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Introduction Several months into the COVID-19 pandemic, safe and effective treatments against this global health disaster have yet to be identified. Clinical research trials around the world are underway testing a wide array of possible medications. In particular, the off-label use of hydroxychloroquine for COVID-19 prophylaxis and treatment has created many unprecedented challenges for the scientific community and the public. Areas covered We critically assessed major events from February – May 2020 that contributed to widespread use of hydroxychloroquine for the treatment and prophylaxis of COVID-19. We aimed to explore how opinions toward hydroxychloroquine may shift from early enthusiasm (based on in vitro and preliminary clinical data) to the hope for a miracle cure (through communication and promotion of questionable results) and, finally, to a rise of skepticism as more in-depth analyses are emerging. Expert opinion Mindful and rigorous acquisition of data, as well as its interpretation, are essential to an effective pandemic response. The rapid and premature promotion of results has had major implications for global crisis management, even creating distrust among the public. It is crucial for the medical and scientific community to incorporate the lessons learned from this situation.

We appreciate the interest of Lo et al in our opinion piece and thank them for the data presented in their letter.1 2 Several reports of QT prolongation and torsades de pointes in patients with COVID-19 receiving antimalarials have been published.3–5 These and other reports have indirectly raised questions regarding the arrhythmogenic potential of hydroxychloroquine (HCQ) when used to treat rheumatic disease. Lo et al used the unique resource of the National Health Insurance Research Database of Taiwan. Through propensity scores, they matched patients who used HCQ and who did not use HCQ for the treatment of newly diagnosed rheumatoid arthritis (RA). Data about other disease-modifying antirheumatic drugs used by the patients was not reported. Therefore, it is unclear if the groups were similar in their RA disease severity, although they seemed similar related to comorbidities. The authors did not find differences in the cumulative risk of arrhythmia between the two groups after 1 year of follow-up. However, a prior meta-analysis on reported cardiotoxic events of antimalarials found that cardiac conduction abnormalities were the most common cardiac adverse events and were associated with higher cumulative doses (median cumulative HCQ dose of 1235 g, …

Coronavirus disease 2019 (COVID-19), the disease caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has resulted in a global pandemic and a disruptive health crisis. COVID-19–related morbidity and mortality have been attributed to an exaggerated immune response. The role of complement activation and its contribution to illness severity is being increasingly recognized. Here, we summarize current knowledge about the interaction of coronaviruses with the complement system. We posit that (a) coronaviruses activate multiple complement pathways; (b) severe COVID-19 clinical features often resemble complementopathies; (c) the combined effects of complement activation, dysregulated neutrophilia, endothelial injury, and hypercoagulability appear to be intertwined to drive the severe features of COVID-19; (d) a subset of patients with COVID-19 may have a genetic predisposition associated with complement dysregulation; and (e) these observations create a basis for clinical trials of complement inhibitors in life-threatening illness.

We thank Santos-Moreno et al for their response to our commentary.1 2 The authors provide data on cardiovascular adverse events associated with maintenance antimalarial use for patients with rheumatoid arthritis (RA). In addition to our previous correspondence response3 from Erre et al ,4 these additional data are reassuring to patients with rheumatic diseases on chronic doses of antimalarials regarding the continued safety of these medications. However, as we have also addressed in a previous response, the safety profile of antimalarials in patients with COVID-19 infection compared with patients with rheumatic disease may differ widely. Observational data regarding cardiovascular events in hospitalised patients with COVID-19 treated with hydroxychloroquine (HCQ) with or …

Two medications often used for treatment of immune-mediated conditions, hydroxychloroquine and chloroquine, have recently attracted widespread interest as potential therapies for coronavirus disease 2019. The authors of this commentary provide guidance for clinical decision making for patients with coronavirus disease 2019 as well as for patients with rheumatologic conditions, such as systemic lupus erythematosus and rheumatoid arthritis

The use of hydroxychloroquine (HCQ) in the prophylaxis and treatment of coronavirus disease 2019 (COVID-19) has received significant attention by politicians and media figures. This has occurred despite limited data supporting its efficacy in COVID-19 as well as considerable concern about its safety when used at high doses (>400 mg daily) and in combination with other QT interval prolonging drugs.1–4 An inaccurate narrative has emerged in recent weeks that patients with systemic lupus erythematosus (SLE) who are taking HCQ as a baseline therapy are less affected by or do not develop COVID-19.5–7 This assumption has been challenged by Monti and Montecucco,8 referencing data from the COVID-19 Global Rheumatology Alliance registry on patients with rheumatic disease that previously identified 19/110 (17%) patients with SLE.9 A case series of 17 patients with lupus or antiphospholipid syndrome who developed COVID-19 on a median HCQ dose of 400 mg daily (median HCQ blood level of 648 ng/mL) has since become available.10 As of 17 April 2020, we have now identified 80 patients with SLE and COVID-19 in the global physician-reported registry. Patients were predominantly female (72/80, 90%) and less than 65 years of age (69/80, 86%). Importantly, 64% (51/80) of patients with SLE were taking an antimalarial (HCQ or chloroquine) prior to infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) (30% as monotherapy). Notably, 21.1% (121/573) of all reported patients with rheumatic disease in the registry were treated with an antimalarial prior to onset of COVID-19, yet 49.6% (60/121) required hospitalisation. In patients with SLE, frequency of hospitalisation with COVID-19 …

Objective The recent hydroxychloroquine (HCQ) shortage due to use in coronavirus disease 2019 (COVID‐19) has forced some rheumatic disease patients to choose between continuing their current dose of HCQ but exhaust their supply early or ration it in order to prolong its use. Blood HCQ concentrations are directly correlated with disease activity in rheumatic diseases such as systemic lupus erythematosus. We sought to model how changes in HCQ dosage will best maintain sufficient blood HCQ concentrations for the longest period of time in order to avoid potential future flares. Methods A one‐compartment pharmacokinetic model was used to predict mean blood HCQ concentrations. Monte Carlo simulations with 10‐fold inflated model parameter variance was utilized to assess the impact of variability. Results Maintenance of 400 mg/d resulted in mean therapeutic whole‐blood HCQ concentrations that exceeded 700 ng/ml for 10.5 days, whereas HCQ rationing by reducing the dose by half resulted in the mean concentration remaining above 700 ng/ml for 2.4 days (net gain = 8 days). Variability analysis demonstrates that results may differ at the individual level, dependent on baseline blood HCQ concentrations. Conclusion Although mean blood concentrations exceed 700 ng/ml for a longer time if patients maintain their full dose of HCQ, more information is needed to fully understand the elimination of HCQ at the patient level, particularly the contribution of tissue stores of HCQ transiting back into the blood.

Introduction: The affinity of hemoglobin for carbon monoxide (CO) is 250 times higher than that for oxygen. Therefore, exposure to CO leads to a reduction in oxygen delivery to tissues, resulting in cellular hypoxia and affects whole body. Hepatic dysfunction in critically ill patients is related to poor outcome, but few studies have been conducted on this subject that occurs after CO poisoning. This study aims to conduct a study of hepatic injury in CO-poisoned patients in emergency department (ED). Methods: This retrospective observational study collected data from patients who were diagnosed with acute CO poisoning at the ED between June 2011 and May 2018 in local tertiary-care hospital (Wonju, Republic of Korea). The primary end point of this study was to describe the prevalence of hepatic injury in acute CO-poisoned patients. The secondary goals were to investigate the recovery trends of hepatic injury caused by acute CO poisoning and the relation to neurologic outcome and mortality. Results: Eight hundred ninety-four patients were enrolled in the final analysis, 128 cases (14.3%) had subclinical hepatic injury and 15 (1.6%) cases had hepatic injury. The relationship with mortality was not statistically significant. However, the hepatic injury group was higher incidence of intensive care unit admission and other complications. Patients in the hepatic injury group recovered through conservative management within 1 week of being admitted to the ED. Conclusions: While CO-induced hepatic injury is relatively uncommon, it can be associated with complications and poor neurologic outcome. However, CO-induced hepatic injury was not found to have a statistically significant effect on mortality rate.

Suppression or mitigation of edge-localized mode (ELM) crashes is necessary for ITER. The strategy to suppress all the ELM crashes by the resonant magnetic perturbation (RMP) should be applied as soon as the first low-to-high confinement (L–H) transition occurs. A control algorithm based on real-time machine learning (ML) enables such an approach: it classifies the H-mode transition and the ELMy phase in real-time and automatically applies the preemptive RMP. This paper reports the algorithm design, which is now implemented in the KSTAR plasma-control system, and the corresponding experimental demonstration of typical high-δ KSTAR H-mode plasmas. As a result, all initial ELM crashes are suppressed with an acceptable safety factor at the edge (q 95) and with RMP field adjustment. Moreover, the ML-driven ELM crash suppression discharges remain stable without further degradation due to the regularization of the plasma pedestal.

Background Calcineurin inhibitors are effective immunosuppressive agents, but associated adverse effects such as nephrotoxicity may limit efficacy. Tacrolimus (FK506) is an immunosuppressive drug used mainly to lower the risk of organ rejection after allogeneic organ transplant. Adverse effects of FK-506 can prompt patients to end treatment despite the efficacy. In the present study, we investigated the protective effect and mechanism of tetrahydrocurcumin (THC) on FK506-induced renal damage, apoptosis, and oxidative stress to evaluate its possible use for kidney protection. Materials and Methods The effect of THC on FK506-induced kidney cell damage was investigated in LLC-PK1 cells. LLC-PK1 cells were pretreated with THC at concentrations of dose for 2 hours followed by addition of FK506 for 24 hours. LLC-PK1 cells were treated with FK506 and THC, and cell viability and glutathione was measured. The number of apoptotic cells was measured using an annexin V/propidium iodide staining with flow cytometry. The effect of apoptosis by THC in LLC-PK1 cells was determined by measuring the caspase-9, caspase-3, B-cell lymphoma-2 (Bcl-2), and Bcl-2-associated X protein levels using Western blotting analyses. Results FK506-induced LLC-PK1 renal cell damage was markedly ameliorated by THC treatment. THC protected LLC-PK1 cells by preventing FK506-induced glutathione decrease. THC protects against FK506-induced apoptosis in LLC-PK1 cells. Apoptosis was significantly decreased, and Bcl-2 was elevated in the THC-treated group. Bcl-2-associated X protein, caspase-3, and caspase-9 were decreased in the THC-treated group. Conclusion These results collectively provide therapeutic evidence that THC ameliorates the FK506-induced renal damage via antioxidant effect and apoptosis inhibition.

Crown shapes in mammalian teeth vary considerably from species to species, and morphological characters in crown shape have been used to identify species. Cusp pattern is one of the characters in crown shape. In the processes governing the formation of cusp pattern, the Shh pathway has been implicated as an important player. Suppression of Shh signaling activity in vitro in explant assays appears to induce supernumerary cusp formation in wild-type tooth germs. However, the in vivo role of Shh signaling in cusp pattern formation and the molecular mechanisms by which Shh regulates cusp patterning are not clear. Here, through in vivo phenotypic analyses of mice in which Shh activity was suppressed and compared with wild-type mice, we characterized differences in the location, number, incidence, and shape of supernumerary cusps in molars at embryonic day 15.5. We found that the distances between cusps were reduced in molars of Shh activity–suppressed mice in vivo. These findings confirm and extend the previous idea that Shh acts as an inhibitor in the reaction-diffusion model for cusp pattern formation by negatively regulating the intercuspal distance. We uncovered a significant reduction of expression level of Sostdc1, which encodes a secreted modulator of Wnt signaling, after suppression of Shh activity. The supernumerary cusp formation in Sostdc1−/− mice and compound Sostdc1 and Lrp mutant mice indicates a strong association between Wnt and Shh signaling pathways in cusp patterning. In further support of this idea, there is a high degree of similarity in the supernumerary cusp patterns of mice lacking Sostdc1 or Shh at embryonic day 15.5. These results suggest that Shh plays an inhibitory role in cusp pattern formation by modulating Wnt signaling through the positive regulation of Sostdc1.

The goal of the Advanced Mo-based Rare process Experiment (AMoRE) is to search for the neutrinoless double beta decay of $$^{100}$$ Mo using low-temperature detectors consisting of Mo-based scintillating crystals read out via metallic magnetic calorimeters. Heat and light signals are measured simultaneously at millikelvin temperatures, which are reached using a cryogen-free dilution refrigerator. The AMoRE-Pilot experiment, using six $$^{100}$$ Mo-enriched, $$^{48}$$ Ca-depleted calcium molybdate crystals with a total mass of about 1.9 kg, has been running in the 700-m-deep Yangyang underground laboratory as the pilot phase of the AMoRE project. Several setup improvements through different runs allowed us to achieve a high energy resolution and an efficient particle discrimination. This article briefly presents the status of the AMoRE-Pilot experiment, as well as the plans for the next, larger-scale, experimental stages.

Objectives: Determine perceived barriers and facilitators to effective mentoring for early career rheumatology investigators and develop a framework for an inter-institutional mentoring program. Methods: Focus groups or interviews with rheumatology fellows, junior faculty, and mentors were conducted, audiotaped and transcribed. Content analysis was performed using NVivo software. Themes were grouped into categories (e.g., mentor-mentee relationship, barriers and facilitators of a productive relationship). Rheumatology fellows and early career investigators were also surveyed nationwide to identify specific needs to be addressed through an inter-institutional mentoring program. Results: Twenty-five individuals participated in focus groups or interviews. Attributes of the ideal mentee-mentor relationship included communication, accessibility, regular meetings, shared interests, aligned goals, and mutual respect. The mentee should be pro-active, efficient, engaged, committed, focused, accountable, and respectful of the mentor's time. The mentor should support/promote the mentee, shape the mentee's goals and career plan, address day-to-day questions, provide critical feedback, be available, and have team leadership skills. Barriers included difficulty with career path navigation, gaining independence, internal competition, authorship, time demands, funding, and work-life balance. Facilitators of a successful relationship included having a diverse network of mentors filling different roles, mentor-mentee relationship management, and confidence. Among 187 survey respondents, the primary uses of an inter-institutional mentoring program were career development planning and oversight, goal setting, and networking. Conclusions: In this mixed methods study, tangible factors for optimizing the mentor-mentee relationship were identified and will inform development of an adult rheumatology inter-institutional mentoring program. This article is protected by copyright. All rights reserved.

Background Although vaccines effectively prevent coronavirus disease 2019 (COVID-19) in healthy individuals, they appear to be less immunogenic in individuals with chronic inflammatory disease (CID) or receiving chronic immunosuppression therapy. Methods Here we assessed a cohort of 77 individuals with CID treated as monotherapy with chronic immunosuppressive drugs for antibody responses in serum against historical and variant severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viruses after immunization with the BNT162b2 mRNA vaccine. Findings Longitudinal analysis showed the greatest reductions in neutralizing antibodies and Fc effector function capacity in individuals treated with tumor necrosis factor alpha (TNF-α) inhibitors (TNFi), and this pattern appeared to be worse against the B.1.617.2 delta virus. Within 5 months of vaccination, serum neutralizing titers of all TNFi-treated individuals tested fell below the presumed threshold correlate for antibody-mediated protection. However, TNFi-treated individuals receiving a third mRNA vaccine dose boosted their serum neutralizing antibody titers by more than 16-fold. Conclusions Vaccine boosting or administration of long-acting prophylaxis (e.g., monoclonal antibodies) will likely be required to prevent SARS-CoV-2 infection in this susceptible population. Funding This study was supported by grants and contracts from the NIH (R01 AI157155, R01AI151178, and HHSN75N93019C00074; NIAID Centers of Excellence for Influenza Research and Response (CEIRR) contracts HHSN272201400008C and 75N93021C00014; and Collaborative Influenza Vaccine Innovation Centers [CIVIC] contract 75N93019C00051)., Graphical abstract, Context and significance In most individuals, mRNA vaccines effectively prevent severe disease following SARS-CoV-2 infection. However, the protective immunity induced by mRNA vaccines is diminished in immunocompromised individuals, and the effect of variant strains is unexplored. Here we evaluated serum antibody responses in individuals with chronic inflammatory disease after immunization with the Pfizer BNT162b2 mRNA vaccine. The lowest neutralizing antibody titers were observed in individuals treated with TNF-α inhibitors, and this pattern appeared to be worse against the delta virus, with the antibody levels falling below the presumed threshold correlate of protection. Administration of a third vaccine dose substantially boosted serum neutralizing titers. Our data suggest that vaccine boosting is needed to prevent SARS-CoV-2 infection in some immunocompromised populations, especially those receiving TNF-α inhibitor therapies., Chen et al. assess serum antibodies from BNT162b2 mRNA-vaccinated individuals with chronic inflammatory disease receiving single immunosuppressive drug therapies. Individuals receiving TNF-α inhibitors (TNFi) had reduced antibody neutralizing and Fc effector function activity against the B.1.351 and B.1.617.2 variants. A third vaccine dose markedly boosted neutralizing titers in TNFi recipients.

Purpose Idiopathic hyperammonemia syndrome (IHS) is a rare, often fatal complication following lung transplantation. Multiple treatment strategies have been documented including dialysis, although no definite treatments exist so far, and mortality remains high. In this study, we analyzed the current treatment strategy to determine the better treatment option in patients with hyperammonemia. Methods 283 patients who underwent lung transplantation from January 2013 to June 2020 were retrospectively reviewed. We defined non-severe hyperammonemia as serum ammonia >38umol/L, severe hyperammonemia as >75umol/L, and HIS >200umol/L at least one occasion. Elevated serum ammonia was detected in 134 patients. For the assessment of the treatment response, patients with severe hyperammonemia were divided into subgroups; the resolved group in which was treated successfully, and the failed group in which had failed to resolve. Results Among 134 patients with hyperammonemia, 38 (28.4%) showed severe hyperammonemia and 10 of 38 have failed to resolve. Mean peak ammonia level was 52.7umol/L in non-severe patients, 111.6umol/L in resolved patients, and 356.6umol/L in the failed group (p=0.001). The peak level was detected on median postoperative 16.7day in non-severe patients, 42.8day in the resolved group, and 25.4day in the failed group (p=0.001). 16 (16.8%) were symptomatic in non-severe patients, 12 (46.2%) in the resolved group and all patients in the failed group were symptomatic (p=0.001). Total amount of transfusion within postoperative 48 hours is greater in the failed group (2912.5ml) than the resolved group (1655.7ml, p=0.040), especially, the tendency was remarkable for red blood cell transfusion (1945.0ml vs. 799.0ml; p=0.018). The proportions of applying renal replacement, nitrogen scavengers, and bowel decontaminant were not significantly different. Although not statistically significant, only the resolved group patients had received empirical antibiotics such as fluoroquinolone (37.5%, p=0.063). All the patients in the failed group died during follow up, 4 of them died due to IHS. Conclusion None of the current treatment was optimally effective for hyperammonemia. However, certain combinations of antibiotics might have potential to lower serum ammonia, which is consistent with recent findings that microbes such as Ureaplasma spp. can cause hyperammonemia after lung transplantation.

PURPOSE/OBJECTIVE(S) Brain metastases (BM) are the most common intracranial tumors in adults. Benefiting from efficient local control, stereotactic ablative radiotherapy (SABR) is becoming popular in the treatment of BM. Detection and manual delineation of BM are labor-intense processes, and BM are occasionally mistaken for normal brain, especially if volumes are very small. Recently, several efforts have been made to develop automatic detection and segmentation for BM using advanced deep learning (DL) algorithms. In this study, we investigated the efficacy and accuracy of a DL model for the detection and segmentation of BM. MATERIALS/METHODS To train and validate the DL model, magnetic resonance imaging (MRI) for 65 patients and 603 BM were collected and analyzed. Manual contouring for BM was done by a radiation oncologist. We utilized 2.5-dimensional training using a two-dimensional U-Net as the DL architecture to avoid inefficiencies of the three-dimensional architecture. Because of MRI characteristic, we applied N4 bias field correction and gamma correction as pre-processing techniques. Also, we utilized the overlapping patch technique and under-sampling technique to extract small-volume BM from the normal brain that occupies most of the slice. During the training, data augmentations (horizontal flip, vertical flip, random rotation, random blur) were applied on the fly randomly. The detection performance was measured with sensitivity and average false positive rate and the segmentation performance with the Dice coefficient with dilation (DWD) with dilation factor set to a radius of 4 pixels. BMs with volumes 0.04 cc and 49.7% in BM with volumes < 0.04 cc. For all BM, the DWD value was 63%. CONCLUSION Our DL model can detect and segment BM with good performance; it is especially effective even for small-volume BM, suggesting its considerable benefit for gross tumor volume detection and segmentation for stereotactic radiosurgery or SABR.

This study evaluates a risk-based hybrid energy management problem by creating a staircase bidding profile for microgrid operators under a confidence-based incentive demand response program. Scenario-based modeling of photovoltaic, wind turbine, and local loads is achieved by implementing a stochastic/information gap decision theory-based optimization technique; the upstream grid price uncertainty is accounted for, based on the errors between the actual and predicted values. By employing a demand response aggregator, the proposed demand response can be applied to reduce the total expected operating cost and enhance the reliability of the microgrid peak-period load, primarily through peak-period load reduction. To demonstrate the applicability and validate the effectiveness of the proposed risk-based hybrid energy management problem, a case study is analyzed and solved by applying an improved particle swarm optimization algorithm. The results demonstrate that the proposed framework can pursue risk-neutral, risk-averse, and risk-seeker strategies to provide microgrid operator with more degrees of freedom for hedging against risks. In addition, to manage price uncertainty in the optimal scheduling of grid-connected microgrid, operators can build staircase bidding curves that can be effectively submitted to the day-ahead market. Further comparative analysis reveals that the proposed method demonstrates superior solution quality and diversity with a reduced computational burden.

Approximately 48 medical institutions in South Korea own and use blood irradiators; however, the quality control of blood irradiators is insufficient. This study was conducted to establish quality control procedures for blood irradiators using an alanine dosimeter and to ensure reliability of dosimetry. For dosimetry using alanine dosimeters, measurements were performed using an alanine dosimeter jig developed in this study to ensure dose delivery system reliability. Furthermore, the dose and dose distribution were verified, and the uncertainty was evaluated.

This study was designed to investigate differences in psychophysiological responses among individuals with psychopathic tendencies. A total 40 students were participated and were divided into two groups based on Levenson Self-Report Psychopathy Scale (LSRP) scores: a high psychopathic tendency group selected from the top 5% of LSRP scores, and a low psychopathic tendency group selected from the bottom 5% of LSRP scores. All participants were instructed to perform a mock crime and complete the concealed information test (CIT). Results indicate that significant differences between crime-relevant questions and irrelevant questions were observed for respiration line length and skin conductance response in both groups, but heart rate did not significantly differ between groups. There were no differences in psychophysiological responses between the groups. In conclusion, CIT was found to be an effective method for detecting crime-relevant information in individuals with psychopathic tendencies.

Purpose: The aim of this study was to investigate the interaction between BMI at breast cancer diagnosis and the various factors including hormone-receptor, menopausal and nodal status, and to find a specific subgroup where BMI has an effect on breast cancer prognosis. Methods: We retrospectively analyzed the data of 8,763 non-metastatic invasive breast cancer patients from the Asan Medical Center's research database. Overall survival (OS) and breast cancer-specific survival (BCSS) among BMI groups were compared using the Kaplan-Meier method and Cox proportional hazard model with interaction term. Results: Only in node-positive breast cancer, there was a significant interaction between obesity (BMI ≥ 30.0 kg/m2) at diagnosis and positive hormone receptor which showed worse overall survival (OS) and breast cancer specific survival (BCSS) than normal weight patients (adjusted hazard ratio [HR] = 1.65, 95% confidence interval [CI] = 1.01 to 2.69 and HR = 1.90, 95% CI = 1.15 to 3.15, respectively). Underweight (BMI Conclusions: BMI interacts with hormone receptor status in node positive setting, thereby playing a role in the breast cancer prognosis. Citation Format: Chung IY, Lee JW, Lee JS, Park YR, Lee Y, Lee SB, Kim HJ, Ko BS, Son BH, Ahn SH. Interaction between body mass index and hormone receptor status as a prognostic factor in node-positive breast cancer [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P6-09-38.

To transition toward sustainable energy systems, next generation power sources must provide high power density at minimum cost. Using inexpensive and environmentally friendly fabrication methods, this work describes a room temperature electrochemical flow cell with a maximum power density of 2.01 W cm −2 or 13.4 W cm −3 . In part, this is achieved by minimizing ohmic resistance through decreased electrode spacing, implementation of current collectors and improvement of electrolyte conductivity. The majority of the performance gain is provided by a novel in operando dynamic flowing deposition method for which the cell design has been optimized. Carbon nanotubes (CNTs) are deposited dynamically at the entrance of and within the carbon paper electrodes during operation of the cell. A natural equilibrium is reached between deposition and detachment of CNTs at which the electrochemical surface area and pore size distribution of the flow-through porous electrodes are greatly enhanced. In this way, the novel deposition method more than doubles the power density of the cell and sets a new performance benchmark for what is practically attainable with aqueous electrochemical flow cells. Overall, it is expected that the design and operation methods illustrated here will enable a wide range of electrochemical flow cell technologies to achieve optimal performance.

Background Evidence for the benefit of intensive blood pressure lowering in diabetic nephropathy is not clear at this time. The objective of this study was to demonstrate whether lower mean blood pressure (BP) in treated hypertensive patients with diabetic nephropathy is associated with better prognosis. Methods From the National Health Insurance Service (NHIS) Health Examination Database, diabetic hypertensive subjects with proteinuria between 2009 and 2010 were selected and followed-up until 2015 (N=8,663). Mean of the recorded systolic and diastolic BP during follow-up health examinations were stratified into five categories (SBP: Results Compared to SBP of 130 to Conclusion In diabetic hypertensive subjects with overt proteinuria, deterioration of renal function decreased with decreasing SBP and the lowest risk of all-cause death and stroke were observed in SBP

Introduction Guideline-directed medical therapy can induce left ventricular reverse remodeling (LVRR) in nonischemic dilated cardiomyopathy (NIDCM). Some predictors for LVRR have been reported but, there were few studies about the relationship between cardiac magnetic resonance imaging (CMR) parameters and LVRR in NIDCM on optimal GDMT. Methods We retrospectively analyzed echocardiogram and CMR data of newly diagnosed 142 NIDCM patients (age: 57±16 years old, 71.8% male) in a single center from Jan 2012 to Dec 2017. NIDCM was defined as left ventricular ejection fraction (LVEF) Results Baseline LVEF and LV end diastolic dimension (LVEDD) were 27±8% and 64±8 mm. There were 87 patients (61.3%) of LVRR in our cohort. In LVRR group, native T1 value was significantly lower (1326±66 for LVRR vs 1369±72ms, p Conclusion Lower native T1, ECV and T2 on CMR is related to higher incidence of LVRR in NIDCM. Further larger prospective study should be warranted to confirm the relationship between CMR parameters and LVRR in NIDCM.

Reduced exercise capacity is common in patients with hypertrophic cardiomyopathy (HCMP), affecting patients along a broad spectrum of clinical severity. Replacement fibrosis is associated with worse outcomes in patients with HCMP. The aim of study was to evaluate cardiopulmonary exercise test (CPET) and cardiac magnetic resonance (CMR) to predict clinical outcomes in HCMP patients. We enrolled 371 patients with HCMP and normal left ventricular (LV) systolic function (ejection fraction >50%), who underwent both CPET and CMR. CMR at 1.5 T, including late gadolinium delayed enhancement (LGE), was carried out to define the amount of myocardial fibrosis. The primary outcome was hard events including cardiac death, myocardial infarction, cardiac transplantation, sustained ventricular tachycardia, cerebral stroke, and heart failure requiring hospitalization. During follow-up (6.1±2.6 years), there were 74 hard events. The patients were older (56.11±10.37 vs. 52.19±11.17, p=0.006) in the group with hard events. Exercise intolerance as peak oxygen consumption (peak VO2) showed in the group with hard events (25.60±6.01 vs. 30.18±6.81, p This study demonstrated that the exercise intolerance, progression of myocardial fibrosis, and abnormal diastolic parameters could be significant predictors of clinical outcome in the patients with HCMP. CPET and CMR may help us to monitor and manage cardiac events in these patients. Acknowledgement/Funding None

Myocardial fibrosis happened to increased left ventricular (LV) stiffness and higher LV filling pressure likewise diastolic dysfunction, as associated with clinical outcomes in patients with hypertrophic cardiomyopathy (HCMP). Additionally, reduced exercise capacity affected patients along a broad spectrum of clinical severity. The aim of study was to determine the relation between exercise intolerance and LV diastolic parameters to myocardial fibrosis in the patients with HCMP. We enrolled 289 patients with HCMP and normal LV systolic function (ejection fraction >50%). Study populations underwent both cardiopulmonary exercise test (CPET) as estimating peak oxygen consumption (peak VO2) and cardiac magnetic resonance (CMR) as myocardial fibrosis by late gadolinium delayed enhancement (LGE). NT-proBNP levels were determined at baseline. Basic echocardiography was used to measure the diastolic parameters. The study population was included with 248 males (85.8%), and the median age of population was 53 years [interquartile range (IQR) 46–60]. Median follow-up was 6.5 years (IQR 3.2–8.6). The median value of Peak VO2 as a representation of exercise tolerance was 29.0 ml/kg/min (IQR 25.0–34.0) in study population. The amount of LGE on CMR was 14.27 mL (IQR 6.30–27.76). The median value of diastolic parameters as left atrium volume index (LAVI) and E/e' ratio, respectively, were 39.10 mL/m2 (IQR 31.30–47.25) and 10.88 (IQR 8.58–13.31). The median NT-proBNP level was 295.40pg/mL (IQR 139.10–687.70). After adjusting for age and gender, peak VO2 was inversely correlated with NT-proBNP (r=−0.274, p In conclusion, through the correlation among exercise tolerance, parameters of diastolic dysfunction, and myocardial fibrosis, we demonstrated that exercise intolerance and parameters of diastolic dysfunction could predict the myocardial fibrosis in patients with HCMP. We inferred the adverse effects of myocardial fibrosis, as assessed by LGE, lead to diastolic dysfunction and reduced the exercise tolerance. Acknowledgement/Funding None

Background There has been an insufficient in-depth analysis of the nature and prevalence of the typologies of child homicide in Asia, particularly in South Korea. Objective In the current study, we sought to determine the prevalence and identify the heterogeneity of the child homicide phenomenon in South Korea. Participant and settings All 341 original case files (i.e., hospital, police, and autopsy reports) of homicide incidents involving children aged 0–18 in 2016 were obtained from the forensic autopsy archives of the National Forensic Service (NFS), which handles 100 % of the medico-legal autopsies in South Korea. These were examined and reclassified based on our definition. Method A cluster analysis using Gower’s distance was applied, which has rarely been utilized in this field of research. By performing a qualitative analysis, we first extracted 70 (numerical, logical, categorical) crime, victim, perpetrator, and household relevant variables, which were later utilized in the cluster analysis. Results Among the 341 cases from 2016, 95 were judged to be at least suspicious child homicide cases. When applying the cluster analysis, eight sub-clusters were extracted: child torture, maternal filicide, neonaticide, death not related to previous abuse, paternal filicide, paternal infanticide, maternal infanticide, and psychotic killings. Conclusions The commonality and the unique aspect of the child homicide phenomenon in South Korea, in comparison with the results from previous research from other countries, are discussed.

Background The gold standard for diagnosing lupus nephritis is the renal biopsy. While it has several significant benefits, this procedure is not without risk (i.e. bleeding) and only interrogates a minute portion of the renal parenchyma. Recently, near-infrared fluorescent (NIRF) probes have been utilized to image protein activity noninvasively in animals and humans. We hypothesized that specific inflammatory processes observed in nephritis can be noninvasively detected and monitored using NIRF-based optical imaging approaches. Using a probe that becomes fluorescent in the presence of the protease cathepsin B (CatB), we tested the ability of using NIR optical imaging to assess renal inflammation as a noninvasive marker for early-stage glomerulonephritis (GN). Methods Experimental GN was induced in 129 mice by nephrotoxic serum (NTS) delivered intravenously. Proteinuria was quantified using albumin ELISA and chromogenic creatinine assay. NIR optical imaging of anesthetized mice was performed following intravenous administration of a cleavable sensor for CatB and fluorescence intensity of kidney regions quantified using fluorescence molecular tomography (FMT)−3000 instrument at days 1 to 10 post-NTS administration. Results In NTS-treated mice, a strong signal from the CatB-activatable probe was observed as early as day 1, which associated with the onset of proteinuria (figure 1). This signal could be detected for at least 10 days. In contrast, control mice were devoid of any CatB signal. To assess the specificity of CatB signal to GN, we examined CD2AP KO mice that develop nephrotic syndrome in the absence of inflammation. CD2AP KO had no CatB signal despite ongoing nephrosis. Conclusions Induction of GN by NTS was specifically detected noninvasively using a CatB-activatable probe and NIR optical imaging. These data establish the proof-of-principle that novel noninvasive tomographic approaches may represent a translatable approach to establishing early stages of GN. We believe that this approach can be expanded to other experimental imaging approaches, such as photoacoustics, as a novel method for detecting lupus nephritis in humans. Funding Source(s): Department of Defense Discovery Award #W81XWH-17–1–0128 (PI: Kim) Representative images of a control mouse and a mouse treated with nephrotoxic serum to induce glomerulonephritis (NTS). A strong fluorescence signal induced by cathepsin B is observed in NTS-treated mice only.

Background Complement activation is a central pathophysiologic event in several autoimmune diseases. A key activation event is the conversion of native C3 to C3(H2O), where a highly reactive thioester bond in C3 is hydrolyzed. C3(H2O) can be utilized to generate C3 convertase, which further drives complement activation via the alternative pathway. C3(H2O) has been elusive to measure, but we have recently developed a novel ELISA-based assay allowing for its accurate measurement. We hypothesized that in autoimmune diseases where complement activation is a central feature, C3(H2O) levels will be elevated reflecting a primed state for triggering inappropriate alternative pathway activation and amplification. Methods Healthy adult subjects (n=5) and adults with classified SLE (n=6) were enrolled and consented for serum collection at Washington University School of Medicine. Frozen serum was tested either immediately after thawing or after incubation at room temperature or 37°C for 6 or 24 hours. C3(H2O) was measured by an ELISA assay that utilizes a capture antibody to C3b and a detection antibody to C3a. Data was analyzed using Prism version 7.0d (GraphPad Software, Inc.). Statistical significance was determined using 2-way ANOVA with Dunns multiple comparisons test. Results Substantial elevation of serum C3(H2O) levels were observed from patients with SLE following incubation at RT and 37°C compared to healthy controls. The differences were most pronounced in samples incubated at 37°C for 6 hours, with over a 4-fold increase in C3(H2O) levels in both the SLE samples. Interestingly, sera from both groups (healthy controls and SLE) did not reflect any difference in baseline C3(H2O) levels. Conclusions Both SLE and RA are associated with elevated C3(H2O) levels following in vitro incubation compared to healthy controls. These data suggest that the potential for C3(H2O) formation in SLE and RA patients are higher compared to healthy controls, which could support additional complement activation or utilization of C3(H2O) in other pathways such as intracellular activation in immune cells. Thus, In addition to a possible diagnostic tool for pathogenic autoimmunity, these data may also suggest novel mechanisms of how complement could drive symptomatic autoimmune disease. Funding Source(s): NIH R01 GM0099111

Background Complement plays a central role in SLE. Its activation by immune complexes drives type II and III hypersensitivity reactions and classical pathway activation, leading to inflammatory responses in target tissues. Its activation generates an array of bioactive soluble and cell-bound complement activation products (CB-CAPs). Data are lacking detailing the types and quantities of each CB-CAP on SLE immune cells. We speculate that discerning the patterns and impacts of complement signatures on SLE B cells will provide insight into the role of complement activation in the pathogenesis of SLE. To characterize the array of CB-CAPs on SLE immune cells, we created and validated a mass cytometry (MC) panel suitable for detecting over 20 CB-CAPs and complement receptors, then examined PBMCs from paired flare and inactive samples from patients with SLE. Methods Adults with ACR- or SLICC-classified SLE (n=5) were enrolled and consented for PBMC collection at Washington University School of Medicine. Paired samples were obtained, one during a flare and one after resolution of the flare. Frozen ficoll gradient isolated buffy coat PBMCs were thawed counted, filtered, and treated with cisplatin to confirm viability. Prepared cells were stained with metal-conjugated antibodies to measure surface complement proteins and markers identifying immune cell subset. Stained cells were treated with an Iridium intercalator stain, recounted, washed in Milli-Q water to remove salts, resuspended with a solution of bead standards to facilitate data normalization, and subjected to single cell MC. Sample to sample consistency is optimized by simultaneously examining multiple cell preparations barcoded with palladium metals. Data analysis was performed with Cytobank. Distinct cell sub-populations were identified and organized in a hierarchal fashion. Results We found the highest frequency of C4d deposition (indicative of classical pathway activation) on B cells compared to T cells and monocytes during SLE flares. Surprising, only B cells had C3d, C5 (common pathway), and Bb (alternative pathway) CAPs with none observed on T cells or monocytes suggesting that incomplete classical pathway activation occurred on these cells. We also found that different B cell subsets differentially activated complement during flares. Transitional B cells universally had C4d and C5 but surprisingly had little C3d, despite the presence of Bb. Mature B cells, particularly the mature anergic subset, and memory B cells had C4d and C3d but little C5. Plasma cells/plasmablasts were devoid of any CB-CAPs. Finally, during disease inactivity, very low levels of all CB-CAPs were observed on all PBMCs. Conclusions We found a high level of CB-CAP deposition in immune cells obtained from subjects with a SLE flare, which was absent during disease inactivity. The types of CB-CAPs on PBMCs were not uniform, and our data suggest that certain immune cells appear regulate complement activation while others do not. The reasons for this are unclear, but it potentially opens up a previously undescribed heterogeneity in SLE. These pilot data demonstrate the feasibility of the MC complement panel on human samples and the power of this approach in discovering novel mechanisms of complement activation and regulation. Funding Source(s): AHK: NIH/NIAMS R21 AR069833, Doris Duke Charitable Foundation