bluuebunny/crossref_metadata_2025 huggingface dataset:
TINGKAT KEPENTINGAN RISIKO DAN RESPON RISIKO PADA TAHAP PELAKSANAAN PROYEK KONSTRUKSI
Authors: Widjaja Anton
Published: March 2019

Frekuensi dan dampak bisa mewakili tingkat kepentingan risiko. Karena itu tingkat kepentingan risiko harus diketahui agar bisa mendapatkan prioritas risiko. Setelah itu respon risiko dilakukan pada masing-masing risiko menurut tingkat kepentingannya. Penelitian ini bertujuan untuk mencari tingkat kepentingan dan respon risiko pada masing-masing risiko yang diidentifikasi. Pengumpulan data dilakukan dengan menyebar kuesioner kepada owner, konsultan perencana, MK, dan kontraktor yang terlibat langsung di lapangan di wilayah Surabaya. Kemudian data dianalisa dengan uji t-test untuk frekuensi dan dampak risiko, sedangkan respon risiko diuji menggunakan uji chi-square. Hasil penelitian menunjukan bahwa pada tingkat kepentingan risiko ditemukan bahwa risiko internal baik masing-masing owner dan kontraktor lebih cenderung pada tingkat kepentingan extreme dan high, sedangkan risiko eksternal lebih cenderung pada tingkat kepentingan medium dan low. Dengan frekuensi dengan mean tertinggi  dan dampak dengan mean tertinggi menurut owner adalah kekurangan pekerja sedangkan pada kontraktor adalah permintaan change order oleh owner, diikuti beberapa perbedaan pendapat untuk frekuensi dan dampak. Kemudian ditemukan bahwa strategi untuk merespon risiko menurut tingkat kepentingan extreme dan high adalah dengan menghindari dan mengurangi, sedangkan pada tingkat kepentingan medium dan low adalah dengan menghindari dan menerima, dengan adanya beberapa perbedaan pendapat untuk merespon risiko.
Missing Heritability of Complex Traits and Diseases
Authors: Nolte Ilja Maria , Tropf Felix Christian , Snieder Harold
Published: March 2019

Genome‐wide association studies (GWASs) have identified thousands of genetic variants involved in complex traits and diseases, but these only explain a minor fraction of the heritability. New methodologies that scrutinise the GWAS data indicate where the missing heritability might be found. About half of the heritability is still hidden in the GWAS data as this concerns common variants with small effects. Furthermore, a large part is still missing because this involves rare variants, which cannot be detected by GWAS due to low linkage disequilibrium. Nevertheless, even estimates of the most sophisticated methods do not fully reach the total genetic contributions derived from twin and family studies, suggesting that these heritabilities may be overestimated due to violation of the underlying assumptions or heterogeneity in heritability estimation across populations. Future variant discovery for complex traits and diseases will capture an ever larger part of the genetic predisposition and eventually bring health care applications within reach.

Key Concepts

Genome‐wide association studies (GWAS) have so far been able to only explain a minority of the heritability of complex traits or diseases, a large part is missing.

The missing heritability can be divided in hidden heritability, still‐missing heritability and phantom heritability.

Part of the missing heritability is hidden in the GWAS data meaning that due to lack of power the underlying common genetic variants have not yet been identified.

About half of the heritability of complex traits or diseases is expected to be caused by common variants and can ultimately be found by GWAS.

The still‐missing heritability can be explained by rare and structural genetic variants, dominance effects and epistasis.

The effects of dominance and epistasis are likely not very large.

Heritability estimates from twin and family studies may be overestimated due to violation of underlying model assumptions and therefore cause phantom heritability.

Heritability is likely also missing due to heterogeneity of effects between and within populations, as estimates from twin and family studies are calculated in homogeneous populations.
The “analysis of competing hypotheses” in intelligence analysis
Authors: Dhami Mandeep K. , Belton Ian K. , Mandel David R.
Published: March 2019

The intelligence community uses “structured analytic techniques” to help analysts think critically and avoid cognitive bias. However, little evidence exists of how techniques are applied and whether they are effective. We examined the use of the analysis of competing hypotheses (ACH)—a technique designed to reduce “confirmation bias.” Fifty intelligence analysts were randomly assigned to use ACH or not when completing a hypothesis testing task that had probabilistic ground truth. Data on analysts' judgement processes and conclusions were collected using written protocols that were then coded for statistical analyses. We found that ACH‐trained analysts did not follow all of the steps of ACH. There was mixed evidence for ACH's ability to reduce confirmation bias, and we observed that ACH may increase judgement inconsistency and error. It may be prudent for the intelligence community to consider the conditions under which ACH would prove useful and to explore alternatives.
Mittag‐Leffler state estimator design and synchronization analysis for fractional‐order BAM neural networks with time delays
Authors: Pratap A. , Raja R. , Rajchakit Grienggrai , Cao Jinde , Bagdasar O.
Published: March 2019

This paper deals with the extended design of Mittag‐Leffler state estimator and adaptive synchronization for fractional‐order bidirectional associative memory neural networks with time delays. By the aid of Lyapunov direct approach and Razumikhin‐type method, a suitable fractional‐order Lyapunov functional is constructed and a new set of novel sufficient condition are derived to estimate the neuron states via available output measurements such that the ensuring estimator error system is globally Mittag‐Leffler stable. Then, the adaptive feedback control rule is designed, under which the considered FBNNs can achieve Mittag‐Leffler adaptive synchronization by means of some fractional‐order inequality techniques. Moreover, the adaptive feedback control may be utilized even when there is no ideal information from the system parameters. Finally, two numerical simulations are given to reveal the effectiveness of the theoretical consequences.
Tumor Microenvironment Responsive Drug‐Dye‐Peptide Nanoassembly for Enhanced Tumor‐Targeting, Penetration, and Photo‐Chemo‐Immunotherapy
Authors: Peng Jinrong , Yang Qian , Xiao Yao , Shi Kun , Liu Qingya , Hao Ying , Yang Fan , Han Ruxia , Qian Zhiyong
Published: March 2019

Nanomedicine constructed by therapeutics has unique and irreplaceable advantages in biomedical applications, especially in drug delivery for cancer therapy. The strategy, however, used to construct the therapeutics‐based nanomedicines with tumor microenvironmental factor responsiveness is still sophisticated. In this study, an easy‐operating procedure is used to construct a therapeutics‐based nanosystem with active tumor‐targeting, enhanced penetration, and stimuli‐responsive drug release behavior as well as programmed cell death‐1/programmed cell death‐ligand 1 (PD‐1/PD‐L1) blockading mediated immunomodulation to enhance tumor immunotherapy. The matrix metalloproteinase‐2 responsive peptide with the existence of Lyp‐1 sequence contributes to the success of active tumor‐targeting and the enhancement of the penetration of the nanoparticles in tumor tissue. The obtained nanosystem strikingly inhibits the primary tumor growth in the first 24 h (more than 97.5% of tumor cells are inhibited), and total inhibition can be achieved with the combination of photothermal therapy. IR820, which is served as the carrier for the therapeutics, is used as a photosensitizer for photothermal therapy. The progress and aggression of distal tumor has further been alleviated by a d‐peptide which is an antagonist for PD‐1/PD‐L1 blockage. Therefore, a therapeutics‐constructed multifunctional nanosystem is provided to realize a combinational therapeutic strategy to enhance the therapeutic outcome.
Copper‐Catalyzed B(dan)‐Installing Allylic Borylation of Allylic Phosphates
Authors: Yoshida Hiroto , Murashige Yuya , Osaka Itaru
Published: March 2019

γ‐Selective B(dan)‐installing allylic borylation was found to proceed efficaciously by the reaction of an unsymmetrical diboron, (pin)B−B(dan), with allylic phosphates under copper catalysis. The resulting allyl−B(dan) was convertible into 1,3‐, 1,2‐, or 1,1‐diborylalkanes with different boron‐Lewis acidity by B(pin)‐installing hydroboration, and its C(sp3)−B(dan) bond turned out to be preferentially transformed into a C(sp3)−N bond, leaving the B(pin) intact, despite its well‐accepted inertness toward various transformations.

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A Universally Applicable Strategy for Construction of Anti‐Biofouling Adsorbents for Enhanced Uranium Recovery from Seawater
Authors: Yu Qiuhan , Yuan Yihui , Wen Jun , Zhao Xuemei , Zhao Shilei , Wang Dong , Li Chaoyang , Wang Xiaolin , Wang Ning
Published: March 2019

The ocean reserves 4.5 billion tons of uranium and amounts to a nearly inexhaustible uranium supply. Biofouling in the ocean is one of the most severe factors that hazard uranium extraction and even cause the failure of uranium extraction. Therefore, development of uranium adsorbents with biofouling resistance is highly urgent. Herein, a strategy for constructing anti‐biofouling adsorbents with enhanced uranium recovery capacity in natural seawater is developed. This strategy can be widely applied to modify currently available carboxyl‐contained adsorbents, including the most popular amidoxime‐based adsorbent and carboxyl metal organic framework adsorbent, using a simple one‐step covalent cross‐link reaction between the antibacterial compound and the adsorbent. The prepared anti‐biofouling adsorbents display broad antibacterial spectrum and show more than 80% inhibition to the growth of marine bacteria. Benefitting from the tight covalent cross‐link, the anti‐biofouling adsorbents show high reusability. The modified amidoxime‐based adsorbents show enhanced uranium recovery capacity both in sterilized and bacteria‐contained simulated seawater. The anti‐biofouling adsorbent Anti‐UiO‐66 constructed in this study exhibits 24.4% increased uranium recovery capacity, with a uranium recovery capacity of 4.62 mg‐U per g‐Ads, after a 30‐day field test in real seawater, suggesting the strategy is a promising approach for constructing adsorbents with enhanced uranium extraction performance.
High‐Performance Perovskite Solar Cells with Excellent Humidity and Thermo‐Stability via Fluorinated Perylenediimide
Authors: Yang Jia , Liu Cong , Cai Chunsheng , Hu Xiaotian , Huang Zengqi , Duan Xiaopeng , Meng Xiangchuan , Yuan Zhongyi , Tan Licheng , Chen Yiwang
Published: March 2019

The notoriously poor stability of perovskite solar cells is a crucial issue restricting commercial applications. Here, a fluorinated perylenediimide (F‐PDI) is first introduced into perovskite film to enhance the device's photovoltaic performance, as well as thermal and moisture stability simultaneously. The conductive F‐PDI molecules filling at grain boundaries (GBs) and surface of perovskite film can passivate defects and promote charge transport through GBs due to the chelation between carbonyl of F‐PDI and noncoordinating lead. Furthermore, an effective multiple hydrophobic structure is formed to protect perovskite film from moisture erosion. As a result, the F‐PDI‐incorporated devices based on MAPbI3 and Cs0.05 (FA0.83MA0.17)0.95 Pb (Br0.17I0.83)3 absorber achieve champion efficiencies of 18.28% and 19.26%, respectively. Over 80% of the initial efficiency is maintained after exposure in air for 30 days with a relative humidity (RH) of 50%. In addition, the strong hydrogen bonding of F···H‐N can immobilize methylamine ion (MA+) and thus enhances the thermal stability of device, remaining nearly 70% of the initial value after thermal treatment (100 °C) for 24 h at 50% RH condition.
Single agents vs combination chemotherapy in relapsed and refractory peripheral T‐cell lymphoma: Results from the comprehensive oncology measures for peripheral T‐cell lymphoma treatment (COMPLETE) registry
Authors: Stuver Robert N. , Khan Niloufer , Schwartz Marc , Acosta Mark , Federico Massimo , Gisselbrecht Christian , Horwitz Steven M. , Lansigan Frederik , Pinter‐Brown Lauren C. , Pro Barbara , Shustov Andrei R. , Foss Francine M. , Jain Salvia
Published: March 2019

Single agents have demonstrated activity in relapsed and refractory (R/R) peripheral T‐cell lymphoma (PTCL). Their benefit relative to combination chemotherapy remains undefined. Patients with histologically confirmed PTCL were enrolled in the Comprehensive Oncology Measures for Peripheral T‐cell Lymphoma Treatment (COMPLETE) registry. Eligibility criteria included those with R/R disease who had received one prior systemic therapy and were given either a single agent or combination chemotherapy as first retreatment. Treatment results for those with R/R disease who received single agents were compared to those who received combination chemotherapy. The primary endpoint was best response to retreatment. Fifty‐seven patients met eligibility criteria. At first retreatment, 46% (26/57) received combination therapy and 54.5% (31/57) received single agents. At median follow up of 2 years, a trend was seen towards increased complete response rate for single agents versus combination therapy (41% vs 19%; P = .02). There was also increased median overall survival (38.9 vs 17.1 months; P = .02) and progression‐free survival (11.2 vs 6.7 months; P = .02). More patients receiving single agents received hematopoietic stem‐cell transplantation (25.8% vs 7.7%, P = .07). Adverse events of grade 3 or 4 occurred more frequently in those receiving combination therapy, although this was not statistically significant. The data confirm the unmet need for better treatment in R/R PTCL. Despite a small sample, the analysis shows greater response and survival in those treated with single agents as first retreatment in R/R setting, while maintaining the ability to achieve transplantation. Large, randomized trials are needed to identify the best strategy.
A novel pathogenic variant in OFD1 results in X‐linked Joubert syndrome with orofaciodigital features and pituitary aplasia
Authors: Aljeaid Deema , Lombardo Rachel C. , Witte David P. , Hopkin Robert J.
Published: March 2019

Orofaciodigital syndrome type I and X‐linked recessive Joubert syndrome are known ciliopathic disorders that are caused by pathogenic variants in OFD1 gene. Endocrine system involvement with these conditions is not well described. We present the first report of a newborn male with a novel hemizygous variant in OFD1 gene c.515T>C, (p.Leu172Pro) resulting in X‐linked Joubert syndrome and orofaciodigital features with complete pituitary gland aplasia and subsequent severe hypoplasia of peripheral endocrine glands. This clinical report expands the phenotypic spectrum of endocrine system involvement in OFD1‐related disorders and suggests that OFD1 gene may be related to pituitary gland development.
11q24.2q24.3 microdeletion in two families presenting features of Jacobsen syndrome, without intellectual disability: Role of FLI1, ETS1, and SENCR long noncoding RNA
Authors: Conrad Solène , Demurger Florence , Moradkhani Kamran , Pichon Olivier , Le Caignec Cédric , Pascal Cécile , Thomas Caroline , Bayart Sophie , Perlat Antoinette , Dubourg Christèle , Jaillard Sylvie , Nizon Mathilde
Published: March 2019

This report presents two families with interstitial 11q24.2q24.3 deletion, associated with malformations, hematologic features, and typical facial dysmorphism, observed in Jacobsen syndrome (JS), except for intellectual disability (ID). The smallest 700 Kb deletion contains only two genes: FLI1 and ETS1, and a long noncoding RNA, SENCR, narrowing the minimal critical region for some features of JS. Consistent with recent literature, it adds supplemental data to confirm the crucial role of FLI1 and ETS1 in JS, namely FLI1 in thrombocytopenia and ETS1 in cardiopathy and immune deficiency. It also supports that combined ETS1 and FLI1 haploinsufficiency explains dysmorphic features, notably ears, and nose anomalies. Moreover, it raises the possibility that SENCR, a long noncoding RNA, could be responsible for limb defects, because of its early role in endothelial cell commitment and function. Considering ID and autism spectrum disorder, which are some of the main features of JS, a participation of ETS1, FLI1, or SENCR cannot be excluded. But, considering the normal neurodevelopment of our patients, their role would be either minor or with an important variability in penetrance. Furthermore, according to literature, ARHGAP32 and KIRREL3 seem to be the strongest candidate genes in the 11q24 region for other Jacobsen patients.
Ptosis as a unique hallmark for autosomal recessive WNT1‐associated osteogenesis imperfecta
Authors: Nampoothiri Sheela , Guillemyn Brecht , Elcioglu Nursel , Jagadeesh Sujatha , Yesodharan Dhanya , Suresh Beena , Turan Serap , Symoens Sofie , Malfait Fransiska
Published: March 2019

Osteogenesis imperfecta (OI) is a heritable connective tissue disorder, mainly characterized by bone fragility and low bone mass. Defects in the type I procollagen‐encoding genes account for the majority of OI, but increasingly more rare autosomal recessive (AR) forms are being identified, which are caused by defects in genes involved in collagen metabolism, bone mineralization, or osteoblast differentiation. Bi‐allelic mutations in WNT1 have been associated with a rare form of AR OI, characterized by severe osteoporosis, vertebral compression, scoliosis, fractures, short stature, and variable neurological problems. Heterozygous WNT1 mutations have been linked to autosomal dominant early‐onset osteoporosis. In this study, we describe the clinical and molecular findings in 10 new patients with AR WNT1‐related OI. Thorough revision of the clinical symptoms of these 10 novel patients and previously published AR WNT1 OI cases highlight ptosis as a unique hallmark in the diagnosis of this OI subtype.
Three additional de novo CTCF mutations in Chinese patients help to define an emerging neurodevelopmental disorder
Authors: Chen Fei , Yuan Haiming , Wu Wenyong , Chen Shaoke , Yang Qi , Wang Jin , Zhang Qiang , Gui Baohen , Fan Xin , Chen Ruimin , Shen Yiping
Published: March 2019

CCCTC‐binding factor (CTCF) is an important regulator for global genomic organization and gene expression. CTCF gene had been implicated in a novel disorder characterized by intellectual disability, feeding difficulty, developmental delay and microcephaly. So far, four patients have been reported with de novo CTCF mutations. We reported three additional Chinese patients with de novo variants in CTCF. The new evidence helped to establish the clinical validity between CTCF and the emerging disorder. We described the consistent phenotypes shared by all patients and revealed additional clinical features such as delayed or abnormal teeth development and a unique pattern of the eyebrow that may help to define a potential recognizable neurodevelopmental disorder. We also reported the first CTCF patient treated with recombinant human growth hormone. Follow‐up and more case studies will further our understanding to the clinical presentations of this novel disorder and the prognosis of patients with this disorder.
Chlorothiomethylation of Alkynes with HCl and Dimethyl Sulfoxide: An Efficient Approach to (E)‐α‐chloro‐β‐(methylthio)alkenes
Authors: Tong Hanqing. , Chen Cui , Liu Weibing. , Pan Yupeng. , Duan Linhai.
Published: March 2019

Synthesis of (E)‐chlorovinyl methylsulfanes via chlorothiomethylation of alkynes with HCl and dimethyl sulfoxide (DMSO) under metal‐free and oxidant‐free conditions has been reported. This methodology is rare, in which chlorovinyl methylsulfanes are constructed using chlorosulfanes rather than the combination of HCl and DMSO to react with alkynes. This procedure introduces a new application of DMSO, which is employed as a source of the SMe group to directly insert into the carbon‐carbon triple bond of alkynes. Additionally, the reaction shows a broad substrate scope, good functional group compatibility, and excellent regioselectivity.
Acylation of Arylamines with Triethylamine Derivatives in Combination with tert‐Butyl Hydroperoxide
Authors: Chen Cui , Liu Weibing. , Liu Bifu. , Zhou Peng , Tan Hua
Published: March 2019

N‐acylation of arylamines with di‐ and trialkyl amines has been reported. This approach provides a general synthesis of aromatic amides by an alkyl transfer through cleavage of the C−N bond, and acts as a model for N‐dealkylations and N‐acylations. Additionally, the synthesis is a promising method towards amidation reactions, wherein di‐ and trialkyl amine derivatives are employed as sources of acyl carbon atoms and tert‐butyl hydroperoxide is employed as the oxygen source of the acyl group.
Hydroxymethylation of technical lignins from South American sources with potential use in phenolic resins
Authors: Taverna María Eugenia , Felissia Fernando , Area María Cristina , Estenoz Diana Alejandra , Nicolau Verónica Viviana
Published: March 2019

This work investigates the valorization of sodium lignosulfonate, kraft, and organosolv lignins from South America. A detailed characterization of the lignins and their chemical modification by hydroxymethylation through its reaction with formaldehyde were performed. The characterization included measurements of moisture, ash, carbohydrate contents, elemental and thermogravimetric analysis, and functional groups, molar mass distributions by Fourier transform infrared spectroscopy, and size exclusion chromatography, respectively. Also, reactive aromatic hydrogens (HAr) were quantified by the measurement of phenolic hydroxyl groups (P‐OH) content by UV–Vis spectroscopy. The different initial formaldehyde/lignin weight ratios (0.07, 1.47), temperatures (40, 50, and 70 °C), and pHs (9, 11); and the following of hydroxymethylation reactions by UV–Vis spectroscopy were investigated. All lignins resulted attractive for the use as replacement of phenol in phenolic resins, but sodium lignosulfonate was the most appropriate due to its water solubility. © 2019 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2019, 136, 47712.
Effect of core–shell rubber toughening on mechanical, thermal, and morphological properties of poly(lactic acid)/multiwalled carbon nanotubes nanocomposites
Authors: Mat Desa Mohd Shaiful Zaidi , Hassan Azman , Arsad Agus , Arjmandi Reza
Published: March 2019

The effect of core–shell rubber (CSR) toughening on mechanical and thermal properties of poly(lactic acid)/multiwalled carbon nanotubes (PLA/CNT) nanocomposites were investigated. The nanocomposites were prepared by direct melt blending method in a counter‐rotating twin‐screw extruder. The contents of CSR were varied between 5 and 20 wt % while the content of CNT was kept at 5 phr. The extruded samples were injection molded into the desired test specimens for mechanical and thermal properties analysis. The impact strength of PLA/CNT increased with increasing CSR content with concomitant decrease in tensile strength and modulus. Interestingly, the flexural strength increased at low CSR content before decreasing at 15 and 20% content. Differential scanning calorimetry analysis on the second heating cycle shows no crystallinity content for PLA/CNT and all CSR toughened PLA/CNT nanocomposites, while thermogravimetric analysis shows lower thermal degradation of all CSR toughened PLA/CNT as compared to PLA/CNT nanocomposite. This study reveals significant correlation between CSR loading with the mechanical and thermal properties of the nanocomposites. © 2019 Wiley Periodicals, Inc. J. Appl. Polym. Sci.2019,136, 47756.
Protective Effect Against Cancer of Antibodies to the Large Subunits of Both RNA Polymerases I and III in Scleroderma
Authors: Shah Ami A. , Laiho Marikki , Rosen Antony , Casciola‐Rosen Livia
Published: March 2019

Objective

While compelling data suggest a cancer‐induced autoimmunity model in scleroderma patients with anti–RNA polymerase III large subunit (anti‐RPC155) antibodies, ~85% of these patients do not manifest cancer. This study was undertaken to determine whether additional autoantigens are targeted in anti‐RPC155–positive scleroderma patients without detectable cancer.

Methods

The study included 168 scleroderma patients with anti‐RPC155 antibodies (80 with a history of cancer and 88 with no cancer diagnosis after >5 years of follow‐up). Thirty‐five sera (17 from patients with cancer and 18 from patients without cancer) were randomly selected for autoantibody discovery using immunoprecipitation (IP). An ~194‐kd band was enriched in the subgroup without cancer; this was identified as RNA polymerase I large subunit (RPA194).

Results

RPA194 generated by in vitro transcription/translation was used for IPs performed on the entire cohort to test whether anti‐RPA194 was enriched among anti‐RPC155–positive patients without cancer. Anti‐RPA194 antibodies were significantly more common in the group without cancer (16 [18.2%] of 88) than in the group with cancer (3 [3.8%] of 80) (P = 0.003). Patients with both anti‐RPA194 and anti‐RPC155 were significantly less likely to have severe gastrointestinal disease than patients with anti‐RPC155 only (26.3% versus 51.0%; P = 0.043).

Conclusion

Anti‐RPA194 antibodies are enriched in anti‐RPC155–positive scleroderma patients without cancer. Since somatic mutations in the gene encoding RPC155 in cancer in scleroderma patients appears to play a role in immune response initiation against RPC155 in those patients, these data raise the possibility that the development of immune responses to both RPC155 and RPA194 may influence clinical cancer emergence. Further study is required to define whether different autoantibody combinations have utility as tools for cancer risk stratification in scleroderma.
The association between prenatal alcohol exposure and protein expression in human placenta
Authors: Holbrook Bradley D. , Davies Suzy , Cano Sandra , Shrestha Shikhar , Jantzie Lauren L. , Rayburn William F. , Bakhireva Ludmila N. , Savage Daniel D.
Published: March 2019

Background

The need for earlier recognition of children at risk for neurobehavioral problems associated with prenatal ethanol exposure (PAE) has prompted investigations of biomarkers prognostic for altered fetal development. Here, we examined whether PAE alters the expression of angiogenesis‐related proteins and cytokines in human placenta in subjects from an Ethanol, Neurodevelopment, Infant and Child Health prospective cohort.

Methods

PAE was ascertained by screening questionnaires, Time‐line Follow‐back interviews and a panel of ethanol biomarkers at two study visits. After delivery, placental tissue samples were collected for protein analysis.

Results

No significant differences in the prevalence of substance use, demographic or medical characteristics were observed between the No PAE and PAE groups. PAE was associated with significant reductions in placental expression of VEGFR2 and annexin‐A4, while the levels of VEGFR1 and CCM‐3 trended downward. A trend toward higher expression of the cytokines TNF‐α and IL‐13 was also observed in the PAE group. Receiver operating characteristic analyses of the data demonstrated a moderate‐to‐high degree of diagnostic accuracy for individual placental proteins. Combinations of proteins substantially increased their ability to differentiate between PAE and No PAE subjects.

Conclusions

These results establish the feasibility of harvesting placental tissue for protein analyses of PAE in a prospective manner. In addition, given the importance of vascular remodeling in both placenta and developing brain, the role of angiogenic and cytokine proteins in this process warrants further investigation for their utility for predicting alterations in brain development, as well as their mechanistic role in PAE‐induced pathology.
Clinical value of additional resection of a margin-positive distal bile duct in perihilar cholangiocarcinoma
Authors: Otsuka S , Ebata T , Yokoyama Y , Mizuno T , Tsukahara T , Shimoyama Y , Ando M , Nagino M
Published: March 2019

Background

Little is known about the effect of additional resection for a frozen-section-positive distal bile duct margin (DM) in perihilar cholangiocarcinoma.

Methods

Patients who underwent surgical resection for perihilar cholangiocarcinoma between 2001 and 2015 were analysed retrospectively, focusing on the DM.

Results

Of 558 consecutive patients who underwent frozen-section examination for a DM, 74 (13·3 per cent) had a frozen-section-positive DM with invasive cancer or carcinoma in situ. Eventually, 53 patients underwent additional resection (bile duct resection in 44 and pancreatoduodenectomy in 9), whereas the remaining 21 patients did not. Ultimately, R0 resection was achieved in 30 of the 53 patients (57 per cent). No patient who underwent additional resection died from surgical complications. The 44 patients with additional bile duct resection had a 5-year overall survival rate of 31 per cent. Overall survival of the nine patients who had pancreatoduodenectomy was better, with a 10-year rate of 67 per cent. Survival of the 21 patients without additional resection was dismal: all died within 5 years. Multivariable analyses identified nodal status and additional resection as independent prognostic factors (lymph node metastasis: hazard ratio (HR) 2·26, 95 per cent c.i. 1·26 to 4·07; bile duct resection versus no additional resection: HR 0·32, 0·17 to 0·60; pancreatoduodenectomy versus no additional resection: HR 0·08, 0·02 to 0·29).

Conclusion

Additional resection for frozen-section-positive DM in perihilar cholangiocarcinoma frequently yields R0 margins. It offers a better chance of long-term survival, and thus should be performed in carefully selected patients.
Rituximab maintenance overcomes the negative prognostic factor of obesity in CLL: Subgroup analysis of the international randomized AGMT CLL‐8a mabtenance trial
Authors: Egle Alexander , Melchardt Thomas , Obrtlíková Petra , Smolej Lukáš , Kozák Tomáš , Steurer Michael , Andel Johannes , Burgstaller Sonja , Mikušková Eva , Gercheva Liana , Nösslinger Thomas , Papajík Tomáš , Ladická Miriam , Girschikofsky Michael , Hrubiško Mikuláš , Jäger Ulrich , Voskova Daniela , Pecherstorfer Martin , Králiková Eva , Burcoveanu Christina , Spasov Emil , Petzer Andreas , Mihaylov Georgi , Raynov Julian , Oexle Horst , Zabernigg August , Flochová Emília , Palášthy Stanislav , Stehlíková Olga , Doubek Michael , Altenhofer Petra , Weiss Lukas , Magnes Teresa , Pleyer Lisa , Klingler Anton , Mayer Jiří , Greil Richard
Published: March 2019

No data are available regarding obesity and outcome in Chronic Lymphocytic Leukemia (CLL). We analyzed 263 patients from the AGMT CLL‐8a Mabtenance trial for the impact of obesity. The trial included patients after rituximab‐containing induction treatment in first or second line that had achieved at least a PR. A randomization to rituximab maintenance treatment (375 mg/m2 q3 months for 2 years) vs observation was performed. In this cohort 22% of the patients (58/263) were classified as obese. The baseline response to induction treatment was inferior in obese patients with a lower CR rate (43.1% vs 60.5% in obese vs non‐obese, P = 0.018) and with a lower rate of patients achieving MRD negativity after chemoimmunotherapy induction treatment (19.6% vs 35.8%, P = 0.02). The PFS outcome of obese patients was significantly worse in the observation group of the trial (24 vs 39 months median PFS, P = 0.03). However, in the rituximab maintenance group the outcome for obese vs non‐obese was not different (P = 0.4). In summary, obesity was overall associated with a worse outcome of chemoimmunotherapy induction. However, rituximab maintenance treatment seems to be able to overcome this negative effect.
Genotype‐phenotype correlation in 99 familial adenomatous polyposis patients: A prospective prevention protocol
Authors: de Oliveira Junea C. , Viana Danilo V. , Zanardo Cleyton , Santos Erika M. M. , de Paula André E. , Palmero Edenir I. , Rossi Benedito M.
Published: March 2019

Background

Familial adenomatous polyposis (FAP) is a syndrome caused by germline pathogenic variants in the tumor suppressor gene adenomatous polyposis coli (APC). Identification of APC pathogenic variants sites and the genotype‐phenotype correlation are important for characterizing, monitoring, and treating members of affected families. The aim of this study was to correlate genotype‐phenotype of Brazilian individuals carrying APC pathogenic germline variants and that have FAP.

Methods

The polyposis phenotype of 99 individuals from 35 families between July 2013 and December 2014 were prospectively evaluated based on the InSIGHT polyposis staging classification. Seven extra‐colonic manifestations were assessed and the clinical manifestations correlated with the APC genotype.

Results

The age of the study participants ranged from 12 to 67 years (median of 29 years). Twenty‐six APC pathogenic variants were identified. Fifty‐five cases harbored nonsense pathogenic variants (55.6%). Frameshift alterations were noted in 39 cases (39.4%). Aberrant splicing was noted in 1 case (1%). Rearrangements were observed in 3 cases (3%). An association between nonsense variants and rearrangement was noted in 1 case (1%). The genotype‐phenotype correlation analysis led the identification of classic FAP in 94 cases (94.9%). Profuse polyposis was identified in 5 cases (5.1%). Thirty‐six cases were diagnosed with cancer of which 29 cases (80.6%) were colorectal cancer, 1 case (2.7%) was brain cancer, 4 cases (11.2%) were papillary thyroid cancer, and 2 cases (5.5%) were stomach cancer. The extra‐colonic manifestations included 9 individuals with desmoids tumors, 10 with osteomas, and 9 with congenital hypertrophy of the retinal pigment epithelium.

Conclusions

The genotype‐phenotype correlation in Brazilian individuals with FAP revealed specific findings not previously reported for other cohorts, demonstrating the relevance of knowledge regarding the variable pathogenic variants and clinical presentation in different populations for adequate individual clinical management of patients harboring this medical condition.
Optimizing Microwave‐Assisted Extraction Conditions to Obtain Phenolic‐Rich Extract from Chromolaena odorata Leaves
Authors: Alara Oluwaseun Ruth , Abdurahman Nour Hamid , Abdul Mudalip Siti Kholijah
Published: March 2019

Phenolic compounds are secondary metabolites that are mainly responsible for different pharmacological activities of plant extracts. In this study, microwave‐assisted extraction (MAE) variables were optimized for the extraction of phenolic compounds from Chromolaena odorata leaves by using a Box‐Behnken design of response surface methodology. The concentration of polyphenols and functional characteristics of the extracts were identified by using liquid chromatography quadrupolar time‐of‐flight mass spectrometry and FTIR analyses, respectively. The obtained results indicated the MAE conditions for the optimal recoveries of the total phenolic content and total flavonoid content from C. odorata leaves. The results reveal that the C. odorata leaf is enriched with phenolic compounds.
End‐to‐end quantitative analysis modeling of near‐infrared spectroscopy based on convolutional neural network
Authors: Chen Yuan‐Yuan , Wang Zhi‐Bin
Published: March 2019

During the near‐infrared spectroscopy analysis process, modeling the quantitative relationship between the collected spectral information and target components is an important procedure. Before using the traditional modeling methods, it is often necessary to select the most featured wavelengths and eliminate those uninformative wavelengths. However, the wavelength selection algorithms can not only increase the model complexity but also may contain some adjustable parameters, which need the users to have more expertise knowledge and experiences. To solve this problem, this paper proposed a novel end‐to‐end quantitative analysis modeling method for near‐infrared spectroscopy based on convolutional neural network (CNN), which directly takes the whole range of collected raw spectral information as input without wavelength selection. The public corn NIR dataset was taken as example to validate the efficiency of proposed method. The experimental results showed that, firstly, if all the whole range of raw spectral information was taken as the input of modeling, the generalized performance of CNN outperforms the traditional methods, and the difference is statistically significant; secondly, if the traditional methods were combined with wavelength selection algorithms, their generalized performances were similar to CNN model; there is no statistical difference. The results indicated that applying the deep learning methods (take CNN as representative) to establish the quantitative analysis model of near‐infrared spectroscopy is easy to use and has more potential popularize values.
Magnesium Aldimines Prepared by Addition of Organomagnesium Halides to 2,4,6‐Trichlorophenyl Isocyanide: Synthesis of 1,2‐Dicarbonyl Derivatives
Authors: Schwärzer Kuno , Bellan Andreas , Zöschg Maximilian , Karaghiosoff Konstantin , Knochel Paul
Published: March 2019

The selective addition of organomagnesium reagents to 2,4,6‐trichlorophenyl isocyanide leading to magnesiated aldimines is reported. These aldimines react with Weinreb amides, ketones, or carbonates to provide the corresponding carbonyl derivatives after acidic cleavage. This allows for an efficient synthesis of 1,2‐dicarbonyl compounds and α‐hydroxy ketones.
Linear mode regression with covariate measurement error
Authors: Li Xiang , Huang Xianzheng
Published: March 2019

We consider estimating the mode of a response given an error‐prone covariate. It is shown that ignoring measurement error typically leads to inconsistent inference for the conditional mode of the response given the true covariate, as well as misleading inference for regression coefficients in the conditional mode model. To account for measurement error, we first employ the Monte Carlo corrected score method (Novick & Stefanski, 2002) to obtain an unbiased score function based on which the regression coefficients can be estimated consistently. To relax the normality assumption on measurement error this method requires, we propose another method where deconvoluting kernels are used to construct an objective function that is maximized to obtain consistent estimators of the regression coefficients. Besides rigorous investigation on asymptotic properties of the new estimators, we study their finite sample performance via extensive simulation experiments, and find that the proposed methods substantially outperform a naive inference method that ignores measurement error. The Canadian Journal of Statistics 47: 262–280; 2019 © 2019 Statistical Society of Canada
Mer‐Ir(ppy)3 to Fac‐Ir(ppy)3 Photoisomerization
Authors: Escudero Daniel
Published: March 2019

In this contribution a detailed mechanistic investigation of mer‐to‐fac photoisomerization occurring in Ir(ppy)3 (ppy=2‐phenylpyridine) is presented. Facial/meridional stereoisomerism in tris‐bidentate Ir(III) complexes strongly determines their photophysical properties and thereby their efficiency and stability within a phosphorescence‐based organic light‐emitting diode (PhOLED) device. Double‐hybrid density functional theory (DFT) calculations are performed herein to identify the photoactive species involved in the photoisomerization reaction and to assess its kinetic and thermodynamic feasibility at room temperature. These investigations highlight the protagonistic role of a non‐previously described 3MC (triplet metal‐centred) state bearing one stretched trans Ir–N position. Finally, and in view of the computed evidences, phosphor design strategies to prevent photoisomerization are proposed.
Successive Photoswitching and Derivatization Effects in Photochromic Dithienylethene‐Based Coordination Cages
Authors: Li Ru‐Jin , Han Muxin , Tessarolo Jacopo , Holstein Julian J. , Lübben Jens , Dittrich Birger , Volkmann Christian , Finze Maik , Jenne Carsten , Clever Guido H.
Published: March 2019

A new series of [Pd2(L)4] cages based on photochromic dithienylethene (DTE) ligands allowed us to gain insight into the successive photoswitching of multiple DTE moieties in a confined metallo‐supramolecular assembly. Three new X‐ray structures of [Pd2(o‐L4)4], [Pd2(o‐L1)2(c‐L1)2] and [Pd2(c‐L1)4] (o‐L and c‐L = open and closed forms of DTE ligands, respectively) were obtained. The structures deliver snapshots of three different combinations of DTE photoisomeric states within the cage, facilitating a comparison of the all‐open with the all‐closed, and most notably, an intermediate form where open and closed switches co‐exist in the same cage. Moreover, a series of spherical anionic borate clusters was introduced in order to study their roles in the light‐controllable host–guest chemistry. The binding guests show higher affinities with the flexible open cage [Pd2(o‐L1)4] than with the rigid closed cage [Pd2(c‐L1)4]. For the [B12F12]2− guest, thermodynamic data obtained from NMR experiments was compared to results from isothermal titration calorimetry (ITC).
New sinusoidal oscillator configurations using operational transresistance amplifier
Authors: Komanapalli Gurumurthy , Pandey Rajeshwari , Pandey Neeta
Published: March 2019

The objective of this brief is to introduce four new structures of electronically tunable sinusoidal oscillators (SOs) designed using operational transresistance amplifier (OTRA). Each of the proposed SO consists of forward path derived from a generic structure along with one/two OTRA‐based resistive gain stages or differentiator in its feedback path. All the proposed SOs enjoy independent tuning of the frequency of oscillation (FO) through resistors without affecting the condition of oscillation (CO). Further, all topologies are found to exhibit low fo sensitivities at all frequencies with respect to circuit parameters, and the second topology is capable of achieving very low frequencies (VLFs) using less RC component spread and provides linear tuning too. The fourth circuit provides quadrature output. The proposed SOs have been successfully implemented and verified in 180‐nm CMOS technology node using ADE (analog design environment) tool Cadence Virtuoso. Both prelayout and postlayout simulation results have been included. To assess the oscillator prefabrication performances, Monte Carlo and process‐voltage‐temperature (PVT) analyses have been performed. The total harmonic distortion (THD) is observed to be less than 3.5%.
Profiling cocaine residues and pyrolytic products in wastewater by mixed‐mode liquid chromatography–tandem mass spectrometry
Authors: González‐Mariño Iria , Estévez‐Danta Andrea , Rodil Rosario , Da Silva Katyeny Manuela , Sodré Fernando Fabriz , Cela Rafael , Quintana José Benito
Published: March 2019

This work provides a new analytical method for the determination of cocaine, its metabolites benzoylecgonine and cocaethylene, the pyrolytic products anhydroecgonine and anhydroecgonine methyl ester, and the pharmaceutical levamisole in wastewater. Samples were solid‐phase extracted and extracts analyzed by liquid chromatography–tandem mass spectrometry using, for the first time in the illicit drug field, a stationary phase that combines reversed‐phase and weak cation‐exchange functionalities. The overall method performance was satisfactory, with limits of detection below 1 ng/L, relative standard deviations below 21%, and percentages of recovery between 93% and 121%. Analysis of 24‐hour composite raw wastewater samples collected in Santiago de Compostela (Spain) and Brasilia (Brazil) highlighted benzoylecgonine as the compound showing the highest population‐normalized mass loads (300–1000 mg/day/1000 inhabitants). In Brasilia, cocaine and levamisole loads underwent an upsurge on Sunday, indicating a high consumption, and likely a direct disposal, of cocaine powder on this day. Conversely, the pyrolytic product resulting from the smoke of crack, anhydroecgonine methyl ester, and its metabolite anhydroecgonine were relatively stable over the four days, agreeing with a non‐recreational‐associated use of crack.
Underuse of hydralazine and isosorbide dinitrate for heart failure in patients of African ancestry: a cross‐European survey
Authors: Brewster Lizzy M.
Published: March 2019

Aims

Population data indicate that one in 25 persons of African ancestry has heart failure, a condition with relatively high mortality of around 50% in 5 years. Combined hydralazine and isosorbide dinitrate added to conventional therapy in African ancestry patients with heart failure and reduced ejection fraction improves quality of life and reduces the rate of first hospitalization for heart failure by 33% and annual mortality by 43%. The objectives of this study were to quantify the use of this guideline‐recommended therapy in Europe and the potential effect of implementation gaps on mortality.

Methods and results

Prescription drug registration and utilization databases and population statistics were analysed in a cross‐European survey without language restriction. Main outcomes were the number of unique patients prescribed the fixed combination hydralazine–isosorbide dinitrate (primary) or both drugs (secondary) in Europe in 2015, and the excess mortality related to prescribing practices was estimated. The survey indicates that around 12 million persons of African ancestry live in Europe. It is estimated that 480 000 persons of this population group have heart failure, with 120 000 eligible for hydralazine and isosorbide dinitrate therapy. However, single‐pill hydralazine–isosorbide dinitrate is not authorized and therefore not dispensed in Europe in 2015. Out of the 25 European nations surveyed, the UK and the Netherlands are the only countries with major African ancestry populations where both hydralazine and isosorbide dinitrate are available for oral use, aside Norway, Sweden, and Finland. Hydralazine and isosorbide dinitrate are prescribed to <500 European patients in 2015. Thus, despite the recommendations of the European Society of Cardiology, the large majority of African‐European patients with heart failure do not receive this drug combination, potentially resulting in 4800 to 5800 excess deaths yearly.

Conclusions

The life‐saving, guideline‐recommended, adjunctive therapy for heart failure in African ancestry patients with hydralazine and isosorbide dinitrate is rarely used in Europe. This major evidence‐practice gap should urgently be overcome to reduce excess mortality in African‐European patients with heart failure.
The Ubiquitin‐proteasome pathway regulates Nectin2/CD112 expression and impairs NK cell recognition and killing
Authors: Molfetta Rosa , Milito Nadia D. , Zitti Beatrice , Lecce Mario , Fionda Cinzia , Cippitelli Marco , Santoni Angela , Paolini Rossella
Published: March 2019

Nectin2 is a member of immunoglobulin‐like cell adhesion molecules and plays a prominent role in the establishment of adherens and tight junctions. It is also upregulated on the surface of tumor and virus‐infected cells where it functions as a ligand for the activating receptor CD226, thus contributing to cytotoxic lymphocyte‐mediated recognition and killing of damaged cells. Little is currently known about the regulation of Nectin2 expression and, in particular, whether posttranscriptional and posttranslational mechanisms are involved. Here, we analyzed Nectin2 expression on a panel of human tumor cell lines and primary cultures and we found that Nectin2 is mainly expressed in cytoplasmic pools. Moreover, we demonstrated that ubiquitination of Nectin2 promotes its degradation and is responsible for protein intracellular retention. Indeed, inhibition of the ubiquitin pathway results in increased Nectin2 surface expression and enhances tumor cell susceptibility to NK cell cytotoxicity. Our results demonstrate a previously unknown mechanism of Nectin2 regulation revealing that the ubiquitin pathway represents a potential target of intervention in order to increase susceptibility to NK cell‐mediated lysis.