctors to treat the disease. In this work, we present methods on using deep neural network models to perform such multi-modal medical image segmentation. As CT image and MR image of the abdominal area cannot be well registered due to non-affine deformations, a naive approach is to train CT and MR segmentation network separately. However, such approach is time-consuming and resource-inefficient. We propose a new approach to fuse the high-level part of the CT and MR network together, hypothesizing that neurons recognizing the high level concepts of Aortic Aneurysm can be shared across multiple modalities. Such network is able to be trained end-to-end with non-registered CT and MR image using shorter training time. Moreover network fusion allows a shared representation of Aorta in both CT and MR images to be learnt. Through experiments we discovered that for parts of Aorta showing similar aneurysm conditions, their neural presentations in neural network has shorter distances. Such distances on the feature level is helpful for registering CT and MR image.

Ischemia/reperfusion (I/R) injuries commonly lead to breakdown of the blood-brain barrier (BBB). Restoration of the BBB can relieve neurologic damage caused by I/R injuries. The Hippo/YAP signaling pathway mediates cell proliferation, regulated cell death, and differentiation in various organisms and has been shown to participate in the restoration of the heart after I/R. In this study, we investigated whether the Hippo/YAP pathway plays a role in I/R injury in brain, especially in regard to I/R-induced BBB breakdown. The results of our study indicate that I/R injury led to an overall decrease in activity of the core proteins, YAP and TAZ, over a 24-h period. The most dramatic change was observed 1.5 h after reperfusion. In rats that underwent 1.5 h of reperfusion, intraperitoneal injection of YAP agonist dexamethasone activated YAP and TAZ and led to improved neurologic function, smaller brain infarct sizes, increased levels of tight junction proteins, decreased BBB permeability, decreased cerebral edema, and less apoptosis. Our results suggest that YAP exerts neuroprotective effects on the damaged brain that are likely related to restoration of the BBB.

Background At low levels, carbon monoxide (CO) has been shown to have beneficial effects on multiple organs and tissues through its potential anti-inflammatory, anti-apoptotic, and anti-proliferative properties. However, the effect of CO-releasing molecule (CORM)-3, a water-soluble CORM, on ischemic stroke and its mechanism of action are still unclear. Methods We investigated the role of CORM-3 in the mouse model of transient middle cerebral artery occlusion (tMCAO). CORM-3 or saline was administered to mice by retro-orbital injection at the time of reperfusion after 1-h tMCAO or at 1 h after sham surgery. We assessed infarct volume and brain water content at 24 and 72 h after ischemia, blood-brain barrier permeability at 6 and 72 h after ischemia, and neurologic deficits on days 1, 3, 7, and 14. Results Among mice that underwent tMCAO, those that received CORM-3 had significantly smaller infarct volume and greater expression of neuronal nuclear antigen (NeuN) and microtubule-associated protein 2 than did saline-treated mice. CORM-3-treated mice had significantly fewer activated microglia in the peri-infarction zone than did control mice and exhibited downregulated expression of ionized calcium-binding adapter molecule (Iba)-1, tumor necrosis factor-α, and interleukin 1β. CORM-3-treated mice had significantly lower brain water content and enhanced neurologic outcomes on days 3, 7, and 14 post-tMCAO. Lastly, CORM-3 treatment reduced Evans blue leakage; increased expression of platelet-derived growth factor receptor-β, tight junction protein ZO-1, and matrix protein laminin; and decreased protein level of matrix metalloproteinase-9. Conclusion CORM-3 treatment at the time of reperfusion reduces ischemia-reperfusion-induced brain injury by suppressing neuroinflammation and alleviating blood-brain barrier disruption. Our data suggest that CORM-3 may provide an effective therapy for ischemic stroke.

A 79-year-old man with rectal carcinoma presented with a productive cough. Contrast-enhanced computed tomography (CT) scan revealed an intraluminal mass in the right (A10) pulmonary artery ([Figures 1A to 1D][1]). Considerations included leiomyosarcoma, intravascular lymphomatosis, and metastatic

This article provides an overview of the developmental history and rationale of medical ethics to establish the code of ethics and professional conduct of the Korean Academy of Child and Adolescent Psychiatry (KACAP). Most medical professional or-ganizations have their own codes of ethics and conduct because they have continuous responsibility to regulate professional ac-tivities and conducts for their members. The Ethics and Award Committee of the KACAP appointed a Task-Force to establish the code of ethics and conduct in 2012. Because bioethics has become global, the Ethics Task Force examined global standards. Global standards in medical ethics and professional conduct adopted by the World Medical Association and the World Psychiat-ric Association have provided the basic framework for our KACAP’s code of ethics and professional conduct. The Code of Eth-ics of the Americal Academy of Child and Adolescent Psychiatry has provided us additional specific clarifications required for child and adolescent patients. The code of ethics and professional conduct of the KACAP will be helpful to us in ethical clinical practice and will ensure our competence in recognizing ethical violations.

The syntheses of 3,6-dichloro-, -dibromo-, and -diiodopyromellitic diimides—ACl, ABr, and AI, respectively—have been achieved. X-Ray crystallography of single crystals of ACl and ABr unveils the formation of extensive halogen-bonding networks in the solid state as a consequence of interactions between the lone pairs on the carbonyl oxygen atoms with the σ-holes of the halogen atoms. Further, the solid-state superstructure of diiodopyromellitic diimide is characterised by the formation of associated halogen-π dimers. The co-crystallisation of ACl or ABr with a 1,5-diaminonaphthalene derivative DN yields co-crystals of a mixed-stack charge-transfer (CT) complex which are supported by an expansive hydrogen-bonded network in addition to halogen-bonded belts that bring adjacent mixed-stacks into association with each other. 2,6-Dimethoxynaphthalene (DO) proved to be an effective CT complement to AI, yielding solvent-free co-crystals with superstructures which are comprised of a 1:2 ratio of AI to DO. This dimeric halogen-bonding motif is reminiscent of the formation of hydrogen-bonded dimers between carboxylic acids.

Traumatic brain injury (TBI) is a leading cause of death and disability in the USA. Effective therapeutic strategies for TBI are needed, and increasing attention is turning toward traditional herbal medicine. Rhizoma drynariae is a traditional Chinese medicine that has immunomodulatory and anti-inflammatory effects. Here, using the controlled cortical impact model of TBI in rats, we examined whether oral administration of R. drynariae can reduce TBI-induced brain injury in rats. We also identified the likely active compound among its four major phytochemicals in decoction. We found that post-treatment with R. drynariae decreased brain lesion volume, improved neurologic and cognitive function, and reduced anxiety- and depression-like behaviors. These changes were accompanied by reduced blood levels of IL-6 and increased IL-10. R. drynariae treatment also reversed the TBI-induced decrease in blood monocyte numbers and percentage of blood CD3 and CD4 T lymphocytes while inhibiting microglial/macrophage activation. Furthermore, by using ultra performance liquid chromatography and comparing retention times with authentic standards, we identified eriodictyol as the putative active compound of R. drynariae extract in the blood of rats with TBI. These novel findings indicate that the traditional Chinese herbal medicine R. drynariae protects brain against TBI-induced brain injury, possibly via immune-promoting, anti-inflammatory, and neuroprotective effects. Eriodictyol could be its active compound.

TGF-β signaling disorder has emerged as a cause for aortic aneurysm formation. However, mechanistic details of this disorder remain poorly defined. This study sought to understand the TGF-β signaling propagation and its impact on aortic structural homeostasis under conditions of receptor deficiency. An inducible gene deletion system driven by Myh11-CreER was utilized for selective removal of receptors Alk5, Tgfbr2, or both in SMCs, termed Alk5iko, Tgfbr2iko, and Alk5iko Tgfbr2iko, respectively. Alk5-floxed (Alk5f/f) mice served as controls. Animals (male, 9-11 weeks of age) were followed up to six months following gene deletion. Alk5iko caused progressive aortic enlargement (ultrasound scan). In four weeks, 23% of animals (n=42) died from aortic rupture, with the survivals all showing severe aneurysmal degeneration at locations of ascending (100%), descending (43%) and/or suprarenal (50%) aortas. Surprisingly, Tgfbr2iko in age-matched males (n=26) was well tolerated. Neither rupture nor aortic dilation was noted in four weeks. Evidence of aortic pathology was limited to scattered elastic fiber breaks. To evaluate the role of TGF-β in aortic aneurysm formation in Alk5iko animals, we deleted Tgfbr2 simultaneously with Alk5. The additional Tgfbr2iko completely recused aortic rupture, attenuated aortic dilation from 68% to 25%, and significantly improved aortic histology. Compared to the Alk5f/f controls, Alk5iko, Tgfbr2iko, and Alk5iko Tgfbr2iko aortas all displayed a similar but reduced level of Smad2 phosphorylation at various time points, indicating that loss of the canonical TGF-β signal is not the primary driver for the aortic phenotype of Alk5iko aortas. Meanwhile, the Alk5iko aortas produced 3-fold more pERK than Alk5f/f controls, and this elevation was completely abolished by the additional Tgfbr2 deletion. Pharmaceutical treatment of the Alk5iko mice with ERK inhibitor RDEA-119 significantly inhibited aortic dilation and prevented aortic wall from degeneration while those treated with vehicle control exhibited aortic dilation and intimal/medial tears. In conclusion, loss of Alk5 in SMCs triggers a non-Alk5 but Tgfbr2 dependent signal that promotes aortic aneurysm formation through exacerbating ERK activity.

It has been proposed that various groups of cells, such as medial SMCs (mSMCs), bone marrow progenitors, and mature ECs (mECs) hold the potential to become neointimal SMCs via phenotypic switching, differentiation, or endothelial-mesenchymal-transition (EMT). However, no definitive evidence has been provided to support these claims, which renders the in vivo significance of these events in question. Using an inducible Cre-loxP system, where the production of a reporter (e.g. β-gal) is driven by a highly definitive marker gene for mSMCs (e.g. SMC myosin heavy chain, SMMHC) or mECs (e.g. stem cell leukemia, SCL), we traced the fate of these cells during neointimal hyperplasia (NIH) in ligated common carotid and wire-injured femoral arteries. Tamoxifen induction resulted in a homogeneous labeling of mSMCs of the unmanipulated arteries of R26R;SMMHC-CreERtm mice. Following arterial injury, SMCs that were initially located in the medial layer presented in neointimal lesions; however, the fraction of these cells varied widely among vessels with either type of injury. This heterogeneity was not secondary to the random loss of the genetic label as evidenced by the stable β-gal activity in SMC culture. Addition of a second (4wks after surgery) induction did not change the pattern and fraction of the labeled SMCs in the neointima, indicating that few recruited progenitors transform into mature SMCs. This observation is further supported through examination of mice chimeric for R26R;SMMHC-CreERtm bone marrow, where β-gal activity was not detected in injured arteries though strongly induced in culture following PDGF treatment. Neointima formed in R26R;SCL-CreERtm arteries demonstrated a co-localization of β-gal activity to the repopulated ECs, with none being detected in cells underneath the EC monolayer, suggesting a role for mECs in re-endothelialization and indicating EMT as a rare event in NIH development. We have provided direct evidence for the contribution of mSMCs to NIH. The recruited vascular progenitors, particularly bone marrow cells, do not differentiate into fully mature SMCs in NIH lesion. EMT does not serve as a mechanism for populating neointimal cells following vascular injury while occurring under other vascular disease conditions.

SummaryPodosomes are self-organized, dynamic, actin-containing structures that adhere to the extracellular matrix via integrins [1–5]. Yet, it is not clear what regulates podosome dynamics and whether podosomes can function as direct mechanosensors, like focal adhesions [6–9]. We show here that myosin-II proteins form circular structures outside and at the podosome actin ring to regulate podosome dynamics. Inhibiting myosin-II-dependent tension dissipated podosome actin rings before dissipating the myosin-ring structure. As podosome rings changed size or shape, tractions underneath the podosomes were exerted onto the substrate and were abolished when myosin-light-chain activity was inhibited. The magnitudes of tractions were comparable to those generated underneath focal adhesions, and they increased with substrate stiffness. The dynamics of podosomes and of focal adhesions were different. Torsional tractions underneath the podosome rings were generated with rotations of podosome rings in a nonmotile, nonrotating cell, suggesting a unique feature of these circular structures. Stresses applied via integrins at the apical surface directly displaced podosomes near the basal surface. Stress-induced podosome displacements increased nonlinearly with applied stresses. Our results suggest that podosomes are dynamic mechanosensors in which interactions of myosin tension and actin dynamics are crucial for regulating these self-organized structures in living cells.

Objective: The purpose of this study was to examine the clinical validities and efficiencies of the Child Behavior Checklist (CBCL) and the ADHD Rating Scale-IV (ARS) in identifying children with attention-deficit hyperactivity disorder (ADHD) in Korean community-based samples. Method: A large sample of elementary school students ( n = 1668) participated in this study. We used the CBCL and the ARS as the screening instruments. Diagnoses were determined by clinical psychiatric interviews and confirmed by DSM-IV–based structured interviews. Results: Of the 46 subjects who underwent clinical psychiatric interviews, 33 were diagnosed as having ADHD. A T score of 60 with regard to the Attention Problems profile of the CBCL resulted in a reasonable level of sensitivity or positive predictive value in the diagnosis of ADHD. In both the parent and teacher reports of the ARS, 90th percentile cut-off points resulted in a high level of predictive value. The highest levels of specificity and positive predictive value were obtained when we combined the CBCL ( T ≥ 60 in Attention Problems) and the ARS (parent–teacher total ≥ 90th percentile) reports. Conclusions: These findings suggest that the combined use of the CBCL and the ARS could serve as a rapid and useful clinical method of predicting or even diagnosing children with ADHD in epidemiologic case definitions.

Incubation of bovine aortic endothelial cells (BAECs) with erythrocytes from patients with type 2 diabetes induced an increase in endothelin 1 (ET-1) production. The effect of erythrocytes on ET-1 synthesis was dependent on glycemic control. ET-1 levels after incubation with erythrocytes derived from patients with HbA(1c) levels 8%. Nepsilon-(carboxymethyl)lysine (CML)-containing protein isolated from patients' erythrocytes induced ET-1, and CML-containing protein-dependent ET-1 induction was blocked by the recombinant decoy peptide soluble receptor for advanced glycation end products (AGEs), which comprises the NH2-terminal Ig domain of the receptor for AGEs. In vitro-generated AGEs induced ET-1 mRNA transcription (nuclear run-on assay and Northern blot) in a time- and dose-dependent manner. Transient transfection of BAECs with a chimeric construct containing the 5' promoter region of the ET-1 gene linked to a reporter gene confirmed that AGE induced ET-1 promoter activity. Electrophoretic mobility shift assay confirmed AGE-inducible binding of members of the nuclear factor-kappab (NF-kappaB) family to a potential binding site at -2,090 bp. Binding was functionally significant because overexpression of the cytoplasmic inhibitor of NF-kappaB or deletion of the NF-kappaB binding site reduced ET-1 induction, whereas overexpression of NF-kappaB p65 induced ET-1 even in the absence of AGEs. Thus, ET-1 transcription is controlled by the AGE-inducible redox-sensitive transcription factor NF-kappaB.

ObjectiveSpinal cord ischemia (SCI) is a potentially devastating complication of thoracic endovascular aortic repair (TEVAR) that can result in varying degrees of short-term and permanent disability. This study was undertaken to describe the clinical outcomes, long-term functional impact, and influence on survival of SCI after TEVAR.MethodsA retrospective review of all TEVAR patients at the University of Florida from 2000 to 2011 was performed to identify individuals experiencing SCI, defined by any new lower extremity neurologic deficit not attributable to another cause. SCI was dichotomized into immediate or delayed onset, with immediate onset defined as SCI noted upon awakening from anesthesia, and delayed characterized as a period of normal function, followed by development of neurologic injury. Ambulatory status was determined using database query, record review, and phone interviews with patients and/or family. Mortality was estimated using life-table analysis.ResultsA total of 607 TEVARs were performed for various indications, with 57 patients (9.4%) noted to have postoperative SCI (4.3% permanent). SCI patients were more likely to be older (63.9 ± 15.6 vs 70.5 ± 11.2 years; P = .002) and have a number of comorbidities, including chronic obstructive pulmonary disease, hypertension, dyslipidemia, and cerebrovascular disease (P < .0001). At some point in their care, a cerebrospinal fluid drain was placed in 54 patients (95%), with 54% placed postoperatively. In-hospital mortality was 8.8% for the entire cohort (SCI vs no SCI; P = .45). SCI developed immediately in 12 patients, delayed onset in 40, and indeterminate in five patients due to indiscriminate timing from postoperative sedation. Three patients (25%) with immediate SCI had measurable functional improvement (FI), whereas 28 (70%) of the delayed-onset patients experienced some degree of neurologic recovery (P = .04). Of the 34 patients with complete data available, 26 (76%) reported quantifiable FI, but only 13 (38%) experienced return to their preoperative baseline. Estimated mean (± standard error) survival for patients with and without SCI was 37.2 ± 4.5 and 71.6 ± 3.9 months (P < .0006), respectively. Patients with FI had a mean survival of 53.9 ± 5.9 months compared with 9.6 ± 3.6 months for those without improvement (P < .0001). Survival and return of neurologic function were not significantly different when patients with preoperative and postoperative cerebrospinal fluid drains were compared.ConclusionsThe minority of patients experience complete return to baseline function after SCI with TEVAR, and outcomes in patients without early functional recovery are particularly dismal. Patients experiencing delayed SCI are more likely to have FI and may anticipate similar life-expectancy with neurologic recovery compared with patients without SCI. Timing of drain placement does not appear to have an impact on postdischarge FI or long-term mortality.