bluuebunny/crossref_metadata_2025 huggingface dataset:
Predicting Incident Radiographic Knee Osteoarthritis in Middle‐Aged Women Within Four Years: The Importance of Knee‐Level Prognostic Factors
Authors: Garriga Cesar , Sánchez‐Santos Maria T. , Judge Andrew , Hart Deborah , Spector Tim , Cooper Cyrus , Arden Nigel K.
Published: May 2019

Objective

To develop and internally validate risk models and a clinical risk score tool to predict incident radiographic knee osteoarthritis (RKOA) in middle‐aged women.

Methods

We analyzed 649 women in the Chingford 1,000 Women study. The outcome was incident RKOA, defined as Kellgren/Lawrence grade 0–1 at baseline and ≥2 at year 5. We estimated predictors’ effects on the outcome using logistic regression models. Two models were generated. The clinical model considered patient characteristics, medication, biomarkers, and knee symptoms. The radiographic model considered the same factors, plus radiographic factors (e.g., angle between the acetabular roof and the ilium's vertical cortex [hip α‐angle]). The models were internally validated. Model performance was assessed using calibration and discrimination (area under the receiver characteristic curve [AUC]).

Results

The clinical model contained age, quadriceps circumference, and a cartilage degradation marker (C‐terminal telopeptide of type II collagen) as predictors (AUC = 0.692). The radiographic model contained older age, greater quadriceps circumference, knee pain, knee baseline Kellgren/Lawrence grade 1 (versus 0), greater hip α‐angle, greater spinal bone mineral density, and contralateral RKOA at baseline as predictors (AUC = 0.797). Calibration tests showed good agreement between the observed and predicted incident RKOA. A clinical risk score tool was developed from the clinical model.

Conclusion

Two models predicting incident RKOA within 4 years were developed, including radiographic variables that improved model performance. First‐time predictor hip α‐angle and contralateral RKOA suggest OA origins beyond the knee. The clinical tool has the potential to help physicians identify patients at risk of RKOA in routine practice, but the tool should be externally validated.
Living Atomically Dispersed Cu Ultrathin TiO2 Nanosheet CO2 Reduction Photocatalyst
Authors: Jiang Zaiyong , Sun Wei , Miao Wenkang , Yuan Zhimin , Yang Guihua , Kong Fangong , Yan Tingjiang , Chen Jiachuan , Huang Baibiao , An Changhua , Ozin Geoffrey A.
Published: May 2019

Supported atomically dispersed metals are proving to be efficacious photocatalysts for CO2 reduction to solar fuels. While being atom efficient, they suffer from being noble, rare, and costly (Pt, Pd, Au, Ag, Rh) and lacking in long‐term stability. Herein, all of these problems are solved with the discovery that atomically dispersed Cu supported on ultrathin TiO2 nanosheets can photocatalytically reduce an aqueous solution of CO2 to CO. The atomically dispersed Cu can be recycled in a straightforward procedure when they become oxidatively deactivated. This advance bodes well for the development of a solar fuels technology founded on abundant, low‐cost, nontoxic, atomically dispersed metal photocatalysts.
Prediction of DNA Integrity from Morphological Parameters Using a Single‐Sperm DNA Fragmentation Index Assay
Authors: Wang Yihe , Riordon Jason , Kong Tian , Xu Yi , Nguyen Brian , Zhong Junjie , You Jae Bem , Lagunov Alexander , Hannam Thomas G. , Jarvi Keith , Sinton David
Published: May 2019

Intracytoplasmic sperm injection is a popular form of in vitro fertilization, where single sperm are selected by a clinician and injected into an egg. Whereas clinicians employ general morphology‐based guidelines to select the healthiest‐looking sperm, it remains unclear to what extent an individual sperm's physical parameters correlate with the quality of internal DNA cargo—a measurement that cannot be obtained without first damaging the sperm. Herein, a single‐cell DNA fragmentation index (DFI) assay is demonstrated, which combines the single‐cell nature of the acridine orange test with the quantitative aspect of the sperm chromatin structure assay, to create a database of DFI‐scored brightfield images. Two regression predictive models, linear and nonlinear regression, are used to quantify the correlations between individual sperm morphological parameters and DFI score (with model test r at 0.558 and 0.620 for linear and nonlinear regression models, respectively). The sample is also split into two categories of either relatively good or bad DFIs and a classification predictive model based on logistic regression is used to categorize sperm, resulting in a test accuracy of 0.827. Here, the first systematic study is presented on the correlation and prediction of sperm DNA integrity from morphological parameters at the single‐cell level.
Core Content for Pediatric Emergency Medicine Ultrasound Fellowship Training: A Modified Delphi Consensus Study
Authors: Constantine Erika , Levine Marla , Abo Alyssa , Arroyo Alex , Ng Lorraine , Kwan Charisse , Baird Janette , Shefrin Allan E. ,   the P2 Network Point‐of‐care Ultrasound Fellowship Delphi Group
Published: May 2019

Background

Pediatric emergency medicine (PEM) point‐of‐care ultrasound (POCUS) fellowships exist to provide learners with expertise in ultrasound (US) education, administration, and research oversight. Currently, there are no standardized goals or objectives for these programs, resulting in considerable variability in PEM POCUS fellowship training.

Methods

A modified Delphi survey of PEM and general emergency medicine (EM) POCUS experts in Canada and the United States was conducted to obtain consensus regarding the most important curricular components of a PEM POCUS fellowship training program. Participants were solicited from the P2 Network mailing list and from PEM and EM POCUS fellowship directors listed on the Society of Clinical Ultrasound Fellowships and the Canadian Society of POCUS‐EM Fellowships websites. Curricular components considered as part of the survey included US skills, educational skills, administrative skills, and research requirements. Consensus was considered to have been reached when ≥80% of respondents agreed to either include or exclude the component in fellowship training.

Results

Round 1 of the survey was sent to 311 participants. A total of 118 (37.9%) completed eligibility for the survey, and 92 (78.0%) met eligibility criteria. Of those, 80 (67.8% of eligible participants) completed the first round of the survey. Round 2 of the survey was sent to those who completed part 1, and 64 (80.0%) completed that round. During Round 1, consensus was achieved for 15 of 75 US applications, seven of seven educational skills, nine of 11 administrative skills, and four of six research requirements. In Round 2 of the survey, consensus was reached on two additional US skills, but no additional administrative skills or research requirements.

Conclusions

With a consensus‐building process, the core content for PEM POCUS fellowship training was defined. This can help POCUS educators formulate standardized curricula to create consistent training in POCUS fellowship graduates.
Serum 24‐hydroxycholesterol in probable Alzheimer's dementia: Reexploring the significance of a tentative Alzheimer's disease biomarker
Authors: Roy Debashree , Chakrabarti Sankha Shubhra , Banerjee Anindita , Sharma Pallav , Biswas Atanu , Chakrabarti Sasanka
Published: May 2019

Objective

This study measured and analyzed the serum levels of 24‐hydroxycholesterol in patients with probable Alzheimer's disease (AD) and age‐/sex‐matched controls.

Methods

A case‐control study involving 40 AD patients and 40 controls was performed at a tertiary neurological teaching hospital in eastern India. Blood and serum samples were collected for APOE genotyping and 24‐hydroxycholesterol levels, respectively.

Results

Serum 24‐hydroxycholesterol was significantly lower in AD patients compared to controls (median concentration: controls, 47.14 ng/mL (interquartile range, 16.34); AD patients, 32.93 ng/mL (interquartile range, 9.45); P < 0.001) but showed no significant correlation with Mini Mental State Examination (MMSE) score in AD cases (r = −0.169, P = 0.298) or in controls (r = 0.18, P = 0.26). No statistically significant difference was observed between serum 24‐hydroxycholesterol levels of the APOE4‐positive and ‐negative subgroups in AD patients (P = 0.79). Findings were consistent and unchanged even when the ratio of serum 24‐hydroxycholesterol to serum total cholesterol was considered.

Conclusion

The decreased 24‐hydroxycholesterol level in peripheral circulation in AD cases observed in the present study may suggest its role in AD pathogenesis. The lack of a clear correlation between serum levels of 24‐hydroxycholesterol and MMSE score—a surrogate marker of AD severity—raises the question as to whether 24‐hydroxycholesterol level declines with decreasing neuronal mass or whether the steroid continues to play a protective role.
Intelligent Liquid Integrated Functional Entity: A Basic Way to Innovate Future Advanced Biomimetic Soft Robotics
Authors: Liu Tian-Ying , Qin Peng , Liu Jing
Published: May 2019

The liquid is an essential component of natural creatures with profound capacities in assisting homeostatic regulation of physiological functions. However, its participation in more diverse biological behaviors, such as intelligence, motion, energy, etc., is seriously neglected and is undisclosed thus far. Herein, it is considered whether liquid systems can offer pivotal hints in the development of intelligent machines. Starting from this core point, a basic conjecture is proposed that specifically equips a robotic system with liquid that brings about revolutionary design of intelligent systems and plays an elementary role in molding future advanced soft robots. Through a comparative analogy between artificially made machines and natural animals, the basic category of the so‐termed Intelligent Liquid Integrated Functional Entity (I‐LIFE) is drafted and thus enabled. Then, functions of such unconventional robotic liquid are expounded from five aspects, including motion, energy supply, material performance tuning, sensing, and intelligence, respectively. Typical application examples are also illustrated. Furthermore, a group of intelligent liquids are recommended as candidates for developing future robotic systems. The fundamental scientific and technological challenges lying behind these recommendations are outlined. Finally, prospects of I‐LIFE are pointed out, which stimulates the increasing design of a future generation of innovative intelligent robotic systems.
A Bipolar and Self‐Polymerized Phthalocyanine Complex for Fast and Tunable Energy Storage in Dual‐Ion Batteries
Authors: Wang Heng‐guo , Wang Haidong , Si Zhenjun , Li Qiang , Wu Qiong , Shao Qi , Wu Lanlan , Liu Yu , Wang Yinghui , Song Shuyan , Zhang Hongjie
Published: May 2019

Bipolar redox organics have attracted interest as electrode materials for energy storage owing to their flexibility, sustainability and environmental friendliness. However, an understanding of their application in all‐organic batteries, let alone dual‐ion batteries (DIBs), is in its infancy. Herein, we propose a strategy to screen a variety of phthalocyanine‐based bipolar organics. The self‐polymerizable bipolar Cu tetraaminephthalocyanine (CuTAPc) shows multifunctional applications in various energy storage systems, including lithium‐based DIBs using CuTAPc as the cathode material, graphite‐based DIBs using CuTAPc as the anode material and symmetric DIBs using CuTAPc as both the cathode and anode materials. Notably, in lithium‐based DIBs, the use of CuTAPc as the cathode material results in a high discharge capacity of 236 mAh g−1 at 50 mA g−1 and a high reversible capacity of 74.3 mAh g−1 after 4000 cycles at 4 A g−1. Most importantly, a high energy density of 239 Wh kg−1 and power density of 11.5 kW kg−1 can be obtained in all‐organic symmetric DIBs.
Ethical Rationales and Guidelines for the Continued Use of Archival Collections of Embryonic and Fetal Specimens
Authors: Fourniquet Sophie E. , Beiter Kaylin J. , Mussell Jason C.
Published: May 2019

Benefits from the use of cadavers in anatomical education are well described. Historically, human embryos and fetal cadavers were used in anatomy education to understand development and congenital malformations. Recently, three‐dimensional printed models produced from archival fetal specimens, and online repositories of images from archival collections of embryos and fetuses, have been used as an educational tool in human development courses. Given that the archival specimens were likely obtained prior to the era of informed consent, this raises questions about their appropriate and ethical use. Because some institutions in the United States retain archival collections of embryonic and fetal specimens that were once used as educational tools, their existence and utility require frequent reexamination against contemporary ethical frameworks to guide appropriate use or utilization. Four ethical rationales for uses of these collections are examined, including destruction, indefinite storage, use in research, and use in health professions education. Guidelines for the use of archival collections of human embryos and fetuses are presented. Indefinite storage and use in health professions education are supported, while use in research is also permitted, however, such use is limited and dependent on circumstance and purpose. The development of current digital repositories and three‐dimensionally printed models based on archival collections that were collected without informed consent, or those promoting commercial opportunity, are not supported. New embryonic and fetal donations obtained with informed consent should include reference to potential uses with new technology and virtual, genetic, or imaging applications.
Knowledge‐rich teaching: A model of curriculum design coherence
Authors: Rata Elizabeth
Published: May 2019

A theoretical model called ‘Curriculum Design Coherence’ (CDC) is described and justified. The model's purpose is to assist teachers in the compulsory and higher education sectors to design courses that can accommodate the complex and interdependent relationship between concepts and content and between knowledge and skills. Its intended usefulness as a curriculum design tool may also contribute to teachers’ pedagogical decision‐making. The model was initially developed in a New Zealand university Engineering study and is now being trialled in a study in the compulsory schooling sector with the ‘Knowledge‐Rich School Project’. The CDC model integrates concepts, content and competencies in a coherent way, thereby avoiding several tendencies which have affected curriculum studies in recent decades. These are: a ‘skills’ versus ‘concepts’ bifurcation; an over‐emphasis on fragmented content without conceptual integration; and a similar over‐emphasis on pedagogy (the ‘how’) at the expense of what is taught. The first sections of the article discuss the theories used to justify the model's connections between the elements of concepts, content and competencies. The theories concern (1) knowledge types (disciplinary and socio‐cultural) and (2) knowledge forms (propositional/conceptual and procedural/competencies). The justification is followed by a description of the CDC model itself.
Bringing Stem Cell‐Based Therapies for Type 1 Diabetes to the Clinic: Early Insights from Bioprocess Economics and Cost‐Effectiveness Analysis
Authors: Bandeiras Cátia , Cabral Joaquim M. S. , Gabbay Robert A. , Finkelstein Stan N. , Ferreira Frederico Castelo
Published: May 2019

Differentiation of pluripotent stem cells (PSCs) into β cells could provide insulin independence for type 1 diabetes (T1D) patients. This approach would reduce the clinical complications that most patients managed on intensive insulin therapy (IIT) face. However, bottlenecks of PSC manufacturing and limited engraftment of encapsulated cells hinder the long‐term effectiveness of these therapies. A bioprocess decision‐support tool is combined with a disease state‐transition model to evaluate the cost‐effectiveness of the stem cell‐based therapy against IIT. Clinical effectiveness is assessed in quality‐adjusted life years (QALYs). Manufacturing costs per patient reduce from $430 000 to $160 000 with optimization of batch size and annual demand. For 96% of the patients, cell therapy improves the quality of life compared to IIT. Cost savings are achieved for 2% of the population through prevention of renal disease. The therapy is cost‐effective for 3.4% of patients when a willingness to pay (WTP) of up to $150 000 per QALY is considered. A 75% cost reduction in the cell therapy price increases cost‐effectiveness likelihood to 51% at $100 000 per QALY. This study highlights the need for scalable manufacturing platforms for stem cell therapies, as well as to prioritizing access to the therapy to patients with an increased likelihood of costly complications.
An LC–MS/MS method for quantification of HR011303, a novel highly selective urate transporter 1 inhibitor in beagle dogs and the application to a pharmacokinetic study
Authors: Wang Ju , Yao Wei , Fan Di , Qiu Zhenjun , Song Jieqiong , Pan Kai , Hang Taijun
Published: May 2019

HR011303 is a novel and highly selective urate transporter 1 (URAT1) inhibitor. In this study, a sensitive liquid chromatography–tandem mass spectrometry (LC–MS/MS) method was developed and validated for quantification of HR011303 in beagle dog plasma. Plasma samples were pretreated with protein‐precipitation extraction by acetonitrile and added with a trifluoromethyl substituted analog of HR011303 as internal standard. The chromatographic separation was performed on a Shiseido C18 column (100 × 4.6 mm, i.d., 5 μm) by mobile phases consisting of 5 mm ammonium–formic acid (100:0.1) and acetonitrile–formic acid (100:0.1) solutions in gradient elution. The MS detection was conducted in electrospray positive ionization with multiple reactions monitoring at m/z 338 → 240 for HR011303 and m/z 328 → 230 for the internal standard using 25 eV argon gas collision induced dissociation. The established LC–MS/MS method showed good selectivity, sensitivity, precision and accuracy. The plasma pharmacokinetics of HR011303 in beagle dogs following both oral and intravenous administration were then successfully evaluated using this LC–MS/MS method.
Prognostic factor of lenvatinib for unresectable hepatocellular carcinoma in real‐world conditions—Multicenter analysis
Authors: Hiraoka Atsushi , Kumada Takashi , Atsukawa Masanori , Hirooka Masashi , Tsuji Kunihiko , Ishikawa Toru , Takaguchi Koichi , Kariyama Kazuya , Itobayashi Ei , Tajiri Kazuto , Shimada Noritomo , Shibata Hiroshi , Ochi Hironori , Tada Toshifumi , Toyoda Hidenori , Nouso Kazuhiro , Tsutsui Akemi , Nagano Takuya , Itokawa Norio , Hayama Korenobu , Imai Michitaka , Joko Kouji , Koizumi Yohei , Hiasa Yoichi , Michitaka Kojiro , Kudo Masatoshi ,   the Real‐life Practice Experts for HCC (RELPEC) Study Group, HCC 48 Group (hepatocellular carcinoma experts from 48 clinics in Japan)
Published: May 2019

Background/aim

We assessed suitable factors indicating newly developed lenvatinib (LEN) treatment for unresectable hepatocellular carcinoma (u‐HCC) by investigating real‐world clinical features of patients.

Materials/methods

One hundred fifty two u‐HCC patients, who receive LEN treatment from March to December 2018, were enrolled. (Child‐Pugh score [CPS] 5/6/7/8 = 76/61/13/2, modified albumin‐bilirubin grade [mALBI] 1/2a/2b/3 = 53/35/60/4). Clinical features were evaluated retrospectively.

Results

Overall‐response rate (ORR)/disease control rate (DCR) at 1 month after starting LEN were 38.7%/86.0%, respectively. Estimated median time to progression (TTP) was 7.0 months, while median survival time was not reached within the observation period. CPS (≥7) and past history of tyrosine‐kinase inhibitor (TKI) were not significant prognostic factors. mALBI ≥2b was an only significant prognostic factor (HR 4.632, 95%CI 1.649‐13.02, P = 0.004) in Cox‐hazard multivariate analysis. In patients with Child‐Pugh A, c‐index/Akaike's information criterion (AIC) of prognostic predictive value of mALBI were superior to CPS (0.682/135.6 vs 0.652/138.7), while those of stopping LEN also showed that mALBI was better (0.575/447.3 vs 0.562/447.8). Additional analysis of patients with good mALBI (1/2a) revealed that time to stopping LEN was significantly shorter in those with the adverse event (AE) of appetite loss (any grade) than those without (P = 0.006) and body mass index (BMI) was also lower in patients with that AE (20.3 ± 3.0 vs 23.6 ± 4.0kg/m2, P < 0.001), while patients with a hand‐foot skin reaction (any grade) showed good ORR/DCR (59.1%/86.4%) and longer TTP as compared to patients without (P = 0.007).

Conclusion

Good hepatic function (mALBI 1/2a) is the best indication for LEN, while potential appetite loss in association with low BMI should be kept in mind in such cases.
Clinical analysis of 547 patients with neuroendocrine tumors in a Chinese population: A single‐center study
Authors: Song Lijie , Zhai Xuejia , Yu Shunli , Ma Yihui , Wang Feng , Yu Xuxu , Tao Shuang , Lian Yujin , Yang Minjie , Tao Weili , Fan Qingxia
Published: May 2019

Background

Neuroendocrine tumors (NETs) are rare, which has resulted in a lack of published data on their epidemiology and clinical features. We therefore aimed to investigate the epidemiology, clinical features, treatments, and prognosis of patients with NETs.

Methods

The clinicopathologic characteristics of 547 patients who were pathologically diagnosed with NETs were retrospectively analyzed, including age, sex, primary and metastatic sites, symptoms, pathology, treatment, and prognosis.

Results

The 547 patients had a wide age range (9‐87 years), with a male to female ratio of 1:1.1. The primary tumor sites included 413 in the digestive system, 74 in the lung, 15 in the mediastinum, 8 in unknown sites, and 37 in other sites. Of the 413 patients with digestive system NETs, the pancreas, rectum, and stomach were the most common primary sites. Blood metastases were found in 84 patients at initial diagnosis, and the liver, bone, and lung were the most frequent sites of metastasis. Lymph node metastases were found in 82 patients at initial diagnosis. Surgery and chemotherapy were the most widely applied treatments. Statistical analysis showed that age <50 years, female sex, lower‐grade tumor, no distant metastasis, intestinal NET and surgery indicated a favorable prognosis.

Conclusions

A difference between China and other countries is that small intestinal NETs are quite common in other countries but are rare in China. In China, the most common primary sites are the pancreas, rectum, and stomach. Furthermore, no unified treatments exist, though prognoses could be improved by using methods such as surgery, targeted therapies, and somatostatin analogs.

Clinical Trial Registration

This study was not a clinical trial.
Molecular characterization of colorectal cancer using whole‐exome sequencing in a Taiwanese population
Authors: Chang Ya‐Sian , Lee Chien‐Chin , Ke Tao‐Wei , Chang Chieh‐Min , Chao Dy‐San , Huang Hsi‐Yuan , Chang Jan‐Gowth
Published: May 2019

Next‐generation sequencing (NGS) technology is currently used to establish mutational profiles in many heterogeneous diseases. The aim of this study was to evaluate the mutational spectrum in Taiwanese patients with colorectal cancer (CRC) to help clinicians identify the best treatment method. Whole‐exome sequencing was conducted in 32 surgical tumor tissues from patients with CRC. DNA libraries were generated using the Illumina TruSeq DNA Exome, and sequencing was performed on the Illumina NextSeq 500 system. Variants were annotated and compared to those obtained from publicly available databases. The analysis revealed frequent mutations in APC (59.38%), TP53 (50%), RAS (28.13%), FBXW7 (18.75%), RAF (9.38%), PIK3CA (9.38%), SMAD4 (9.38%), and SOX9 (9.38%). A mutation in TCF7L2 was also detected, but at lower frequencies. Two or more mutations were found in 22 (68.75%) samples.

The mutation rates for the WNT, P53, RTK‐RAS, TGF‐β, and PI3K pathways were 78.13%, 56.25%, 40.63%, 18.75%, and 15.63%, respectively. RTK‐RAS pathway mutations were correlated with tumor size (P = 0.028). We also discovered 23 novel mutations in NRAS, PIK3CA, SOX9, APC, SMAD4, MSH3, MSH4, PMS1 PMS2, AXIN2, ERBB2, PIK3R1, TGFBR2, and ATM that were not reported in the COSMIC, The Cancer Genome Atlas, and dbSNP databases. In summary, we report the mutational landscape of CRC in a Taiwanese population. NGS is a cost‐effective and time‐saving method, and we believe that NGS will help clinicians to treat CRC patients in the near future.
Digital images as meaning bridges: Case study of assimilation using avatar software in counselling with a 14‐year‐old boy
Authors: van Rijn Biljana , Chryssafidou Evi , Falconer Caroline J. , Stiles William B.
Published: May 2019

Objectives

According to the assimilation model, psychotherapeutic progress involves building semiotic meaning bridges between disconnected parts of the person. Previous research has focused on verbal meaning bridges; this case study investigated whether and how digital imagery might serve as well.

Design

This was a qualitative theory‐building case study.

Method

The client was a 14‐year‐old boy with autism spectrum disorder seen in school counselling for 60 sessions. Assimilation analysis was applied to screen recordings and accompanying voice recording nine sessions, drawn from an early part of his treatment, during which he participated in an evaluation of video game‐like software designed for therapy and coaching.

Results

The client created avatars representing aspects of himself and significant others, and scenes representing his problems and coping. The imagery and meanings evolved across this segment of treatment, providing a channel of interpersonal and intra‐personal communication.

Conclusion

Observations showed how digital imagery can serve as meaning bridges between client and counsellor, and between internal parts of the client.
Discussion on the pressure drop calculation for oil‐water separated flow using a one dimensional two‐fluid model
Authors: Liu Nannan , Wang Wei , Liu Yingying , Ma Liang , Gong Jing
Published: May 2019

The purpose of this work is to seek the key factors influencing the pressure drop calculation for oil‐water separated flow using a one dimensional two‐fluid model. Closure relations published for the two‐fluid model such as interface configuration, wall, and interfacial shear stress correlations are summarized. Interface configurations are established by numerically solving the Young‐Laplace equation, correlated with the Bond number, contact angle, and water holdup. Results show that the interface transforms from concave to convex with the enlargement of the contact angle and becomes flat as the Bond number increases. For the pressure drop calculation, a limited difference of predicted accuracy between the curve and flat interface is found. Discussions of both the wall and interfacial friction factor correlation on the pressure drop calculation are performed. In contrast to the effect of the interfacial friction factor, the correlation of the wall friction factor is found to have more contributions. We validate the prediction accuracy of different wall frictions factors using eight groups of published experiment results, and one correlation is recommended and being further extended.
A Comprehensive Analysis of Ontogeny of Renal Drug Transporters: mRNA Analyses, Quantitative Proteomics, and Localization
Authors: Cheung Kit Wun Kathy , van Groen Bianca D. , Spaans Edwin , van Borselen Marjolein D. , de Bruijn Adrianus C.J.M. , Simons‐Oosterhuis Ytje , Tibboel Dick , Samsom Janneke N. , Verdijk Robert M. , Smeets Bart , Zhang Lei , Huang Shiew‐Mei , Giacomini Kathleen M. , de Wildt Saskia N.
Published: May 2019

Human renal membrane transporters play key roles in the disposition of renally cleared drugs and endogenous substrates, but their ontogeny is largely unknown. Using 184 human postmortem frozen renal cortical tissues (preterm newborns to adults) and a subset of 62 tissue samples, we measured the mRNA levels of 11 renal transporters and the transcription factor pregnane X receptor (PXR) with quantitative real‐time polymerase chain reaction, and protein abundance of nine transporters using liquid chromatography tandem mass spectrometry selective reaction monitoring, respectively. Expression levels of p‐glycoprotein, urate transporter 1, organic anion transporter 1, organic anion transporter 3, and organic cation transporter 2 increased with age. Protein levels of multidrug and toxin extrusion transporter 2‐K and breast cancer resistance protein showed no difference from newborns to adults, despite age‐related changes in mRNA expression. Multidrug and toxin extrusion transporter 1, glucose transporter 2, multidrug resistance‐associated protein 2, multidrug resistance‐associated protein 4 (MRP4), and PXR expression levels were stable. Using immunohistochemistry, we found that MRP4 localization in pediatric samples was similar to that in adult samples. Collectively, our study revealed that renal drug transporters exhibited different rates and patterns of maturation, suggesting that renal handling of substrates may change with age.
All‐Optical Temperature Sensing in Organogel Matrices via Annihilation Upconversion
Authors: Nazarova Nadzeya , Avlasevich Yuri , Landfester Katharina , Baluschev Stanislav
Published: May 2019

Modified organogels are bicontinuous colloidal systems which form a three‐dimensional network embedding well‐solvated organic dyes sensitive to minor changes in its microenvironment. It was demonstrated that these natural wax/oils based organogels can be applied for minimally invasive temperature sensing in life‐science objects. The desired temperature sensitivity of better than 100 mK, centered around the physiologically relevant temperature of 36 °C, is warranted by using the process of triplet‐triplet annihilation photon energy upconversion (TTA‐UC) as a sensing mechanism. This all‐optical sensing technique, based on ratiometric‐type signal registration, ensures significant independence of the data obtained on excitation intensity instabilities, local molecular concentration fluctuations and field‐of‐view variations. The TTA‐UC system is effectively protected for more than 1000 s against oxygen‐induced damage, allowing stable performance of this temperature‐sensing system even in ambient environments without lost of sensitivity and applying the same calibration curve.
Experimental and Theoretical Investigation of the Effect of Oxygen Vacancies on the Electronic Structure and Pseudocapacitance of MnO2
Authors: Yan Lijin , Shen Cheng , Niu Lengyuan , Liu Mao‐cheng , Lin Jianhua , Chen Taiqiang , Gong Yinyan , Li Can , Liu Xinjuan , Xu Shiqing
Published: May 2019

Defect engineering is an effective way to modulate the intrinsic physicochemical properties of materials. In this work, δ‐MnO2 with oxygen vacancies is fabricated by a simple oxidation or reduction process, and the relationship between the electronic structure and pseudocapacitance is systematically studied through experimental analysis and theoretical calculations. The peaks in the Raman spectra of the as‐prepared samples are shifted compared with those of pure MnO2 and the Mn3+/Mn4+ ratio and O species content also change after the introduction of oxygen vacancies. The optimized samples exhibit a better specific capacitance of 207 F g−1 after the oxidation process and 181.4 F g−1 after the reduction treatment compared with only 143.9 F g−1 for the pure MnO2. The samples obtained through the oxidation or reduction process also retain 93.3 or 86.4 % of the initial capacity after 5000 cycles. The excellent properties are attributed to the enhanced conductivity and increased surface reactivity or electrochemically active sites. Theoretical calculations demonstrate that the presence of oxygen vacancies leads to an increase in the density of states, which improves the redox reaction of MnO2. This study will provide a reference for exploring and designing highperformance pseudocapacitive materials.
Assessment of autonomic function in the late term fetus: The effects of sex and state
Authors: Zavala Julia H. , Ecklund‐Flores Lisa , Myers Michael M. , Fifer William P.
Published: May 2019

Researchers have reported associations between fetal sex and heart rate (FHR) and heart rate variability (FHRV) but rarely in the context of fetal behavioral sleep state. We examined differences in measures of fetal autonomic function by sex and sleep state. Fetal abdominal ECG monitoring technology was used to measure FHR and two measures of FHRV—standard deviation of FHR (SD) and beat‐to‐beat variability (RMSSD). FHR and movement patterns were also recorded with standard Doppler ultrasound monitor technology employed to code sleep states. Data were collected from 82 healthy fetuses ranging from 36 to 39 weeks gestation. A one‐way MANOVA showed that FHR was significantly lower and SD was significantly higher for males than females. Independent samples t tests found that these sex differences were only in the active sleep state. There were no significant differences in RMSSD by sex. Repeated measures MANOVA for a subset that exhibited more than one state (N = 22) showed that SD was significantly different by state. RMSSD showed a marginally significant sleep state difference. In conclusion, fetal sex differences in HR and HRV may indicate more mature autonomic functioning in near‐term males than females and fetal sleep state can influence abdominal fECG derived measures of FHR and FHRV.
Summary statistics for drug concentrations in post‐mortem femoral blood representing all causes of death
Authors: Ketola Raimo A. , Ojanperä Ilkka
Published: May 2019

Concentration distributions for 183 drugs and metabolites frequently found in post‐mortem (PM) femoral venous blood were statistically characterized based on an extensive database of 122 234 autopsy cases investigated during an 18‐year period in a centralized laboratory. The cases represented all causes of death, with fatal drug poisonings accounting for 8%. The proportion of males was 74% with a median age of 58 years compared with 26% females with a median age of 64 years. In 36% of these cases, blood alcohol concentration was higher than or equal to 0.2‰, the median being 1.6‰. The mean, median, and upper percentile (90th, 95th, 97.5th) drug concentrations were established, as the median PM concentrations give an idea of the “normal” PM concentration level, and the upper percentile concentrations indicate possible overdose levels. A correspondence was found between subsets of the present and the previously published PM drug concentrations from another laboratory that grouped cases according to the cause of death. Our results add to the knowledge for evidence‐based interpretation of drug‐related deaths.
Spatial behavior and habitat use in widely separated breeding and wintering distributions across three species of long‐distance migrant Phylloscopus warblers
Authors: Lerche‐Jørgensen Mathilde , Mallord John W. , Willemoes Mikkel , Orsman Christopher J. , Roberts Japheth T. , Skeen Roger Q. , Eskildsen Daniel P. , Salewski Volker , Tøttrup Anders P. , Thorup Kasper
Published: May 2019

Aim

To investigate the ecological relationship between breeding and wintering in specialist and generalist long‐distance migratory species, and the links between densities and range sizes.

Location

Denmark, Senegal and Ghana.

Methods

We use radio tracking to study spatial behavior and habitat use in three morphologically and ecologically similar and closely related Phylloscopus species on their widely separated breeding and wintering distributions. During wintering and breeding, willow warblers P. trochilus (winter: n = 9, breeding: n = 13), chiffchaffs P. collybita (n = 11, n = 7), and wood warblers P. sibilatrix (n = 17, n = 14) were tracked.

Results

Willow warblers P. trochilus increased home range sizes in winter, whereas it was similar in chiffchaffs P. collybita and wood warblers P. sibilatrix, in both seasons. Home ranges overlapped more in winter than in the breeding season. In winter, home range overlap was similar among species but larger overlap during breeding was indicated for willow warblers. Tree cover was unrelated to home range size but significantly higher in breeding than in winter in all species. However, whereas willow warblers and wood warblers maintained some degree of tall tree cover inside their home ranges in winter, chiffchaffs changed from more than 80% to <1% tree cover, indicating a niche shift.

Main conclusions

Individuals of all three species showed changes between breeding and wintering areas in spatial behavior and habitat availability, with larger overlap in winter. The differences in patterns were potentially related to being generalist (willow warbler) or specialist (chiffchaff and wood warbler). These ecological relationships are important for the conservation of migrants and for understanding the link between breeding and wintering distributions and ecology.
Conservation of genetic uniqueness in remaining populations of red squirrels (Sciurus vulgaris L.) in the South of England
Authors: Hardouin Emilie A. , Baltazar‐Soares Miguel , Schilling Anna‐Katarina , Butler Helen , García‐Rodríguez Oxala , Crowley Eloise , Liang Wei‐Jun , Meredith Anna , Lurz Peter W. W. , Forster Jane , Kenward Robert E. , Hodder Kathy H.
Published: May 2019

The Eurasian red squirrel (Sciurus vulgaris) is an emblematic species for conservation, and its decline in the British Isles exemplifies the impact that alien introductions can have on native ecosystems. Indeed, red squirrels in this region have declined dramatically over the last 60 years due to the spread of squirrelpox virus following the introduction of the gray squirrel (Sciurus carolinensis). Currently, red squirrel populations in Britain are fragmented and need to be closely monitored in order to assess their viability and the effectiveness of conservation efforts. The situation is even more dramatic in the South of England, where S. vulgaris survives only on islands (Brownsea Island, Furzey Island, and the Isle of Wight). Using the D‐loop, we investigated the genetic diversity and putative ancestry of the squirrels from Southern England and compared them to a European dataset composed of 1,016 samples from 54 populations. We found that our three populations were more closely related to other squirrels from the British Isles than squirrels from Europe, showed low genetic diversity, and also harbored several private haplotypes. Our study demonstrates how genetically unique the Southern English populations are in comparison with squirrels from the continental European range. We report the presence of four private haplotypes, suggesting that these populations may potentially harbor distinct genetic lineages. Our results emphasize the importance of preserving these isolated red squirrel populations for the conservation of the species.
Regional processes are stronger determinants of rocky intertidal community dynamics than local biotic interactions
Authors: Hacker Sally D. , Menge Bruce A. , Nielsen Karina J. , Chan Francis , Gouhier Tarik C.
Published: May 2019

Understanding the relative roles of species interactions and environmental factors in structuring communities has historically focused on local scales where manipulative experiments are possible. However, recent interest in predicting the effects of climate change and species invasions has spurred increasing attention to processes occurring at larger spatial and temporal scales. The “meta‐ecosystem” approach is an ideal framework for integrating processes operating at multiple scales as it explicitly considers the influence of local biotic interactions and regional flows of energy, materials, and organisms on community structure. Using a comparative‐experimental design, we asked (1) what is the relative importance of local biotic interactions and oceanic processes in determining rocky intertidal community structure in the low zone within the Northern California Current System, and (2) what factors are most important in regulating this structure and why? We focused on functional group interactions between macrophytes and sessile invertebrates and their consumers (grazers, predators), how these varied across spatial scales, and with ocean‐driven conditions (upwelling, temperature) and ecological subsidies (nutrients, phytoplankton, sessile invertebrate recruits). Experiments were conducted at 13 sites divided across four capes in Oregon and northern California. Results showed that biotic interactions were variable in space and time but overall, sessile invertebrates had no effect on macrophytes while macrophytes had weakly negative effects on sessile invertebrates. Consumers, particularly predators, also had weakly negative effects on both functional groups. Overall, we found that 40–49% of the variance in community structure at the local scale was explained by external factors (e.g., spatial scale, time, upwelling, temperature, ecological subsidies) vs. 19–39% explained by functional group interactions. When individual functional group interaction strengths were used, only 2–3% of the variation was explained by any one functional group while 28–54% of the variation was explained by external factors. We conclude that community structure in the low intertidal zone is driven primarily by external factors at the regional scale with local biotic interactions playing a secondary role.
Clinical phenotypes of acute heart failure based on signs and symptoms of perfusion and congestion at emergency department presentation and their relationship with patient management and outcomes
Authors: Javaloyes Patricia , Miró Òscar , Gil Víctor , Martín‐Sánchez Francisco Javier , Jacob Javier , Herrero Pablo , Takagi Koji , Alquézar‐Arbé Aitor , López Díez María Pilar , Martín Enrique , Bibiano Carlos , Escoda Rosa , Gil Cristina , Fuentes Marta , Llopis García Guillermo , Álvarez Pérez José María , Jerez Alba , Tost Josep , Llauger Lluís , Romero Rodolfo , Garrido José Manuel , Rodríguez‐Adrada Esther , Sánchez Carolina , Rossello Xavier , Parissis John , Mebazaa Alexandre , Chioncel Ovidiu , Llorens Pere ,   on behalf of the ICA‐SEMES Research Group
Published: May 2019

Objective

To compare the clinical characteristics and outcomes of patients with acute heart failure (AHF) according to clinical profiles based on congestion and perfusion determined in the emergency department (ED).

Methods and results

Overall, 11 261 unselected AHF patients from 41 Spanish EDs were classified according to perfusion (normoperfusion = warm; hypoperfusion = cold) and congestion (not = dry; yes = wet). Baseline and decompensation characteristics were recorded as were the main wards to which patients were admitted. The primary outcome was 1‐year all‐cause mortality; secondary outcomes were need for hospitalisation during the index AHF event, in‐hospital all‐cause mortality, prolonged hospitalisation, 7‐day post‐discharge ED revisit for AHF and 30‐day post‐discharge rehospitalisation for AHF. A total of 8558 patients (76.0%) were warm + wet, 1929 (17.1%) cold + wet, 675 (6.0%)

warm + dry, and 99 (0.9%) cold + dry; hypoperfused (cold) patients were more frequently admitted to intensive care units and geriatrics departments, and warm + wet patients were discharged home without admission. The four phenotypes differed in most of the baseline and decompensation characteristics. The 1‐year mortality was 30.8%, and compared to warm + dry, the adjusted hazard ratios were significantly increased for cold + wet (1.660; 95% confidence interval 1.400–1.968) and cold + dry (1.672; 95% confidence interval 1.189–2.351). Hypoperfused (cold) phenotypes also showed higher rates of index episode hospitalisation and in‐hospital mortality, while congestive (wet) phenotypes had a higher risk of prolonged hospitalisation but decreased risk of rehospitalisation. No differences were observed among phenotypes in ED revisit risk.

Conclusions

Bedside clinical evaluation of congestion and perfusion of AHF patients upon ED arrival and classification according to phenotypic profiles proposed by the latest European Society of Cardiology guidelines provide useful complementary information and help to rapidly predict patient outcomes shortly after ED patient arrival.
Controlled decongestion by Reprieve therapy in acute heart failure: results of the TARGET‐1 and TARGET‐2 studies
Authors: Biegus Jan , Zymlinski Robert , Siwolowski Pawel , Testani Jeffrey , Szachniewicz Joanna , Tycińska Agnieszka , Banasiak Waldemar , Halpert Andrew , Levin Howard , Ponikowski Piotr
Published: May 2019

Aims

Safe and effective decongestion is the main goal of therapy in acute heart failure (AHF). In the non‐randomized, prospective TARGET‐1 and TARGET‐2 studies (NCT03897842), we investigated whether adding the Reprieve System® (which continuously monitors urine output and delivers a matched volume of hydration fluid sufficient to maintain the set fluid balance rate) to standard diuretic‐based regimen improves decongestion in AHF.

Methods and results

The population consisted of 19 patients hospitalized with AHF (mean age 67 ± 10 years, 18 male, ejection fraction 34 ± 15%, median N‐terminal pro‐B‐type natriuretic peptide 4492 pg/mL). Patients served as their own controls: each patient underwent 24 h of standard diuretic therapy followed by 24 h of diuretics with Reprieve therapy (with normal saline used for matched volume replacement). The primary efficacy endpoint of actual fluid loss not exceeding the target fluid loss at the end of therapy was met in all 19 (100%) patients. The mean diuresis during Reprieve therapy was 6284 ± 2679 mL (vs. 1966 ± 1057 mL 24 h before therapy) and 2053 ± 888 mL (24 h after therapy) (both P < 0.0001). At the end of therapy, patient global assessment improved from 7.7 ± 1.1 to 3.0 ± 1.3 points (P < 0.001), central venous pressure decreased from 15.5 ± 5.3 mmHg to 12.8 ± 4.8 mmHg (P < 0.05) and the median urine sodium loss was 9.7 [3–13] mmol/h. The Reprieve therapy was safe, systolic blood pressure remained stable, mean creatinine dropped from 1.45 ± 0.4 mg/dL to 1.26 ± 0.4 mg/dL (P < 0.001) and biomarkers of renal injury did not change during treatment.

Conclusions

The Reprieve System in conjunction with diuretic therapy supports safe and controlled decongestion in AHF.
Peptidase inhibitor 16 identifies a human regulatory T‐cell subset with reduced FOXP3 expression over the first year of recent onset type 1 diabetes
Authors: Hope Christoper M , Welch John , Mohandas Arunesh , Pederson Stephen , Hill Danika , Gundsambuu Batjargal , Eastaff‐Leung Nicola , Grosse Randall , Bresatz Suzanne , Ang Grace , Papademetrios Michael , Zola Heddy , Duhen Thomas , Campbell Daniel , Brown Cheryl Y , Krumbiegel Doreen , Sadlon Timothy , Couper Jennefer J , Barry Simon C
Published: May 2019

CD4+ T‐cell subsets play a major role in the host response to infection, and a healthy immune system requires a fine balance between reactivity and tolerance. This balance is in part maintained by regulatory T cells (Treg), which promote tolerance, and loss of immune tolerance contributes to autoimmunity. As the T cells which drive immunity are diverse, identifying and understanding how these subsets function requires specific biomarkers. From a human CD4 Tconv/Treg cell genome wide analysis we identified peptidase inhibitor 16 (PI16) as a CD4 subset biomarker and we now show detailed analysis of its distribution, phenotype and links to Treg function in type 1 diabetes.

To determine the clinical relevance of Pi16 Treg, we analysed PI16+ Treg cells from type 1 diabetes patient samples. We observed that FOXP3 expression levels declined with disease progression, suggesting loss of functional fitness in these Treg cells in Type 1 diabetes, and in particular the rate of loss of FOXP3 expression was greatest in the PI16+ve Treg. We propose that PI16 has utility as a biomarker of functional human Treg subsets and may be useful for tracking loss of immune function in vivo. The ability to stratify at risk patients so that tailored interventions can be applied would open the door to personalised medicine for Type 1 diabetes.