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Abstract Background An anomalous origin and inter-arterial course of the right coronary artery is a rare anomaly that can lead to sudden ischemic cardiac death if left untreated. We present a case of a patient with an anomalous right coronary artery originating from the left coronary sinus and an inter-arterial course that was managed with coronary artery bypass surgery using a suitable internal mammary artery conduit. The proximal right coronary artery was ligated to prevent competitive flow. Case Presentation A 69 year-old-male with a ten-year history of intermittent chest pain and dyspnea with a negative workup underwent a cardiac catheterization, which showed an anomalous right coronary artery (RCA) originating from the left coronary sinus, with an inter-arterial course between the ascending aorta and pulmonary artery, and approximately 70% narrowing of the proximal RCA. The patient underwent an on-pump coronary artery bypass using the right internal mammary artery (RIMA) as a conduit, with segment 2 of the RCA being the target. The proximal RCA was ligated. Intra-operatively, there were no signs of ischemia or arrhythmia. The patient was successfully taken off cardiopulmonary bypass and eventually discharged home. Conclusion Symptomatic anomalous origin of the right coronary artery with an inter-arterial course can be treated successfully with coronary artery bypass surgery with the internal mammary artery as a conduit. Ligation of the proximal right coronary artery is essential to minimize competitive flow through the bypass graft.

This article analyzes the origin and the development of the women’s partisan journals that were published during the Greek Civil War (1946-1949). It constitutes an unexplored topic despite the fact that it can provide crucial insights into the women of that time. In the beginning, it describes the basic factors of the early feminist editions. Subsequently, it examines the course of those newspapers during WWI and the Interwar period in order to delineate the disruption of their progressive evolution. Afterwards, it presents the changes that affected the character of the women’s publications throughout the Second World War, the Axis occupation and the first post-liberation years. Then, it focuses on the fundamental characteristics of the women’s partisan newspapers, their technical aspects, their objectives, their thematic content and the journalistic coverage of the feminist issues. In parallel, it makes several comparisons with the Spanish case and it places the Hellenic example within a broader framework (pertinent European phenomena, feminist waves, etc.) to outline a clear, satisfying and comprehensive picture. Keywords: press, clandestine, underground, women, publishing, newspapers, journals

Determining the early time prayer is very fundamental for Muslims as it directly relates to the legal requirements of prayer. Prayers are not performed whenever we want, but rather there is a determination of the beginning and end of the prayer time as a guideline for Muslims to carry it out. The Indonesia government sets standards for Muslims to perform the dawn prayer service, by precisely determining the degree of the emergence of the dawn of Sadiq by -200. This study aims to compare the determination of the government's dawn time using different sensors, specifically drone cameras as image sensors. Drones were chosen due to their several advantages. The data generated by the drone is in the form of photos, which are subsequently processed using digital image processing software, called image-J. The data obtained are in the form of mean and standard deviation. All data collected in 1 day is recorded using Excel to form a graph of data which is then carried out by a polynomial approach to find out the cutoff point as the beginning of the dawn of Sadiq which indicates the start of dawn. The method used in this research is using the 4th order polynomial approach and the Sarrus method and the data obtained is the mean value and standard deviation. The conclusions obtained in the image analysis research are that the government's dawn time is 15 minutes too fast, the standard obtained in this study is -14.98° and unlike 2D SQM data, 3D drone data results in more accurate data analysis.

Sudden variability in solar photovoltaic (PV) power output to electrical grid can not only cause grid instability but can also affect power and frequency quality. Therefore, to study the balance of electrical grid or micro-grid power generated by PV systems in an upstream direction, predicting models can help. The power output conversion is directly proportional to the solar irradiance. Unlike time horizons predictions, many technics of irradiance forecasting have been proposed, long, medium and short term forecasting. For the Island of Mauritius in the Indian Ocean, and regards to key policy decisions, the government has outlined its intention to promote the PV technologies through the local electricity supplier but oversee the technical requirements of PV power output predicts for 1 hour to 15-minutes ahead. So, this paper is illustrating results of the Johansen vector error correction model (VECM) cointegration approach, from the author original and previous studies, but for a very short term prediction of 15-minutes to PV power output in Mauritius. The novelty of this study, is the long run equilibrium relationship of the Johansen model, that was initially determined in previous research works and from dataset in Reunion Island, is then applied to the PV plant in the Island of Mauritius. The proposed prediction model is trained for an hourly and 15-minutes period from year 2019 to year 2022 for a random month and a random day. The experimental results show that the performance metric R2 values are more than 93% signifying that Johansen model is positively and strongly correlated to onsite measurements. This proposed model is a powerful predicting tool and more accuracy should be attained when associated to a machine learning method that can learn from datasets.

A 30-year-old nulligravid woman with a history of polycystic ovarian syndrome presented for evaluation of left adnexal mass. The patient was referred to the gynecologic oncology clinic after endorsing signs of abdominal pain for a month and the pelvis ultrasound demonstrated hypoechoic solid mass in the left ovary. Magnetic resonance imaging with T1- and T2-weighted images demonstrated progressive centripetal “filling-in” of the mass suggesting a unique variation of malignant ovarian mass, similar to what is seen in hepatic hemangioma. Upon resection of the ovarian mass, pathology reported that the mass was filled with numerous small blood vessels with single later of endothelial cells confirming the diagnosis of ovarian hemangioma, capillary-type—a rare finding.

Abstract Several FLT3 inhibitors(i) are available to treat relapsed/refractory (R/R) FLT3‐internal tandem duplicated acute myeloid leukemia (AML). This study analyzes the efficacies of various FLT3i (types 1 and 2) tested in clinical trials in treating R/R AML and high‐risk myelodysplastic syndromes (HR‐MDS). PubMed and EMBASE databases were searched for single/double‐arm phase I/II/III R/R AML or HR‐MDS clinical trials published between 1/1/2000 and 6/1/2021. The outcomes studied were composite response rate (CRc) and overall response rate (ORR). Toxicities were compared based on the organ system. The 28 studies analyzed had 1927 patients. The pooled ORR and (CRc) for all FLT3i were 53% (95% CI, 43%–63%) and 34% (95% CI, 26%–44%). Pooled ORR and CRc were 37% (95% CI, 25%–51%) and 35% (95% CI, 21%–52%) for type 1 and 58% (95% CI, 43%–71%) and 38% (95% CI, 27%–50%) for type 2, respectively. Gastrointestinal (GI) and hematological toxicity occurred in 22% (95% CI, 19%–25.4%) and 74.6% (95% CI, 70%–79%) with type 1 and 13.9% (95% CI, 12%–16%) and 57.7% (95% CI, 54.6%–60.8%) with type 2 FLT3i. QTc prolongation occurred in 2.06% (95% CI, 1.03%–3.65%) with type 1 and 7% (95% CI, 5.3%–9%) with type 2 FLT3i. Type 2 FLT3i had less GI toxicity but more QTc prolongation. Prospective studies are needed to compare the efficacy of type 1 and 2 FLT3i.

Classic dyskeratosis congenita is a hereditary disease where the majority of patients present with bone marrow failure and mucocutaneous changes: mainly skin pigmentation, nail dystrophy, oral premalignant leukoplakia, in addition to increased risk for malignancies. A 63-year-old man with a long history of untreated chronic pulmonary disease, a smoker in the past, presented initially with pancytopenia and a clinical diagnosis of myelodysplastic syndrome with excess blasts returned a month later with leukocytosis (WBC 215.9 × 106/μL) and diagnosed with acute myeloid leukemia (AML) with deletion of chromosome 7 and FLT3-TKD mutation. The patient’s mother and sister died in their 6th decade from rapidly progressing fulminant pulmonary fibrosis. He had abnormal skin pigmentation and oral leukoplakia on presentation. He was induced with 7 + 3 chemotherapy and started on midostaurin but experienced prolonged cytopenias, complicated by hypoxic acute on chronic respiratory failure requiring intubation and mechanical ventilation. D + 28 and D + 36 bone marrow examination showed trilineage hypoplasia but no blasts, though the D + 28 bone marrow biopsy revealed one metaphase with del (7) that was cleared on D + 35. The constellation of clinical features and strong family history along with del 7 and FLT3-TKD AML with preceding MDS highly suggests a germline predisposition state dyskeratosis congenita. Germline predispositions are often underrecognized as delayed onset conditions leading to AML and may have treatment and preventative implications especially genetic counseling for blood-related family members.

Abstract A hallmark of ARDS is progressive shrinking of the ‘baby lung,’ now referred to as the ventilator-induced lung injury (VILI) ‘vortex.’ Reducing the risk of the VILI vortex is the goal of current ventilation strategies; unfortunately, this goal has not been achieved nor has mortality been reduced. However, the temporal aspects of a mechanical breath have not been considered. A brief expiration prevents alveolar collapse, and an extended inspiration can recruit the atelectatic lung over hours. Time-controlled adaptive ventilation (TCAV) is a novel ventilator approach to achieve these goals, since it considers many of the temporal aspects of dynamic lung mechanics.

Abstract Background Mediastinal teratomas are rare tumors that frequently occur in the anterior mediastinum. The majority of these tumors are benign and slow growing. Due to their low malignant potential, the treatment for these tumors is surgical resection. More recently, the surgical management has shifted from invasive approaches such as a sternotomy to minimally invasive ones such as robotic-assisted thoracoscopic resections utilizing lung isolation ventilation. We present a rare case of a locally advanced mediastinal teratoma requiring resection, which was initially attempted thoracoscopically using double lung ventilation. Case presentation A 43 year-old female was found to have an anterior mediastinal mass during work-up for an intermittent cough in 2009. Chest imaging and biopsy at the time showed evidence of a cystic teratoma without concerning features. She underwent imaging surveillance until 2018, when repeat chest imaging showed increasing growth and worrisome radiologic features concerning for malignant degeneration. She underwent an elective robotic-assisted thoracoscopic resection utilizing double lung ventilation, but due to extensive involvement of the right lung, pericardium, superior vena cava, and right phrenic nerve the patient had to be repositioned and started on single lung ventilation mid-procedure to facilitate a safe and complete resection. Conclusions Anterior mediastinal teratomas can be successfully removed by robotic-assisted thoracoscopic resections utilizing single lung ventilation. Though robotic-assisted thoracoscopic resection utilizing double lung ventilation can be effective in performing certain procedures such as lung wedge resections, thymectomy, pleural biopsies and minimally invasive cardiac procedures, it is limited in removing locally advanced mediastinal tumors.

Scar quantification on cardiovascular magnetic resonance (CMR) late gadolinium enhancement (LGE) images is important in risk stratifying patients with hypertrophic cardiomyopathy (HCM) due to the importance of scar burden in predicting clinical outcomes. We aimed to develop a machine learning (ML) model that contours left ventricular (LV) endo- and epicardial borders and quantifies CMR LGE images from HCM patients.We retrospectively studied 2557 unprocessed images from 307 HCM patients followed at the University Health Network (Canada) and Tufts Medical Center (USA). LGE images were manually segmented by two experts using two different software packages. Using 6SD LGE intensity cutoff as the gold standard, a 2-dimensional convolutional neural network (CNN) was trained on 80% and tested on the remaining 20% of the data. Model performance was evaluated using the Dice Similarity Coefficient (DSC), Bland-Altman, and Pearson’s correlation. The 6SD model DSC scores were good to excellent at 0.91 ± 0.04, 0.83 ± 0.03, and 0.64 ± 0.09 for the LV endocardium, epicardium, and scar segmentation, respectively. The bias and limits of agreement for the percentage of LGE to LV mass were low (-0.53 ± 2.71%), and correlation high (r = 0.92). This fully automated interpretable ML algorithm allows rapid and accurate scar quantification from CMR LGE images. This program does not require manual image pre-processing, and was trained with multiple experts and software, increasing its generalizability. Author summary Accurate scar quantification of cardiac magnetic resonance (CMR) late gadolinium enhancement (LGE) images is important in managing hypertrophic cardiomyopathy (HCM) patients. We developed a 2D convolutional neural network to quantify CMR LGE in HCM patients that is computationally interpretable and trained using multicenter data analyzed by 2 expert readers using 2 different analysis packages. Our model demonstrated low bias and limits of agreement and high correlation with expert analysis. Benchmarking comparison was performed between our algorithm and standard U-Net model with and without cropped raw images. Our method showed superior performance and has high potential for clinical adaptability.

Background Patients with hypertrophic cardiomyopathy (HCM) are at risk of ventricular arrhythmia (VA) attributed to abnormal electrical activation arising from myocardial fibrosis and myocyte disarray. We sought to quantify intra‐QRS peaks (QRSp) in high‐resolution ECGs as a measure of abnormal activation to predict late VA in patients with HCM. Methods and Results Prospectively enrolled patients with HCM (n=143, age 53±14 years) with prophylactic implantable cardioverter‐defibrillators had 3‐minute, high‐resolution (1024 Hz), digital 12‐lead ECGs recorded during intrinsic rhythm. For each precordial lead, QRSp was defined as the total number of peaks detected in the QRS complex that deviated from a smoothing filtered version of the QRS. The VA end point was appropriate implantable cardioverter‐defibrillator therapy during 5‐year prospective follow‐up. After 5 years, 21 (16%) patients had VA. Patients who were VA positive had greater QRSp (6.0 [4.0–7.0] versus 4.0 [2.0–5.0]; P

Antena-filter mikrostrip merupakan gabungan antara antena dengan filter yang terintegrasi dan multifungsi. Sebagaimana antena mikrostrip lainnya, antena-filter mikrostrip memiliki kekurangan yaitu perolehan yang rendah dan lebar pita yang sempit. Untuk mengatasi perolehan yang rendah, maka penelitian ini mengusulkan penambahan Artificial Magnetic Conductor (AMC) yang diberi lapisan celah udara. Antena-filter terdiri dari sebuah radiator lingkaran yang diintegrasikan dengan dua buah resonator hairpin. Resonator terhubung dengan radiator secara langsung sedangkan antara resonator dengan pencatu 50-ohm terhubung secara kopel. AMC dengan struktur split ring resonator ditambahkan pada bagian atas antena dan diberi celah udara antara keduanya. AMC dirancang sebagai reflektor, fungsi reflektor ini menerima dan memantulkan gelombang ke radiator antena-filter sehingga dapat meningkatkan perolehan. Antena difabrikasi dan diukur dimana hasil pengukuran dengan penambahan AMC berhasil meningkatkan perolehan dari 6,4 dBi menjadi 13,88 dBi pada frekuensi 4,45 GHz. Selain peningkatan perolehan, AMC juga memperbesar lebar pita yang semula 105 MHz menjadi 125 MHz pada rentang frekuensi 3,99 - 4,525 GHz.

ABSTRAK- Penelitian ini merupakan bentuk kajian sederhana yang memanfaatkan biomassa pertanian yaitu batok kelapa yang disintesis menjadi material maju grafen. Grafen merupakan salah satu material maju dan terbarukan dalam bidang sains dan teknologi terkini karena kemanfaatannya yang multifungsi. Penelitian ini diawali dengan mengubah biomassa batok kelapa menjadi karbon melalui suatu reaksi pembakaran. Arang hasil dari pembakaran selanjutnya diberikan perlakuan dengan metode reduksi kimia atau metode Hummer tereduksi. Hasil penelitian ini memperlihatkan bentuk morfologi grafen berupa serpihan-serpihan atau dikenal dengan istilah grafen Flakes. Hasil ini terkonfirmasi melalui uji visualisasi SEM, dimana grafen Flakes diperlihatkan dalam formasi tumpukan mengindikasikan struktur multilayer. Hasil uji TEM memperlihatkan jarak antar kisi kristal yang dimilikinya yaitu berkisar pada 2,40 dan 2,46 Å. Berdasarkan pada data jarak antar kisi kristal tersebut, hasil simulasi energi menggunakan prinsip DOS didapatkan bahwan grafen hasil sintesis memiliki energi secara berturut-turut adalah 4,0 eV untuk level konduksi dan 3,3 eV untuk level valensi. Hasil uji optik sifat absorbansi dan fluoresens memperlihatkan grafen memiliki dua puncak serapan utama yang berkorelasi dengan terjadinya transisi energi dan dari bentuk ikatan C=C dan C-O-C. Adapun pendaran yang dihasilkan melalui uji fluoresensi adalah warna hijau dengan panjang gelombang 525 nm. Secara sederhana rancangan penelitian dapat dikatakan telah berhasil dalam mensintesis grafen dari arang batok kelapa, meskipun belum sempurna dan masih perlu untuk dilakukan kajian kembali. Hasil dari penelitian ini selanjutnya akan dikembangkan lagi menjadi bentuk grafen dengan morfologi yang berpori. ABSTRACT− This research is a simple study that takes an advantage of agricultural biomass that is synthesized cocconut shell to become graphene, an advanced material. Graphene is one of advanced-and-renewable material in the recent science and technology due to its multifunctional values.The research started with a changed cocconut shell being carbon through a burning reaction. Then the next procedure is given to the charcoal, produced from the burning process, by chemical reduction method or reduced hummer method.The observation showed a morphological form of graphen known as graphen flakes. It had been confirmed by SEM visualization test where the graphene flakes exhibited in a drift formafion indicated a multilayer structure. TEM test result showed a space in the owned crystal lattice approximately from 2.4 to 2.46 Å. Based on the data of the crystal lattice space, the result of energy simulation using DOS principal impressed that synthesized graphen has energy respectively 4.0 eV for a conduction and 3.3 eV for valency level. Therefore, the absorbantion and fluorecence result of the optical test showed that the graphen has two main absorptions corellated with the transitional energy of and to the form of C=C and C-O-C. However, emission resulted from fluorecence test is green with wavelength 525 nm. In a simple way, this reseach project can be resumed as a success study in the synthesized coconut from cocconut shell, while it had not been perfect, yet, and it needed to be advanced. Next, the outcome of the study will be developed more to be a porous graphen form

This article presents a Johansen test assessing the predetermined long-term relationships of datasets from a photovoltaic (PV) plant to predict the power output of an island zone. The goal was to use Johansen’s model to predict the PV power generation in the island of Mauritius. In this article, time series using an on-site measurement dataset have been used to design an original prediction model, the Johansen model for PV power output. This model is trained to predict random monthly, weekly, and daily PV power outputs in different seasons and years. The experimental results demonstrate that the Johansen model is a powerful medium-term predicting tool.

Since 2007 Reunion Island, a French overseas region located in the Indian Ocean, aims to achieve energy self-sufficiency by 2030. The French government has made this insular zone an experimental territory for renewable energy resources (RES) by implementing great powers photovoltaic (PV) plants. However, the performance of PV conversion is highly climate dependent, and there have been many research contributions to show that the two main factors that influence PV cell efficiency are solar radiation and cell temperature. Moreover, considering the high variability of environmental factors on PV plants, the high penetration of PV in electric systems may threaten the stability and reliability of the electrical power grid. In this study, a linear relation analysis of time series data collected over one year is performed in order to investigate the dependent variable of PV power output from explanatory variables such as solar irradiance, cell temperature, wind speed and humidity. The originality of this paper is to apply cointegration methods, usual tools of econometrics, to PV systems. More precisely, this research work lies in the use a robust statistical method to model a vector cointegrating relationship linking the PV power output and the four environmental parameters mentioned above, to make accurate forecasts in a tropical area. The Johansen vector error correction model (VECM) cointegration approach is used to determine the most appropriate PV power output forecasting when the desired model is concerned with N explanatory variables and for N > 2. This long run equilibrium relationship has been tested over many years of data and the outcome is more than reliable when comparing the model to measured data.

Latar belakang. Talasemia merupakan penyakit keturunan akibat kelainan sel darah merah yang belum dapat disembuhkan, tetapi dapat dicegah. Berbagai studi memperlihatkan bahwa program pencegahan melalui skrining talasemia jauh lebih menguntungkan dibandingkan pengobatan. Skrining dapat dilakukan melalui berbagai metode, di antaranya skrining populasi umum dan populasi khusus. Sampai saat ini belum ada pedoman skrining khusus pada populasi dengan risiko tinggi. Tujuan. Mengumpulkan bukti ilmiah mengenai validitas, manfaat, dan rekomendasi metode skrining keluarga (cascade family screening) pada penyandang talasemia. Metode. Penelusuran pustaka secara daring lewat Pubmed Clinical Queries, Cochrane Library, dan Google Scholar. Hasil. Didapatkan tiga artikel studi potong lintang yang berhubungan dengan pertanyaan klinis penelitian. Ketiga penelitian tersebut mempraktikan skrining kaskade pada anggota keluarga pasien talasemia-β mayor dalam tiga generasi. Studi pertama (Ansari, dkk) menunjukkan 62,2% anggota keluarga yang diskrining merupakan pembawa sifat talasemia beta. Studi kedua (Gorakshakar, dkk) menunjukkan angka pembawa sifat sebesar 21,9%. Studi ketiga (Baig, dkk) menunjukkan angka pembawa sifat sebesar 44,4%. Angka ini lebih besar dari frekuensi pembawa sifat talasemia dari populasi umum sebesar 5−8%. Kesimpulan. Skrining kaskade merupakan pilihan yang efektif dan praktikal dibandingkan dengan skrining populasi pada negara-negara dengan keterbatasan biaya dan sumber daya fasilitas kesehatan.

Pediatric acute respiratory distress syndrome (PARDS) remains a significant cause of morbidity and mortality, with mortality rates as high as 50% in children with severe PARDS. Despite this, pediatric lung injury and mechanical ventilation has been poorly studied, with the majority of investigations being observational or retrospective and with only a few randomized controlled trials to guide intensivists. The most recent and universally accepted guidelines for pediatric lung injury are based on consensus opinion rather than objective data. Therefore, most neonatal and pediatric mechanical ventilation practices have been arbitrarily adapted from adult protocols, neglecting the differences in lung pathophysiology, response to injury, and co-morbidities among the three groups. Low tidal volume ventilation has been generally accepted for pediatric patients, even in the absence of supporting evidence. No target tidal volume range has consistently been associated with outcomes, and compliance with delivering specific tidal volume ranges has been poor. Similarly, optimal PEEP has not been well-studied, with a general acceptance of higher levels of FiO2 and less aggressive PEEP titration as compared with adults. Other modes of ventilation including airway pressure release ventilation and high frequency ventilation have not been studied in a systematic fashion and there is too little evidence to recommend supporting or refraining from their use. There have been no consistent outcomes among studies in determining optimal modes or methods of setting them. In this review, the studies performed to date on mechanical ventilation strategies in neonatal and pediatric populations will be analyzed. There may not be a single optimal mechanical ventilation approach, where the best method may simply be one that allows for a personalized approach with settings adapted to the individual patient and disease pathophysiology. The challenges and barriers to conducting well-powered and robust multi-institutional studies will also be addressed, as well as reconsidering outcome measures and study design.

Pediatric hypertrophic cardiomyopathy (HCM) is the most common form of cardiomyopathy in children and a leading cause of sudden cardiac death. Yet, the association between genotype variation, phenotype expression, and adverse events in pediatric HCM has not been fully elucidated. Although the literature on this topic is evolving in adult HCM, the evidence in children is lacking. Solidifying our understanding of this relationship could improve risk stratification as well as improve our comprehension of the underlying pathophysiological characteristics of pediatric HCM. In this state‐of‐the‐art review, we examine the current literature on genetic variations in HCM and their association with outcomes in children, discuss the current approaches to identifying cardiovascular phenotypes in pediatric HCM, and explore possible avenues that could improve sudden cardiac death risk assessment.

Background Unlike T‐wave alternans (TWA), the relation between QRS alternans (QRSA) and ventricular arrhythmia (VA) risk has not been evaluated in hypertrophic cardiomyopathy (HCM). We assessed microvolt QRSA/TWA in relation to HCM risk factors and late VA outcomes in HCM. Methods and Results Prospectively enrolled patients with HCM (n=130) with prophylactic implantable cardioverter‐defibrillators underwent digital 12‐lead ECG recordings during ventricular pacing (100–120 beats/min). QRSA/TWA was quantified using the spectral method. Patients were categorized as QRSA+ and/or TWA+ if sustained alternans was present in ≥2 precordial leads. The VA end point was appropriate implantable cardioverter‐defibrillator therapy over 5 years of follow‐up. QRSA+ and TWA+ occurred together in 28% of patients and alone in 7% and 7% of patients, respectively. QRSA magnitude increased with pacing rate (1.9±0.6 versus 6.2±2.0 µV; P=0.006). Left ventricular thickness was greater in QRSA+ than in QRSA− patients (22±7 versus 20±6 mm; P=0.035). Over 5 years follow‐up, 17% of patients had VA. The annual VA rate was greater in QRSA+ versus QRSA− patients (5.8% versus 2.0%; P=0.006), with the QRSA+/TWA− subgroup having the greatest rate (13.3% versus 2.6%; P

Abstract Tumor immunology has changed the landscape of cancer treatment. Yet, not all patients benefit as cancer immune responsiveness (CIR) remains a limitation in a considerable proportion of cases. The multifactorial determinants of CIR include the genetic makeup of the patient, the genomic instability central to cancer development, the evolutionary emergence of cancer phenotypes under the influence of immune editing, and external modifiers such as demographics, environment, treatment potency, co-morbidities and cancer-independent alterations including immune homeostasis and polymorphisms in the major and minor histocompatibility molecules, cytokines, and chemokines. Based on the premise that cancer is fundamentally a disorder of the genes arising within a cell biologic process, whose deviations from normality determine the rules of engagement with the host’s response, the Society for Immunotherapy of Cancer (SITC) convened a task force of experts from various disciplines including, immunology, oncology, biophysics, structural biology, molecular and cellular biology, genetics, and bioinformatics to address the complexity of CIR from a holistic view. The task force was launched by a workshop held in San Francisco on May 14–15, 2018 aimed at two preeminent goals: 1) to identify the fundamental questions related to CIR and 2) to create an interactive community of experts that could guide scientific and research priorities by forming a logical progression supported by multiple perspectives to uncover mechanisms of CIR. This workshop was a first step toward a second meeting where the focus would be to address the actionability of some of the questions identified by working groups. In this event, five working groups aimed at defining a path to test hypotheses according to their relevance to human cancer and identifying experimental models closest to human biology, which include: 1) Germline-Genetic, 2) Somatic-Genetic and 3) Genomic-Transcriptional contributions to CIR, 4) Determinant(s) of Immunogenic Cell Death that modulate CIR, and 5) Experimental Models that best represent CIR and its conversion to an immune responsive state. This manuscript summarizes the contributions from each group and should be considered as a first milestone in the path toward a more contemporary understanding of CIR. We appreciate that this effort is far from comprehensive and that other relevant aspects related to CIR such as the microbiome, the individual’s recombined T cell and B cell receptors, and the metabolic status of cancer and immune cells were not fully included. These and other important factors will be included in future activities of the taskforce. The taskforce will focus on prioritization and specific actionable approach to answer the identified questions and implementing the collaborations in the follow-up workshop, which will be held in Houston on September 4–5, 2019.

Penjatuhan sanksi pidana terhadap Jaksa Penuntut Umum diakarenakan tidak melakukan kewajiban mengeluarkan anak dari tahanan sebagaimana diatur dalam Pasal 34 Undang-undang Nomor 11 Tahun 2012. Pelanggaran tersebut merupakan pelanggaran administratif bukan merupakan suatu perbuatan pidana. Ancaman pidana terhadap perbuatan pelanggaran yang bersifatadministratif merupakan tanggungjawab bersama dengan lembagapemasyarakatn dalam hal penahanan seorang anak yang berhadapandengan hukum sangatlah tidak tepat dan error in iuris karena sanksi administratifmerupakan konsekuensi logis pertama yang harus didahulukan dari sanksipidana. Berdasarkan pengalaman penulis sebagai Jaksa Penuntut Umum, adanya sanksi pidana terhadap jaksa dalam penanganan perkara anak berdampak buruk bagi kalangan jaksa. Banyak jaksa yang menghindar bahkan ketakutan dalam menangani perkara anak. Kebanyakan jaksa menolak jika ditunjuk untuk menangani perkara anak. Dengan status jaksa sebagai PNS sebagaimana diamanatkan dalam UU Kejaksaan, membuat profesi jaksa harus tunduk pula kepada UU ASN. Oleh karena itu secara tidak langsung, Jaksa wajib menerapkan AUPB dalam melaksanakan tugas-tugasnya. Dalam rangka mewujudkan jaksa yang memiliki integritas kepribadian serta disiplin tinggi guna melaksanakan tugas penegakan hukum dalam rangka mewujudkan keadilan dan kebenaran, maka dikeluarkanlah kode etik prilaku jaksa sebagaimana tertuang dalam Peraturan Jaksa Agung Republik Indonesia Nomor Per –014/A/Ja/11/2012 Tentang Kode Perilaku Jaksa. Berdasarkan ketentuan Pasal 12 Kode Prilaku Jaksa, Jaksa yang terbukti melakukan pelanggaran dijatuhi tindakan administratif dengan tidak mengesampingkan ketentuan pidana dan hukuman disiplin berdasakan peraturan disiplin pegawai negeri sipil apabila atas perbuatan tersebut terdapat ketentuan yang dilanggar.

Research on superheavy elements enables probing the limits of nuclear existence and provides a fertile ground to advance our understanding of the atom’s structure. However, experimental access to these atomic species is very challenging and often requires the development of new technologies and experimental techniques optimized for the study of a single atomic species. The Laser Resonance Chromatography (LRC) technique was recently conceived to enable atomic structure investigations in the region of the superheavy elements. Here, we give an update on the experimental progress and simulation results.

The electronic structure of coordination compounds with lanthanide ions is studied by means of density functional theory (DFT) calculations. This work deals with the electronic structure and properties of open-shell systems based on the calculation of multiplet structure and ligand-field interaction, within the framework of the Ligand–Field Density-Functional Theory (LFDFT) method. Using effective Hamiltonian in conjunction with the DFT, we are able to reasonably calculate the low-lying excited states of the molecular [Eu(NO3)3(phenanthroline)2] complex, subjected to the Eu3+ configuration 4f6. The results are compared with available experimental data, revealing relative uncertainties of less than 5% for many energy levels. We also demonstrate the ability of the LFDFT method to simulate absorption spectrum, considering cerocene as an example. Ce M4,5 X-ray absorption spectra are simulated for the complexes [Ce(η8−C8H8)2] and [Ce(η8−C8H8)2][Li(tetrahydrofurane)4], which are approximated by the Ce oxidation states 4+ and 3+, respectively. The results showed a very good agreement with the experimental data for the Ce3+ compound, unlike for the Ce4+ one, where charge transfer electronic structure is still missing in the theoretical model. Therefore this presentation reports the benefits of having a theoretical method that is primarily dedicated to coordination chemistry, but it also outlines limitations and places the ongoing developmental efforts in the broader context of treating complex molecular systems.

The four-component relativistic Dirac–Coulomb Hamiltonian and the multireference configuration interaction (MRCI) model were used to provide the reliable energy levels and spectroscopic properties of the Lr+ ion and the Lu+ homolog. The energy spectrum of Lr+ is very similar to that of the Lu+ homolog, with the multiplet manifold of the 7s2, 6d17s1 and 7s17p1 configurations as the ground and low-lying excited states. The results are discussed in light of earlier findings utilizing different theoretical models. Overall, the MRCI model can reliably predict the energy levels and properties and bring new insight into experiments with superheavy ions.

Power output from photovoltaic (PV) systems in outdoor conditions is substantially influenced by climatic parameters such as solar irradiance and temperature. PV manufacturers always provide technical specifications in laboratory conditions but reliable relationship for the power output must be determined for accurate prediction under real operating conditions. For the present study, solar irradiance G, temperature T and electrical power output P data under real conditions are methodically and regularly inscribed in dataloggers. Hence, in this paper, we investigate rigorous and robust statistical methods for small sample such as Augmented Dickey-Fuller and Engle Granger for stationary series to determine the estimate regression between variables P, G & T. A first regression of power output P time series variable on solar irradiance G time series has shown spurious results and thus spurious regression. The first differences of such time series are stationary and a regression is proposed whereas temperature variable is identified as not significant and where autocorrelation of residuals is suspected. Finally, the novelty of this paper is the Engle & Granger method that is used to provide a relationship between variables P and G in a difference level. A final relationship without suspicious heteroscedasticity has been determined. Our model is formulated on the basis of PV real conditions statistical approach and is more realistic than steady approach models.

Ukraine and People's Republic of China (PRC) are cooperating in some areas like: machinery, transportation etc. China is interested in partnering with Ukraine for selling Chinese consumer goods. Ukraine is interested in selling raw materials to China. To study this possible cross-border cooperation and commercial relationship, the current paper uses the "intensity of interaction" (namely, the depth of integration) model, which is based upon the existing “gravity model”. The index for existing model has been obtained by adding a “dummy variable” in the standard "gravity model" which reflects the influence of regional nuances upon the level and direction of trade flow. The strategic partner relationship must be based on: "complementing" the economic structure of the partners, which means equality in the relationship and lack of significant disparities.

Abstract Background Regional variability of longitudinal strain (LS) has been previously described with echocardiography in patients with cardiac amyloidosis (CA), however, the reason for this variability is not completely evident. We sought to describe regional patterns in LS using feature-tracking software applied to cardiovascular magnetic resonance (CMR) cine images in patients with CA, hypertrophic cardiomyopathy (HCM), and Anderson-Fabry’s disease (AFD) and to relate these patterns to the distribution of late gadolinium enhancement (LGE). Methods Patients with CA (n = 45) were compared to LV mass indexed matched patients with HCM (n = 19) and AFD (n = 19). Peak systolic LS measurements were obtained using Velocity Vector Imaging (VVI) software on CMR cine images. A relative regional LS ratio (RRSR) was calculated as the ratio of the average of the apical segmental LS divided by the sum of the average basal and mid-ventricular segmental LS. LGE was quantified for the basal, mid, and apical segments using a threshold of 5SD above remote myocardium. A regional LGE ratio was calculated similar to RRSR. Results Patients with CA had significantly had worse global LS (−15.7 ± 4.6%) than those with HCM (−18.0 ± 4.6%, p = 0.046) and AFD (−21.9 ± 5.1%, p

Background There is little understanding of whether a physician's tendency to order an inappropriate cardiac service is associated with the use of other cardiac services and clinical outcomes in their patients with heart failure (HF). Methods and Results We conducted a secondary analysis of 35 Ontario‐based cardiologists who participated in the control arm of the Echo WISELY (Will Inappropriate Scenarios for Echocardiography Lessen Significantly) trial. Transthoracic echocardiograms, ordered during the trial, were classified as rarely appropriate (rA), appropriate, or maybe appropriate on the basis of the 2011 appropriate use criteria. Cardiologists were grouped into tertiles of rA transthoracic echocardiogram ordering frequency: low ordering (bottom tertile), n=11; moderate ordering, n=12; or high ordering (top tertile), n=12. The main outcomes were measures of cardiac service use, including cardiology‐related physician visits, tests, and medications. Among 1677 patients with heart failure and an outpatient visit to 1 of 35 cardiologists, we found no significant association between rA transthoracic echocardiogram ordering frequency (by tertile) and cardiac testing use, although patients of cardiologists in the high ordering group had fewer physician visits, on average, than patients seen by low ordering cardiologists. In addition, patients of cardiologists in the highest rA ordering tertile had significantly lower odds of receiving potentially effective interventions, such as β blockers (odds ratio, 0.62; 95% CI, 0.43–0.89), than the low ordering group. Conclusions Although patients of cardiologists who frequently order rA transthoracic echocardiograms do not appear more (or less) likely to have subsequent cardiac tests, these patients have fewer follow‐up visits and lower odds of receiving evidence‐based medications. Clinical Trial Registration URL: http://www.clinicaltrials.gov. Unique identifier: NCT02038101.

Latar belakang. Kadar leptin meningkat pada obesitas sehingga diduga ada peran leptin dalam menimbulkan manifestasi penyakit atopik. Tujuan. Mengetahui hubungan antara kadar leptin serum dan manifestasi penyakit atopik pada anak obesitas. Metode. Penelitian cross sectional yang dilaksanakan pada bulan November 2013, melibatkan siswa beberapa Sekolah Dasar di Kota Bandung usia 6-11 tahun, terbagi menjadi kelompok anak obesitas dan gizi normal, masing-masing 34 anak. Dilakukan anamnesis untuk memperoleh data riwayat penyakit atopi di keluarga dan faktor lingkungan yang memengaruhi atopi, pemeriksaan uji tusuk kulit untuk mengetahui adanya atopi, pemeriksaan ELISA untuk kadar leptin serum, dan kuesioner ISAAC untuk manifestasi penyakit atopik. Analisis statistik yang digunakan adalah uji chi kuadrat. Kurva ROC digunakan untuk melihat batas kadar leptin yang dapat menimbulkan manifestasi penyakit atopik. Hasil. Kadar leptin tinggi lebih banyak didapatkan pada anak obes dengan manifestasi penyakit atopik (n=20) dibandingkan dengan tanpa manifestasi penyakit atopik (n=10) dan anak gizi normal dengan manifestasi penyakit atopik (n=10) maupun tanpa manifestasi penyakit atopik (n=13) (p=0,04). Keimpulan. Kadar leptin serum tinggi lebih banyak didapatkan pada anak obes dengan manifestasi penyakit atopik dibandingkan dengan anak obesitas tanpa manifestasi penyakit atopik.

Macro-bending effect unto polymer optical fiber (POF) based splitters study is done to analyse the performance and characterizations using several bending radii of geometrical blocks that hold a customized prepared polymer fiber splitter. A pair of etched fibers with similar core diameters are attached to the ellipse-shaped blocks built using matching refractive index material where the blocks were built with various bending radii. The tapered fibers were lapped closely with some forces exerted upon them in order to stimulate the splitting of modes between the two fibers. This study is done by experimental set-up where each of the splitter ports is connected with optical power meter to measure the power output while pressure is exerted. Characterization is executed in order to investigate and analyse which bending radius gives the most optimize splitting ratio with considerable low loss for the particular splitter prepared. As for normal force of 0.3 lbF, the optimum splitting ratio with low loss is specified having bending radius, Rc, of 13 mm whilst for external force of 3.0 lbF, bending radius is found to be 19 mm. Small bending radius stimulates the radiation of rays into the second fiber while larger Rc gives longer coupling length that optimize the splitting ratios. Efficiencies between simulated values and experimental values are also analysed.

Latar belakang. Terbentuknya inhibitor atau antibodi terhadap FVIII pada pasien hemofilia A menyebabkan FVIII eksogen yang diberikan tidak dapat berfungsi. Penyebab bersifat multifaktorial terdiri atas faktor genetik dan lingkungan. Beberapa penelitian telah dilakukan untuk mengetahui faktor risiko terbentuknya inhibitor, akan tetapi masih terdapat pendapat yang kontroversial. Tujuan. Menentukan faktor risiko non-genetik inhibitor faktor VIII pada pasien hemofilia A. Metode. Penelitian desain potong lintang pada pasien hemofilia A yang terdaftar pada Himpunan Masyarakat Hemofilia Jawa Barat dari bulan Desember 2012–Juni 2013. Analisis bivariat dilakukan dengan uji chi-kuadrat dan uji t. Hasil. Terdapat 85 pasien hemofilia A yang mendapat terapi koate®. Prevalensi inhibitor 81,13% (69/85), usia inhibitor positif 9,96 (6,49) tahun dan inhibitor negatif 8,69 (3,87) tahun. Hubungan faktor risiko usia pertama kali mendapat terapi, jenis hemofilia A, riwayat operasi, dan frekuensi terapi dengan inhibitor faktor VIII pada pasien hemofilia A berturut-turut adalah p=0,512; p=0,202; p=0,663; p=0,276. Kesimpulan. Faktor risiko non-genetik tidak berhubungan dengan inhibitor faktor VIII pada pasien hemofilia A.

Following publication of the original article [1], the author reported that an author name, Roberta Zappasodi, was missed in the authorship list.

BackgroundDisopyramide is effective in ameliorating symptoms in patients with hypertrophic cardiomyopathy; however, its potential for proarrhythmic effect has raised concerns about its use in the ambulatory setting. The risk of initiating disopyramide in this manner has never been evaluated. Methods and ResultsAll charts of patients seen in the outpatient hypertrophic cardiomyopathy clinic between 2010 and 2014 were screened for initiation of disopyramide and data were extracted. Disopyramide in our clinic is usually initiated at a dose of 300 mg daily and titrated during follow‐up. A total of 2015 patients were seen in the clinic, including 168 who were started on disopyramide. There were no cardiac events within 3 months of disopyramide initiation. During long‐term follow‐up (255 patient‐years; mean, 447 days; interquartile range, 201–779), only 2 patients developed cardiac events (syncope of unknown cause in both). Thirty‐eight patients (23%) developed side effects of disopyramide and 18 (11%) stopped the drug because of these side effects. Of the patients continuing disopyramide long term, 63% remained free of septal reduction interventions at end of follow‐up. Disopyramide at a dose of 300 mg prolonged the mean QTc interval by 19±23 ms; however, increasing the dose to 600 mg had no further significant effect. ConclusionsInitiation of disopyramide in the outpatient setting is safe and the risk of subsequent sudden cardiac death is low. Because of its QT‐prolonging effect, precautions may be necessary in patients at higher risk of torsades de pointes.

PT. Pupuk Kaltim is biggest manure manufacturer in Indonesia, where its market area covering entire Sulawesi, Bali, some of Kalimantan East Java, Papua, Japan, Taiwan, India, and Australia. Main produced product of PT Pupuk Kaltim is based fertilizer. To meet the demand, PT Kaltim produce up to 2,3 million tons per year.Identifiaction process of supply chain done by accesing company website of PT Kaltim. Then it is outlined each step of supply chain from aggregate planning, production process, suppliers selection, quality mangement, warehousing, performance measure and used transportation unit. From that criteria would visible supply chain of based-fertilizer in PT Pupuk Kaltim. By having long and wide supply chain, PT Pupuk Kaltim still have bullwhip effect because of inacurate in forecasting cause over-stock or out of stock in many production period. In quality, PT Kaltim had got ISO 9001, ISO 14001 and ISO 17025 certification in production management and sea-port. Keywords: Fertilizer, supply chain, analysis

In this study, we examine the behavior of a propane diffusion flame with air in a burner; the computational investigations are achieved for each case employing the Fluent package. The graphs generated illustrate the influence of flow parameters, the effects of the oxygen percentage in the air, and the effects of the equivalence ratio φ on the entropy generation, the temperature gradients, and the Bejan number. The obtained results show that incorporation of hydrogen with propane reduced both temperature and carbon monoxide emission.

Bank BRI Unit Pasar Baru merupakan unit yang baru didirikan beberapa bulan belakangan ini. BRI unit ini melayani berbagai transaksi perbankan, diantaranya menabung, penarikan uang, peminjaman bahkan melakukan transfer baik sesama bank BRI maupun ke beberapa bank yang lain. Bank ini didirikan karena banyak nasabah yang berada di sekitar Pasar Baru yang biasanya melakukan transaksi ke BRI Unit Bandar Buat sekarang sudah dapat dilakukan di BRI Unit Pasar Baru. Ini merupakan salah satu langkah dari BRI untuk meningkatkan kualitas pelayanannya kepada masyarakat. Dalam melakukan kegiatan transaksinya bank ini mempunyai dua teller. Kedua teller ini melayani semua jenis transaksi, sehingga teller harus memahami masing-masing sistem dalam setiap jenis transaksi. Berdasarkan keterangan diatas, Hal ini merupakan masalah yang menarik untuk dibahas karena sistem yang ada pada bank ini masih melakukan penyesuaian dalam operasinya dikarenakan bank ini merupakan unit baru dari Bank BRI. Setiap hari bank ini melayani banyak nasabah untuk melakukan transaksi yang berbeda-beda. Jumlah nasabah yang melakukan transaksi tertentu tidak sama setiap harinya, kadang-kadang pada hari tertentu jumlah nasabah yang menabung tinggi, misalnya pada awal bulan dan begitu juga sebaliknya. Oleh karena itu, keadaan yang dinamis seperti ini perlu dilakukan simulasi sistem agar probabilitas atau kemungkinan dari sistem pada setiap harinya dapat ditentukan. Hasil yang diperoleh dari simulasi yang dilakukan Bank BRI Unit Pasar Baru Padang adalah jumlah teller yang dimiliki sekarang yaitu sebanyak 2 teller cukup untuk melayani nasabah Bank BRI untuk wilayah Pasar Baru dan sekitarnya. Hal ini dikarenakan jumlah nasabah yang datang perhari rata-rata 13-14 nasabah, sehingga utilitas masing-masing teller adalah 0.204 pada teller 1 dan 0.221 pada teller 2.

Background Febrile neutropenia is the most common side effect of myelosuppressive chemotherapy. It is important to identify its risk factors to decrease the morbidity and mortality of febrile neutropenia. Objective To identify whether age, type of malignancy, phase and dose of chemotherapy, nutritional status, and absolute neutrophyl count are risk factors for febrile neutropenia. Methods A hospital-based case control study was conducted at Hasan Sadikin Hospital from June 2000 to July 2005. Data was collected from medical records. The case group consisted of children with malignancy who received chemotherapy and suffered from febrile neutropenia, while the control group consisted of children without febrile neutropenia. Chi square and logistic regression analysis were performed to analyze data using SPSS for Windows version 13.0. Results Eighty-seven cases and 94 controls were evaluated. Analysis showed that malignancy type i.e, hematologic malignancy, chemotherapy phase, and absolute neutrophyl count might be the risk factors for febrile neutropenia (OR=4.6, 95% CI 1.3;16.7, P=0.019; OR=8.1, 95% CI 2.2;30.5, P=0.002; and OR=1.0, 95% CI 1.003;1.007, P

Tolerogenic dendritic cells (tolDC) are a new immunotherapeutic tool for the treatment of rheumatoid arthritis (RA) and other autoimmune disorders. We have established a method to generate stable tolDC by pharmacological modulation of human monocyte-derived DC. These tolDC exert potent pro-tolerogenic actions on CD4 + T cells. Lack of interleukin (IL)-12p70 production is a key immunoregulatory attribute of tolDC but does not explain their action fully. Here we show that tolDC express transforming growth factor (TGF)-β1 at both mRNA and protein levels, and that expression of this immunoregulatory cytokine is significantly higher in tolDC than in mature monocyte-derived DC. By inhibiting TGF-β1 signalling we demonstrate that tolDC regulate CD4 + T cell responses in a manner that is at least partly dependent upon this cytokine. Crucially, we also show that while there is no significant difference in expression of TGF-βRII on CD4 + T cells from RA patients and healthy controls, RA patient CD4 + T cells are measurably less responsive to TGF-β1 than healthy control CD4 + T cells [reduced TGF-β-induced mothers against decapentaplegic homologue (Smad)2/3 phosphorylation, forkhead box protein 3 (FoxP3) expression and suppression of (IFN)-γ secretion]. However, CD4 + T cells from RA patients can, nonetheless, be regulated efficiently by tolDC in a TGF-β1-dependent manner. This work is important for the design and development of future studies investigating the potential use of tolDC as a novel immunotherapy for the treatment of RA., (© 2016 British Society for Immunology.)

Background: Alemtuzumab, an anti-CD52 monoclonal antibody, was administered to patients with RA between 1991 and 1994. We have followed a cohort of recipients since that time and previously reported significant delays in immune reconstitution. Here we report >20 years of follow-up data from this unique cohort., Method: Surviving alemtuzumab recipients were age, sex and disease duration matched with RA controls. Updated mortality and morbidity data were collected for alemtuzumab recipients. For both groups antigenic responses were assessed following influenza, Pneumovax II and combined diphtheria/tetanus/poliovirus vaccines. Circulating cytokines and lymphocyte subsets were also quantified., Results: Of 16 surviving alemtuzumab recipients, 13 were recruited: 9 recipients underwent a full clinical assessment and 4 had case notes review only. Since our last review 10 patients had died from causes of death consistent with long-standing RA, and no suggestion of compromised immune function. Compared with controls the alemtuzumab cohort had significantly reduced CD4 + and CD8 + central memory T-cells, CD5 + B cells, naïve B cells and CD19 + CD24 hi CD38 hi transitional (putative regulatory) B cells. Nonetheless vaccine responses were comparable between groups. There were significantly higher serum IL-15 and IFN-γ levels in the alemtuzumab cohort. IL-15 levels were inversely associated with CD4 + total memory and central memory T cells., Conclusion: After 20 years the immune system of alemtuzumab recipients continues to show differences from disease controls. Nonetheless mortality and morbidity data, alongside vaccination responses, do not suggest clinical immune compromise. As lymphodepleting therapies, including alemtuzumab, continue to be administered this work is important with regard to long-term immune monitoring and stages of immune recovery.

Cellular therapies with tolerogenic antigen-presenting cells (tolAPC) show great promise for the treatment of autoimmune diseases and for the prevention of destructive immune responses after transplantation. The methodologies for generating tolAPC vary greatly between different laboratories, making it difficult to compare data from different studies; thus constituting a major hurdle for the development of standardised tolAPC therapeutic products. Here we describe an initiative by members of the tolAPC field to generate a minimum information model for tolAPC (MITAP), providing a reporting framework that will make differences and similarities between tolAPC products transparent. In this way, MITAP constitutes a first but important step towards the production of standardised and reproducible tolAPC for clinical application., Competing Interests: The authors declare there are no competing interests.

Objective: Tolerogenic dendritic cells (DCs) are antigen-presenting cells with an immunosuppressive function. They are a promising immunotherapeutic tool for the attenuation of pathogenic T cell responses in autoimmune arthritis. The aims of this study were to determine the therapeutic action of tolerogenic DCs in a type II collagen-induced arthritis model and to investigate their effects on Th17 cells and other T cell subsets in mice with established arthritis., Methods: Tolerogenic DCs were generated by treating bone marrow-derived DCs with dexamethasone and vitamin D(3) during lipopolysaccharide-induced maturation. Mice with established arthritis received 3 intravenous injections of tolerogenic DCs, mature DCs, or saline. Arthritis severity was monitored for up to 4 weeks after treatment. Fluorescence-labeled tolerogenic DCs were used for in vivo trafficking studies. The in vivo effect of tolerogenic DCs on splenic T cell populations was determined by intracellular cytokine staining and flow cytometry., Results: Tolerogenic DCs displayed a semi-mature phenotype, produced low levels of inflammatory cytokines, and exhibited low T cell stimulatory capacity. Upon intravenous injection into arthritic mice, tolerogenic DCs migrated to the spleen, liver, lung, feet, and draining lymph nodes. Treatment of arthritic mice with type II collagen-pulsed tolerogenic DCs, but not unpulsed tolerogenic DCs or mature DCs, significantly inhibited disease severity and progression. This improvement coincided with a significant decrease in the number of Th17 cells and an increase in the number of interleukin-10-producing CD4+ T cells, whereas tolerogenic DC treatment had no detectable effect on Th1 cells or interleukin-17-producing γ/δ T cells., Conclusion: Treatment with type II collagen-pulsed tolerogenic DCs decreases the proportion of Th17 cells in arthritic mice and simultaneously reduces the severity and progression of arthritis., (Copyright © 2010 by the American College of Rheumatology.)

Autoimmune pathologies are caused by a breakdown in self-tolerance. Tolerogenic dendritic cells (tolDC) are a promising immunotherapeutic tool for restoring self-tolerance in an antigen-specific manner. Studies about tolDC have focused largely on generating stable maturation-resistant DC, but few have fully addressed questions about the antigen-presenting and migratory capacities of these cells, prerequisites for successful immunotherapy. Here, we investigated whether human tolDC, generated with dexamethasone and the active form of vitamin D3, maintained their tolerogenic function upon activation with LPS (LPS-tolDC), while acquiring the ability to present exogenous autoantigen and to migrate in response to the CCR7 ligand CCL19. LPS activation led to important changes in the tolDC phenotype and function. LPS-tolDC, but not tolDC, expressed the chemokine receptor CCR7 and migrated in response to CCL19. Furthermore, LPS-tolDC were superior to tolDC in their ability to present type II collagen, a candidate autoantigen in rheumatoid arthritis. tolDC and LPS-tolDC had low stimulatory capacity for allogeneic, naïve T cells and skewed T cell polarization toward an anti-inflammatory phenotype, although LPS-tolDC induced significantly higher levels of IL-10 production by T cells. Our finding that LPS activation is essential for inducing migratory and antigen-presenting activity in tolDC is important for optimizing their therapeutic potential.

Dendritic cells (DC) are sensitive to their local environment and are affected by proximal cell death. This study investigated the modulatory effect of cell death on DC function. Monocyte-derived DC exposed to apoptotic Jurkat or primary T cells failed to induce phenotypic maturation of the DC and were unable to support CD4+ allogeneic T-cell proliferation compared with DC exposed to lipopolysaccharide (LPS) or necrotic cells. Apoptotic cells coincubated with LPS- or necrotic cell-induced mature DC significantly suppressed CD80, CD86 and CD83 and attenuated LPS-induced CD4+ T-cell proliferation. Reduced levels of interleukin-12 (IL-12), IL-10, IL-6, tumour necrosis factor-alpha and interferon-gamma (IFN-gamma) were found to be concomitant with the suppressive activity of apoptotic cells upon DC. Furthermore, intracellular staining confirmed IFN-gamma expression by DC in association with apoptotic environments. The specific generation of IFN-gamma by DC within apoptotic environments is suggestive of an anti-inflammatory role by the induction of indoleamine 2,3-dioxygenase (IDO). Both neutralization of IFN-gamma and IDO blockade demonstrated a role for IFN-gamma and IDO in the suppression of CD4+ T cells. Moreover, we demonstrate that IDO expression within the DC was found to be IFN-gamma-dependent. Blocking transforming growth factor-beta (TGF-beta) also produced a partial release in T-cell proliferation. Our study strongly suggests that apoptosis-induced DC suppression is not an immunological null event and two prime mediators underpinning these functional effects are IFN-gamma-induced IDO and TGF-beta.