bluuebunny/crossref_metadata_2025 huggingface dataset:
How does dementia with Lewy bodies start? prodromal cognitive changes in REM sleep behavior disorder
Authors: Génier Marchand Daphné , Postuma Ronald B. , Escudier Frédérique , De Roy Jessie , Pelletier Amélie , Montplaisir Jacques , Gagnon Jean‐François
Published: April 2018

Objective

We describe the progression of cognitive decline and identify the predictive values of cognitive tests in three groups of REM sleep behavior disorder (RBD) patients classified at their last follow‐up as having Parkinson's disease (PD), dementia with Lewy bodies (DLB), or still‐idiopathic.

Methods

Patients (n = 109) underwent polysomnographic, neurological, and neuropsychological assessments. We used linear mixed‐model analyses to compare the progression of cognitive test performance between the three groups over a 3‐year prodromal period, and performed linear regressions for a 6‐year prodromal period. We compared the proportions of patients with clinically impaired performance (z scores < –1.5). DLB patients were pair‐matched according to age, sex, and education to healthy controls (2:1 ratio), and receiver operating characteristic curves were performed to identify the psychometric properties of cognitive tests to predict dementia.

Results

At follow‐up, 38 patients (35%) developed a neurodegenerative disorder: 20 had PD and 18 DLB. Cognitive performance changes over time were strongly associated with later development of dementia. Clear deficits in attention and executive functions were observed 6 years before diagnosis. Verbal episodic learning and memory deficits started later, deviating from normal approximately 5 to 6 years and becoming clinically impaired at 1 to 2 years before diagnosis. Visuospatial abilities progressed variably, with inconsistent prodromal latencies. The Trail Making Test (part B), Verbal Fluency (semantic), and Rey Auditory‐Verbal Learning Test (total, immediate, and delayed recalls) were the best predictors for dementia (area under the curve = 0.90–0.97).

Interpretation

Prodromal DLB is detectible up to 6 years before onset. For clinical utility, the Trail Making Test (part B) best detects early prodromal dementia stages, whereas Verbal Fluency (semantic) and verbal episodic learning tests are best for monitoring changes over time. Ann Neurol 2018;83:1016–1026
Tunneling Mode of Scanning Electrochemical Microscopy: Probing Electrochemical Processes at Single Nanoparticles
Authors: Sun Tong , Wang Dengchao , Mirkin Michael V.
Published: April 2018

Electrochemical experiments at individual nanoparticles (NPs) can provide new insights into their structure–activity relationships. By using small nanoelectrodes as tips in a scanning electrochemical microscope (SECM), we recently imaged individual surface‐bound 10–50 nm metal NPs. Herein, we introduce a new mode of SECM operation based on tunneling between the tip and a nanoparticle immobilized on the insulating surface. The obtained current vs. distance curves show the transition from the conventional feedback response to electron tunneling between the tip and the NP at separation distances of less than about 3 nm. In addition to high‐resolution imaging of the NP topography, the tunneling mode enables measurement of the heterogeneous kinetics at a single NP without making an ohmic contact with it. The developed method should be useful for studying the effects of nanoparticle size and geometry on electrocatalytic activity in real‐world applications.
Block–Stereoblock Copolymers of Poly(ϵ‐Caprolactone) and Poly(Lactic Acid)
Authors: Rosen Tomer , Goldberg Israel , Navarra Wanda , Venditto Vincenzo , Kol Moshe
Published: April 2018

A magnesium complex of the type {ONNN}Mg‐HMDS wherein {ONNN} is a sequential tetradentate monoanionic ligand is introduced. In the presence of an alcohol initiator this complex catalyzes the living and immortal homopolymerization of the lactide enantiomers and ϵ‐caprolactone at room‐temperature with exceptionally high activities, as well as the precise block copolymerization of these monomers in a one‐pot synthesis by sequential monomer addition. Copolymers of unprecedented microstructures such as the PCL‐b‐PLLA‐b‐PDLA and PDLA‐b‐PLLA‐b‐PCL‐b‐PLLA‐b‐PDLA block–stereoblock microstructures that feature unique thermal properties are readily accessed.
Aid Policy and Australian Public Opinion
Authors: Wood Terence
Published: April 2018

Since 2013, Australian aid has been reduced and increasingly focused on delivering benefits to Australia. Motivated by these changes, this paper fills three gaps in the existing literature on public opinion about aid. It provides the only recent detailed study of Australians' opinions about aid. It studies specific policy questions in addition to the broader questions typical of international research. And it studies views on the purpose of aid, an area not previously researched. Although Australians are generally supportive of aid, most backed major aid cuts in 2015. However, most Australians think the purpose of Australian aid should be helping people in poor countries, not bringing benefits to Australia. There is a clear left–right divide in responses to all questions; however, some variables correlated with support for aid fail to explain variation in views about aid's purpose. The paper concludes by discussing ramifications for those who seek to change aid policy.
Framing Sino‐American military relations: The power and problem of perception in preventing geostrategic security cooperation between China and the United States
Authors: Rudolph Rachael M.
Published: April 2018

Sino‐American relations are composed of a complex field of factors that have influenced both cooperation and confrontation between the Chinese and Americans. The factors that present the most obstacles are undoubtedly rooted in the Sino‐American military relationship where there has been a great deal of potentially dangerous misunderstandings. Part one of this study provides an overview of the literature on Sino‐American relations, Sino‐American military relations, and perception within the context of those relations. Part two builds on the sparse literature that focuses on perception by further exploring how western media perceives military relations through the analysis of media articles published in the Washington Post and the New York Times between 2001 and 2017. How military relations are framed in the media is important for understanding the perceptual boundaries within which policymakers can act along the cooperative‐confrontational continuum. The study concludes that the confrontational discursive approach dominating the framing of military relations is problematic for determining the most effective means of maintaining regional stability, order, and peace in the Asia Pacific region as well as facilitating geostrategic security cooperation between the two countries.
The 40th Anniversary of the Congenital Anomaly Research Center, Kyoto University Graduate School of Medicine
Authors: Yamada Shigehito , Nagai Momoko , Hagiwara Masatoshi
Published: April 2018

The Congenital Anomaly Research Center at Kyoto University's Graduate School of Medicine was established in 1975; in 2015 the center celebrated its 40th anniversary. The celebration of this anniversary included three special projects: (1) forming an achievement list, (2) preparing for a specimen exhibition, and (3) holding an anniversary symposium. This special issue of The Anatomical Record is devoting to detailing these anniversary projects. Anat Rec, 301:947–950, 2018. © 2018 Wiley Periodicals, Inc.
Magnetic Resonance Microscopy of Chemically Fixed Human Embryos Performed in University of Tsukuba Since 1999 to 2015
Authors: Kose Katsumi
Published: April 2018

Magnetic resonance (MR) microscopy of chemically fixed human embryos performed in University of Tsukuba since 1999 to 2015 was reviewed. More than 1,000 chemically fixed human embryos stored in the Congenital Anomaly Research Center of Kyoto University were used throughout the MR microscopy project, which was divided into three terms. In the first term (1999–2005), 3D MR images of 1,204 embryo specimens were acquired with 128 × 128 × 256 voxels by a super‐parallel MR microscope using a 2.35 T horizontal‐bore superconducting magnet. In the second term (2005–2006), 3D MR images of seven embryo specimens were acquired with 256 × 256 × 512 voxels by an MR microscope using a 9.4 T vertical wide‐bore superconducting magnet. In the third term (2013–2015), 3D MR images of a Carnegie Stage (CS) 21 specimen were acquired with 512 × 512 × 1024 voxels by an MR microscope using a 4.7 T vertical wide‐bore superconducting magnet and nuclear magnetic resonance parameters of a CS23 specimen were measured with 128 × 128 × 256–256 × 256 × 512 voxels by an MR microscope using a 9.4 T vertical narrow‐bore superconducting magnet. Based on the results obtained in this project, the author has proposed the future MR microscopy project in which a number of embryo specimens will be imaged with 256 × 256 × 512–512 × 512 × 1024 voxels using a newly designed super‐parallel MR microscope. Anat Rec, 301:987–997, 2018. © 2018 Wiley Periodicals, Inc.
What Could Hominoid Fetuses Tell Us about Human Evolution?
Authors: Morimoto Naoki
Published: April 2018

The increasing availability of developmental data on humans and great apes has become essential for furthering our understanding of human evolution. Although postnatal ontogeny is relatively well documented, our knowledge about variation of developmental patterns during the prenatal period among primate species remains lacking. There are various limitations to studying fetuses, but investigating the fetal period, directly or indirectly, has the potential to answer questions that are otherwise difficult to tackle with postnatal examination. Anat Rec, 301:970–972, 2018. © 2018 Wiley Periodicals, Inc.
Clinical and Demographic Evaluation of a Holoprosencephaly Cohort From the Kyoto Collection of Human Embryos
Authors: Abe Yu , Kruszka Paul , Martinez Ariel F. , Roessler Erich , Shiota Kohei , Yamada Shigehito , Muenke Maximilian
Published: April 2018

Holoprosencephaly (HPE) is a genetically and phenotypically heterogeneous disorder involving developmental defects. HPE is a rare condition (1/10,000–20,000 newborns) but can be found as frequently as 1/250 among conceptions, suggesting that most HPE embryos are incompatible with postnatal life and result in spontaneous abortions during the first trimester of gestation. Beginning in 1961, the Kyoto University in Japan collected over 44,000 human conceptuses in collaboration with several hundred domestic obstetricians. Over 200 cases of HPE have been identified in the Kyoto collection, which represents the largest single cohort of HPE early stage embryo specimens. In this study, we present a comprehensive clinical and demographic evaluation of this HPE cohort prior to genomic analysis. The total percentage of the threatened abortion among HPE embryos in the Kyoto collection was 67%. Almost 20% of the women with embryos affected by HPE had experienced spontaneous miscarriage. In addition, there was a significant tendency that the mothers with HPE cases had fewer live births than the control. Moreover, in 70% of cases, the mother reported bleeding during pregnancy, a higher percentage than expected, indicating that most of the conceptions with HPE embryos tend to be terminated spontaneously. There were no differences in smoking between mothers with HPE affected and unaffected pregnancies; however, alcohol use was higher in women with pregnancies affected by HPE. In this study, we precisely characterize the phenotype and environmental influences of embryos affected by HPE allowing the future leveraging of genomic technologies to further understand the genetics of forebrain development. Anat Rec, 301:973–986, 2018. © 2018 Wiley Periodicals, Inc.
RhIII‐Catalyzed Direct C8‐Arylation of Quinoline N‐Oxides using Diazonaphthalen‐2(1H)‐ones: A Practical Approach towards 8‐aza BINOL
Authors: Ghosh Bidhan , Biswas Aniruddha , Chakraborty Soumen , Samanta Rajarshi
Published: April 2018

An efficient RhIII‐catalyzed redox‐neutral method for the direct C8‐arylation of quinoline N‐oxides using diazonaphthalen‐2(1H)‐one as coupling partner has been demonstrated. The developed method is simple, scalable and straightforward with a wide range of substrate scope. The applicative potential was extended with a late‐stage functionalization and straightforward synthesis of 8‐azaBINOL derivative. A plausible reaction pathway was proposed after carrying out preliminary control studies.
Multi‐Responsive Supramolecular Gels Based on Charge Transfer Interactions
Authors: Li Chen , Shen Chengshuo , Nie Jiucheng , Qiu Huibin
Published: April 2018

We report the co‐assembly of aromatic donor (D) and acceptor (A) molecules into purple sponge‐like supramolecular gels through susceptible charge transfer interactions with the aid of solvophobic interactions. The gel remained intact with the addition of up to 23 % (v/v) of nonpolar good solvents, such as toluene and xylene, but dissociated in the presence of <2 % (v/v) of polar solvents, such as tetrahydrofuran, ethyl acetate, and alcohols, with highly distinguishable changes of color. Notably, the gel dissolved within 1 min and the solution turned blue when 0.1 % (v/v) of methanol was added. The response to trifluoroacetic acid was extremely sensitive (i.e., the gel vanished immediately in the presence of 2 equivalents of trifluoroacetic acid), and the subsequent addition of trimethylamine could recover the purple gel. The multiple and visible response thus render the D–A gels as a potential detector for sensing complex chemical environments.
Multi‐Step Control Set‐Based Nonlinear Model Predictive Control with Persistent Disturbances
Authors: Shi Donglin , Mao Zhizhong
Published: April 2018

A robust model predictive control algorithm is proposed for a constrained nonlinear system with bounded persistent disturbance in this paper. Based on polytopic descriptions that include the initial system, the proposed algorithm computes a series of multi‐step control sets offline and the convex combination of them online respectively by solving convex optimization problems described by a few linear matrix inequalities. At each sampling time, the control moves satisfying the control constraint are obtained and implemented in the system. The controller design is illustrated with two examples. The proposed MPC controller achieves closed‐loop input‐to‐state (practical) stability (ISS/ISpS) and strong robustness in respect of bounded persistent disturbances.
Disturbance Decoupling Control for Flexible Air‐Breathing Hypersonic Vehicles with Mismatched Condition
Authors: Hao Feng , Zhang Dong , Cao Lin , Tang Shuo
Published: April 2018

The disturbance decoupling control method is investigated for flight control of a flexible air‐breathing hypersonic vehicle (FAHV). First, the longitudinal dynamics of the FAHV are simplified into nonlinear forms with mismatched system disturbances. Then a new nonlinear disturbance observer base on hyperbolic sine function is applied to estimate the mismatched disturbances. The disturbance decoupling control law for flight control of FAHV is deduced theoretically and its proof is provided. Finally, the stability of the closed‐loop control system under the action of disturbance decoupling control law is proved by Lyapunov stability theory. Simulation results exhibit the performance and effectiveness of the proposed disturbance decoupling control law.
Contract cheating in UK higher education: A covert investigation of essay mills
Authors: Medway Dominic , Roper Stuart , Gillooly Leah
Published: April 2018

Contract cheating is currently a concern for universities and the higher education (HE) sector. It has been brought into the spotlight in recent years through the growth of online essay mills, where students can easily commission and purchase written assessment responses. This study contributes to the wider literature on academic integrity in HE by examining the phenomenon of contract cheating from a supply‐side perspective, thereby considering the essay mill offering and student interaction with it. The authors covertly engage with five essay mills, before successfully completing an assignment purchase with two of these providers. The pre‐purchase stage of an assignment transaction is first examined, unpacking ten reassurance cues used by essay mill providers in the text of their websites. These reassurance cues help to ensure the attractiveness of the essay mill product to potential student consumers. The analysis then moves to explore the ethical discourses around academic integrity that essay mills provide, revealing inconsistencies in their stance towards the potential for academic misconduct from the use of essay mill services. Finally, the article explores the quality of the essay mill product, through grading and Turnitin® reports for the two purchased essay mill assignments. Following recent calls for the outlawing of essay mills, this article provides a timely addition to current understanding of this phenomenon, and the associated challenges of contract cheating in HE.
Amino Acid‐Based Advanced Liquid Formulation Development for Highly Concentrated Therapeutic Antibodies Balances Physical and Chemical Stability and Low Viscosity
Authors: Kemter Kristina , Altrichter Jens , Derwand Roland , Kriehuber Thomas , Reinauer Eva , Scholz Martin
Published: April 2018

To develop highly concentrated therapeutic antibodies enabling convenient subcutaneous application, well stabilizing pharmaceutical formulations with low viscosities are considered to be key. The purpose of this study is to select specific amino acid combinations that reduce and balance aggregation, fragmentation and chemical degradation, and also lower viscosity of highly concentrated liquid antibodies. As a model, the therapeutically well‐established antibody trastuzumab (25–>200 mg mL−1) in liquid formulation is used. Pre‐testing of formulations based on a stabilizing and protecting solutions (SPS®) platform is conducted in a thermal unfolding model using differential scanning fluorimetry (DSF) and accelerated aging at 37 and 45 °C. Pre‐selected amino acid combinations are further iteratively adjusted to obtain stable highly concentrated antibody formulations with low viscosity. Size exclusion chromatography (SE‐HPLC) reveals significantly lower aggregation and fragmentation at specific amino acid:sugar and protein:excipient ratios. Dynamic viscosities <20 mPa * s of highly concentrated trastuzumab (≥200 mg mL−1) are measured by falling ball viscosimetry. Moreover, less chemical degradation is found by cationic exchange chromatography (CEX‐HPLC) even after 6 months liquid storage at 25 °C. In conclusion, specifically tailored and advanced amino acid‐based liquid formulations avoid aggregation and enable the development of stable and low viscous highly concentrated biopharmaceuticals.
Modular Ligation Extension of Guide RNA Operons (LEGO) for Multiplexed dCas9 Regulation of Metabolic Pathways in Saccharomyces cerevisiae
Authors: Deaner Matthew , Holzman Allison , Alper Hal S.
Published: April 2018

Metabolic engineering typically utilizes a suboptimal step‐wise gene target optimization approach to parse a highly connected and regulated cellular metabolism. While the endonuclease‐null CRISPR/Cas system has enabled gene expression perturbations without genetic modification, it has been mostly limited to small sets of gene targets in eukaryotes due to inefficient methods to assemble and express large sgRNA operons. In this work, we develop a TEF1p‐tRNA expression system and demonstrate that the use of tRNAs as splicing elements flanking sgRNAs provides higher efficiency than both Pol III and ribozyme‐based expression across a variety of single sgRNA and multiplexed contexts. Next, we devise and validate a scheme to allow modular construction of tRNA‐sgRNA (TST) operons using an iterative Type IIs digestion/ligation extension approach, termed CRISPR‐Ligation Extension of sgRNA Operons (LEGO). This approach enables facile construction of large TST operons. We demonstrate this utility by constructing a metabolic rewiring prototype for 2,3‐butanediol production in 2 distinct yeast strain backgrounds. These results demonstrate that our approach can act as a surrogate for traditional genetic modification on a much shorter design‐cycle timescale.
Pro region engineering of nerve growth factor by deep mutational scanning enables a yeast platform for conformational epitope mapping of anti‐NGF monoclonal antibodies
Authors: Medina‐Cucurella Angélica V. , Zhu Yaqi , Bowen Scott J. , Bergeron Lisa M. , Whitehead Timothy A.
Published: April 2018

Nerve growth factor (NGF) plays a central role in multiple chronic pain conditions. As such, anti‐NGF monoclonal antibodies (mAbs) that function by antagonizing NGF downstream signaling are leading drug candidates for non‐opioid pain relief. To evaluate anti‐canine NGF (cNGF) mAbs we sought a yeast surface display platform of cNGF. Both mature cNGF and pro‐cNGF displayed on the yeast surface but bound conformationally sensitive mAbs at most 2.5‐fold in mean fluorescence intensity above background, suggesting that cNGF was mostly misfolded. To improve the amount of folded, displayed cNGF, we used comprehensive mutagenesis, FACS, and deep sequencing to identify point mutants in the pro‐region of canine NGF that properly enhance the folded protein displayed on the yeast surface. Out of 1,737 tested single point mutants in the pro region, 49 increased the amount of NGF recognized by conformationally sensitive mAbs. These gain‐of‐function mutations cluster around residues A‐61–P‐26. Gain‐of‐function mutants were additive, and a construct containing three mutations increased amount of folded cNGF to 23‐fold above background. Using this new cNGF construct, fine conformational epitopes for tanezumab and three anti‐cNGF mAbs were evaluated. The epitope revealed by the yeast experiments largely overlapped with the tanezumab epitope previously determined by X‐ray crystallography. The other mAbs showed site‐specific differences with tanezumab. As the number of binding epitopes of functionally neutralizing anti‐NGF mAbs on NGF are limited, subtle differences in the individual interacting residues on NGF that bind each mAb contribute to the understanding of each antibody and variations in its neutralizing activity. These results demonstrate the potential of deep sequencing‐guided protein engineering to improve the production of folded surface‐displayed protein, and the resulting cNGF construct provides a platform to map conformational epitopes for other anti‐neurotrophin mAbs.
Enhanced isobutanol production from acetate by combinatorial overexpression of acetyl‐CoA synthetase and anaplerotic enzymes in engineered Escherichia coli
Authors: Song Hun‐Suk , Seo Hyung‐Min , Jeon Jong‐Min , Moon Yu‐Mi , Hong Ju Won , Hong Yoon Gi , Bhatia Shashi Kant , Ahn Jungoh , Lee Hongweon , Kim Wooseong , Park Yong‐Cheol , Choi Kwon‐Young , Kim Yun‐Gon , Yang Yung‐Hun
Published: April 2018

Acetic acid is an abundant material that can be used as a carbon source by microorganisms. Despite its abundance, its toxicity and low energy content make it hard to utilize as a sole carbon source for biochemical production. To increase acetate utilization and isobutanol production with engineered Escherichia coli, the feasibility of utilizing acetate and metabolic engineering was investigated. The expression of acs, pckA, and maeB increased isobutanol production by up to 26%, and the addition of TCA cycle intermediates indicated that the intermediates can enhance isobutanol production. For isobutanol production from acetate, acetate uptake rates and the NADPH pool were not limiting factors compared to glucose as a carbon source. This work represents the first approach to produce isobutanol from acetate with pyruvate flux optimization to extend the applicability of acetate. This technique suggests a strategy for biochemical production utilizing acetate as the sole carbon source.
Prognostic impact of perihepatic lymph node metastases in patients with resectable colorectal liver metastases
Authors: Okuno M , Goumard C , Mizuno T , Kopetz S , Omichi K , Tzeng C-W D , Chun Y S , Lee J E , Vauthey J-N , Conrad C
Published: April 2018

Background

Although perihepatic lymph node metastases (PLNMs) are known to be a poor prognosticator for patients with colorectal liver metastases (CRLMs), optimal management remains unclear. This study aimed to determine the risk factors for PLNMs, and the survival impact of their number and location in patients with resectable CRLMs.

Methods

Data on patients with CRLM who underwent hepatectomy during 2003–2014 were analysed retrospectively. Recurrence-free (RFS) and overall (OS) survival were calculated according to presence, number and location of PLNMs. Risk factors for PLNM were evaluated by logistic regression analysis.

Results

Of 1485 patients, 174 underwent lymphadenectomy, and 54 (31·0 per cent) had PLNM. Ten patients (5·7 per cent) who had lymphadenectomy and 176 (13·4 per cent) who did not underwent repeat hepatectomy. Survival of patients with PLNM was significantly poorer than that of patients without (RFS: 5·3 versus 13·8 months, P < 0·001; OS: 20·5 versus 71·3 months; P < 0·001). Median OS was significantly better in patients with para-aortic versus hepatoduodenal ligament PLNMs (58·2 versus 15·5 months; P = 0·011). Patients with three or more PLNMs had significantly worse median OS than those with one or two (16·3 versus 25·4 months; P = 0·039). The presence of primary tumour lymph node metastases (odds ratio 2·35; P = 0·037) and intrahepatic recurrence requiring repeat hepatectomy (odds ratio 5·61; P = 0·012) were significant risk factors for PLNM on multivariable analysis.

Conclusion

Patients undergoing repeat hepatectomy and those with primary tumour lymph node metastases are at significant risk of PLNM. Although PLNM is a poor prognostic factor independent of perihepatic lymph node station, patients with one or two PLNMs have a more favourable outcome than those with more PLNMs.
Randomized clinical trial of the effect of a fibrin sealant patch on pancreatic fistula formation after pancreatoduodenectomy
Authors: Schindl M , Függer R , Götzinger P , Längle F , Zitt M , Stättner S , Kornprat P , Sahora K , Hlauschek D , Gnant M
Published: April 2018

Background

The potential for a fibrin sealant patch to reduce the risk of postoperative pancreatic fistula (POPF) remains uncertain. The aim of this study was to evaluate whether a fibrin sealant patch is able to reduce POPF in patients undergoing pancreatoduodenectomy with pancreatojejunostomy.

Methods

In this multicentre trial, patients undergoing pancreatoduodenectomy were randomized to receive either a fibrin patch (patch group) or no patch (control group), and stratified by gland texture, pancreatic duct size and neoadjuvant treatment. The primary endpoint was POPF. Secondary endpoints included complications, drain-related factors and duration of hospital stay. Risk factors for POPF were identified by logistic regression analysis.

Results

A total of 142 patients were enrolled. Forty-five of 71 patients (63 per cent) in the patch group and 40 of 71 (56 per cent) in the control group developed biochemical leakage or POPF (P = 0·392). Fistulas were classified as grade B or C in 16 (23 per cent) and ten (14 per cent) patients respectively (P = 0·277). There were no differences in postoperative complications (54 patients in patch group and 50 in control group; P = 0·839), drain amylase concentration (P = 0·494), time until drain removal (mean(s.d.) 11·6(1·0) versus 13·3(1·3) days; P = 0·613), fistula closure (17·6(2·2) versus 16·5(2·1) days; P = 0·740) and duration of hospital stay (22·1(2·2) versus 18·2(0·9) days; P = 0·810) between the two groups. Multivariable logistic regression analysis confirmed that obesity (odds ratio (OR) 5·28, 95 per cent c.i. 1·20 to 23·18; P = 0·027), soft gland texture (OR 9·86, 3·41 to 28·54; P < 0·001) and a small duct (OR 5·50, 1·84 to 16·44; P = 0·002) were significant risk factors for POPF. A patch did not reduce the incidence of POPF in patients at higher risk.

Conclusion

The use of a fibrin sealant patch did not reduce the occurrence of POPF and complications after pancreatoduodenectomy with pancreatojejunostomy. Registration number: 2013-000639-29 (EudraCT register).
Mortality in patients with permanent hypoparathyroidism after total thyroidectomy
Authors: Almquist M , Ivarsson K , Nordenström E , Bergenfelz A
Published: April 2018

Background

Permanent hypoparathyroidism remains the most common adverse outcome after total thyroidectomy, but long-term effects of hypoparathyroidism are unknown. The aim was to investigate mortality in patients with permanent hypoparathyroidism after total thyroidectomy.

Methods

Data from the Scandinavian Quality Register for Thyroid, Parathyroid and Adrenal Surgery were linked with the Swedish National Prescription Register for Pharmaceuticals and the Swedish National Inpatient Register. Patients who underwent total thyroidectomy between 1 July 2005 and 30 June 2014 for benign thyroid disease, and who used active vitamin D for at least 6 months after surgery, were classified as having permanent hypoparathyroidism and included in the study cohort. Risk of death was assessed using Cox regression analysis, adjusting for age, sex, thyrotoxicosis and co-morbidity.

Results

There were 4899 patients, with a mean(s.d.) age of 46·3(15·8) years; 83·1 per cent were women, and 2932 patients (59·8 per cent) had thyrotoxicosis. In all, 246 patients (5·2 per cent) were classified as having permanent hypoparathyroidism. Mean(s.d.) follow-up was 4·4(2·4) years, and 109 patients (2·2 per cent) died during follow-up. Compared with patients without permanent hypoparathyroidism, the risk of death was significantly higher among patients with permanent hypoparathyroidism after total thyroidectomy (adjusted hazard ratio 2·09, 95 per cent c.i. 1·04 to 4·20).

Conclusion

Permanent hypoparathyroidism after total thyroidectomy for benign disease is common and associated with an increased risk of death.
Multicentre phase II trial of near-infrared imaging in elective colorectal surgery
Authors: Ris F , Liot E , Buchs N C , Kraus R , Ismael G , Belfontali V , Douissard J , Cunningham C , Lindsey I , Guy R , Jones O , George B , Morel P , Mortensen N J , Hompes R , Cahill R A
Published: April 2018

Background

Decreasing anastomotic leak rates remain a major goal in colorectal surgery. Assessing intraoperative perfusion by indocyanine green (ICG) with near-infrared (NIR) visualization may assist in selection of intestinal transection level and subsequent anastomotic vascular sufficiency. This study examined the use of NIR-ICG imaging in colorectal surgery.

Methods

This was a prospective phase II study (NCT02459405) of non-selected patients undergoing any elective colorectal operation with anastomosis over a 3-year interval in three tertiary hospitals. A standard protocol was followed to assess NIR-ICG perfusion before and after anastomosis construction in comparison with standard operator visual assessment alone.

Results

Five hundred and four patients (median age 64 years, 279 men) having surgery for neoplastic (330) and benign (174) pathology were studied. Some 425 operations (85·3 per cent) were started laparoscopically, with a conversion rate of 5·9 per cent. In all, 220 patients (43·7 per cent) underwent high anterior resection or reversal of Hartmann's operation, and 90 (17·9 per cent) low anterior resection. ICG angiography was achieved in every patient, with a median interval of 29 s to visualization of the signal after injection. NIR-ICG assessment resulted in a change in the site of bowel division in 29 patients (5·8 per cent) with no subsequent leaks in these patients. Leak rates were 2·4 per cent overall (12 of 504), 2·6 per cent for colorectal anastomoses and 3 per cent for low anterior resection. When NIR-ICG imaging was used, the anastomotic leak rates were lower than those in the participating centres from over 1000 similar operations performed with identical technique but without NIR-ICG technology.

Conclusion

Routine NIR-ICG assessment in patients undergoing elective colorectal surgery is feasible. NIR-ICG use may change intraoperative decisions, which may lead to a reduction in anastomotic leak rates.
Prophylactic thyroidectomy in children with multiple endocrine neoplasia type 2
Authors: Prete F P , Abdel-Aziz T , Morkane C , Brain C , Kurzawinski T R , Hindmarsh P , Dattani M , Spoudeas H , Amin R , Watkinson J , Shaw N , Alvi S , Squire R , Harrison B , Wales J , Wright N , Clayton P , Eatock F , Buchanan C , Albanese A , Bano G , Storr H , Korbonits M , Gevers E , Randell T , Denvir L , Davies J , Cheetham T , Lennard T , Warner J , Smith D , Crowne L , Hulse T , Izatt L , Blair J
Published: April 2018

Background

In patients with multiple endocrine neoplasia type 2 (MEN2) syndrome, genetic testing offers early diagnosis, stratifies the risk of developing medullary thyroid cancer (MTC) and informs the timing of thyroidectomy. The efficacy of treatment, which depends on timely and safe surgery, is not well established.

Methods

This was a retrospective review of diagnostic and clinicopathological outcomes of prophylactic thyroidectomy in children with MEN2 between 1995 and 2013 in the UK. American Thyroid Association (ATA) 2009 guidelines were used as a benchmark for adequate treatment.

Results

Seventy-nine children from 16 centres underwent total thyroidectomy. Thirty-eight patients (48 per cent) underwent genetic testing and 36 (46 per cent) had an operation performed above the age recommended by the ATA 2009 guidelines; pathology showed MTC in 30 patients (38 per cent). Late surgery, above-normal preoperative calcitonin level and MTC on pathology correlated with late genetic testing. Twenty-five children had lymphadenectomy; these patients had more parathyroid glands excised (mean difference 0·61, 95 per cent c.i. 0·24 to 0·98; P = 0·001), and were more likely to have hypocalcaemia requiring medication (relative risk (RR) 3·12, 95 per cent c.i. 1·54 to 6·32; P = 0·002) and permanent hypoparathyroidism (RR 3·24, 1·29 to 8·11; P = 0·010) compared with those who underwent total thyroidectomy alone. Age did not influence the development of complications.

Conclusion

Late genetic testing may preclude age-appropriate surgery, increasing the risk of operating when MTC has already developed. Early genetic testing and age-appropriate surgery may help avoid unnecessary lymphadenectomy and improve outcomes.
Mortality following surgery for trauma in an Indian trauma cohort
Authors: Mansourati M , Kumar V , Khajanchi M , Saha M L , Dharap S , Seger R , Gerdin Wärnberg M
Published: April 2018

Background

India accounts for 20 per cent of worldwide trauma mortality. Little is known about the quality of trauma surgery in an Indian setting. The aim of this study was to estimate the overall perioperative mortality rate, and to assess the association between type of acute surgical intervention and perioperative mortality among adult patients treated for trauma in an urban Indian setting.

Methods

Data were obtained from injured adult patients enrolled in four urban Indian hospitals during 2013–2015. Those who had surgery within 24 h of arrival at hospital were included in the analysis. Patients with missing data were excluded. The perioperative mortality rate was measured at 48 h and 30 days after arrival at hospital. Generalized linear mixed models were used for risk adjustment of procedure-specific mortality.

Results

Among 2986 patients who underwent trauma surgery, the overall 48-h mortality rate was 6·0 per cent, and the 30-day mortality rate was 23·1 per cent. The highest adjusted odds ratios (ORs) for 48-h mortality were found for patients who underwent surgery on the peripheral vasculature (OR 4·71, 95 per cent c.i. 1·18 to 16·59; P = 0·030) and the digestive system and spleen (OR 3·77, 1·33 to 9·01; P = 0·010) compared with those who had nervous system surgery.

Conclusion

In this study of surgery in an Indian trauma cohort, there was an excess of late perioperative deaths. Mortality differed significantly according to the type of surgery being undertaken.
Predictors of complications after direct-to-implant breast reconstruction with an acellular dermal matrix from a multicentre randomized clinical trial
Authors: Negenborn V L , Dikmans R E G , Bouman M B , Winters H A H , Twisk J W R , Ruhé P Q , Mureau M A M , Smit J M , Tuinder S , Hommes J , Eltahir Y , Posch N A S , van Steveninck-Barends J M , Meesters-Caberg M A , van der Hulst R R W J , Ritt M J P F , Mullender M G
Published: April 2018

Background

In the multicentre randomized trial BRIOS (Breast Reconstruction In One Stage), direct-to-implant (DTI) breast reconstruction with an acellular dermal matrix (ADM) was associated with a markedly higher postoperative complication rate compared with two-stage tissue expander/implant breast reconstruction. This study aimed to identify factors that contribute to the occurrence of complications after DTI ADM-assisted breast reconstruction.

Methods

Data were obtained from the BRIOS study, including all patients treated with DTI ADM-assisted breast reconstruction. Logistic regression analyses were performed to identify factors predictive of postoperative complications.

Results

Fifty-nine patients (91 breasts) were included, of whom 27 (35 breasts) developed a surgical complication. Reoperations were performed in 29 breasts (32 per cent), with prosthesis removal in 22 (24 per cent). In multivariable analyses, mastectomy weight was associated with complications (odds ratio (OR) 1·94, 95 per cent c.i. 1·33 to 2·83), reoperations (OR 1·70, 1·12 to 2·59) and removal of the implant (OR 1·55, 1·11 to 2·17). Younger patients (OR 1·07, 1·01 to 1·13) and those who received adjuvant chemotherapy (OR 4·83, 1·15 to 20·24) more frequently required reoperation. In univariable analyses, adjuvant radiotherapy showed a trend towards more complications (OR 7·23, 0·75 to 69·95) and removal of the implant (OR 5·12, 0·76 to 34·44), without reaching statistical significance.

Conclusion

Breast size appeared to be the most significant predictor of complications in DTI ADM-assisted breast reconstruction. The technique should preferably be performed in patients with small to moderate sized breasts. Registration number: NTR5446 (http://www.trialregister.nl).
Prognostic value of pathological node status after neoadjuvant radiotherapy for rectal cancer
Authors: Duchalais E , Glyn Mullaney T , Spears G M , Kelley S R , Mathis K , Harmsen W S , Larson D W
Published: April 2018

Background

The prognostic value of pathological lymph node status following neoadjuvant radiotherapy (ypN) remains unclear. This study was designed to determine whether ypN status predicted overall survival.

Methods

Patients with locally advanced rectal adenocarcinoma who underwent neoadjuvant long-course radiation between 2005 and 2014 were identified from the National Cancer Data Base, and divided into ypN0, ypN1 and ypN2 groups. The primary outcome was overall survival. Univariable and multivariable analyses were used to determine factors associated with overall survival.

Results

Of 12 271 patients, 3713 (30·3 per cent) were found to have residual nodal positivity. A majority of patients with ypN1 (1663 of 2562) and ypN2 (878 of 1151) disease had suspected lymph node-positive disease before neoadjuvant therapy, compared with 3959 of 8558 with ypN0 tumours (P < 0·001). Moreover, ypN1 and ypN2 were significantly associated with ypT3–4 disease (65·7 and 83·0 per cent respectively versus 39·4 per cent for ypN0; P < 0·001). In unadjusted analyses, survival differed significantly between ypN groups (P < 0·001). Five-year survival rates were 81·6, 71·3 and 55·0 per cent for patients with ypN0, ypN1 and ypN2 disease respectively. After adjustment for confounding variables, ypN1 and ypN2 remained independently associated with overall survival: hazard ratio (HR) 1·61 (95 per cent c.i. 1·46 to 1·77) and 2·63 (2·34 to 2·95) respectively (P < 0·001). Overall survival was significantly longer in patients with ypN1–2 combined with ypT0–2 status than among those with ypT3–4 tumours even with ypN0 status (P = 0·031). Clinical nodal status before neoadjuvant therapy was not significantly associated with overall survival (HR 1·05, 0·97 to 1·13; P = 0·259).

Conclusion

Both ypT and ypN status is of prognostic significance following neoadjuvant therapy for rectal cancer.
The effects of cognitive behavioral therapy on resting‐state functional brain network in drug‐naive patients with obsessive–compulsive disorder
Authors: Li Ping , Yang Xiangyun , Greenshaw Andrew J. , Li Sufang , Luo Jia , Han Haiying , Liu Jing , Zhong Zhaoxi , Guo Zhihua , Xiong Hongfang , Yao Shumin , Chen Yunhui , Sun Jing , Li Zhanjiang
Published: April 2018

Objectives

Although cognitive behavioral therapy (CBT) is an effective treatment for obsessive–compulsive disorder (OCD), the treatment mechanisms remain poorly understood. This study aimed to investigate the effects of CBT on changes in the intrinsic whole‐brain functional network of OCD patients.

Materials and Methods

Twenty drug‐naive and noncomorbid OCD patients were recruited, and resting‐state functional magnetic resonance imaging was performed before and after 12 weeks of CBT. Moreover, 20 healthy controls were scanned twice with a 12‐week interval. A graph‐theory degree centrality (DC) approach and functional connectivity method were used to analyze the whole‐brain functional network hub and connectivity changes in OCD patients before and after CBT treatment.

Results

A significant group × time interaction on DC was found in the left dorsolateral prefrontal cortex (DLPFC); the DC in the left DLPFC was significantly reduced after CBT treatment. Resting‐state functional connectivity (RSFC) between the left DLPFC and right orbitofrontal cortex was increased in the OCD patients at baseline, and normalized after CBT treatment. RSFC changes between the left DLPFC and default mode network (DMN) positively correlated with changes in clinical symptoms in OCD patients.

Conclusions

These findings suggest that CBT can modulate changes in intrinsic functional network hubs in the cortico–striato–thalamo‐cortical circuit in OCD patients. Cognitive control network and DMN connectivity may be a potential imaging biomarker for evaluating CBT treatment for OCD.
Living on a farm, contact with farm animals and pets, and childhood acute lymphoblastic leukemia: pooled and meta‐analyses from the Childhood Leukemia International Consortium
Authors: Orsi Laurent , Magnani Corrado , Petridou Eleni T. , Dockerty John D. , Metayer Catherine , Milne Elizabeth , Bailey Helen D. , Dessypris Nick , Kang Alice Y. , Wesseling Catharina , Infante‐Rivard Claire , Wünsch‐Filho Victor , Mora Ana M. , Spector Logan G. , Clavel Jacqueline
Published: April 2018

The associations between childhood acute lymphoblastic leukemia (ALL) and several factors related to early stimulation of the immune system, that is, farm residence and regular contacts with farm animals (livestock, poultry) or pets in early childhood, were investigated using data from 13 case–control studies participating in the Childhood Leukemia International Consortium. The sample included 7847 ALL cases and 11,667 controls aged 1–14 years. In all studies, the data were obtained from case and control parents using standardized questionnaires. Pooled odds ratios (ORs) and 95% confidence intervals (CIs) were estimated by unconditional logistic regression adjusted for age, sex, study, maternal education, and maternal age. Contact with livestock in the first year of life was inversely associated with ALL (OR = 0.65, 95% CI: 0.50, 0.85). Inverse associations were also observed for contact with dogs (OR = 0.92, 95% CI: 0.86, 0.99) and cats (OR = 0.87, 95% CI: 0.80, 0.94) in the first year of life. There was no evidence of a significant association with farm residence in the first year of life. The findings of these large pooled and meta‐analyses add additional evidence to the hypothesis that regular contact with animals in early childhood is inversely associated with childhood ALL occurrence which is consistent with Greaves’ delayed infection hypothesis.
Clinical significance of TM4SF1 as a tumor suppressor gene in gastric cancer
Authors: Peng Xing‐Chun , Zeng Zhi , Huang Yu‐Ning , Deng Yun‐Chao , Fu Guo‐Hui
Published: April 2018

Transmembrane‐4‐L‐six‐family member‐1 (TM4SF1), a tumor‐associated antigen, is overexpressed in most epithelial cell carcinomas and a potential target for antibody‐mediated therapy. However, the role of TM4SF1 in gastric cancer has not been elucidated. The aim of this study was to investigate the clinical significance of TM4SF1 expression in gastric carcinoma (GC) tissues using 152 GC tissue samples and matched adjacent nontumor tissue samples analyzed by immunohistochemistry, and 13 fresh GC tissue samples analyzed by Western blotting. The results showed that TM4SF1 was heterogeneously expressed in normal gastric mucosa, with a high expression rate in fundus mucosa. Higher levels and strong expression rate of TM4SF1 were associated with GC tissues of higher‐grade differentiation. TM4SF1 levels were lower in gastric cancer tissues than gastric noncancerous tissues. Expression of TM4SF1 was not correlated with USP10 (P = 0.157), S100A12 (P = 0.479), p53 (P = 0.249), or Ki67 (P = 0.166) in GC. The expression of TM4SF1 was significantly and negatively correlated with depth of invasion (P = 0.031), nodal metastasis (P = 0.042), TNM stage (P = 0.030), and Lauren classification (P = 0.026). There was no significant correlation between TM4SF1 expression and age, gender, tumor size, or distant metastasis (P > 0.05). The expression of TM4SF1 was associated with well overall survival (P = 0.0164). The 5‐year survival rate for patients with GC showing TM4SF1 positive was 58.82% (10/17), and the median survival time was 78 months, higher than that (12.90%, 12/93) of patients who were TM4SF1 negative, whose median survival time was 62 months. These data suggested that low expression of TM4SF1 is associated with carcinogenesis and development, tumor progression and invasion of gastric cancer, and poor overall survival of patients with GC. TM4SF1 is a tumor suppressor for GC and a novel prognostic marker for patients with GC.
Myricetin‐induced oxidative stress suppresses murine T lymphocyte activation
Authors: Ghassemi‐Rad Javad , Maleki Mahdis , Knickle Allison F. , Hoskin David W.
Published: April 2018

A number of polyphenolic compounds present in fruits and vegetables have the capacity to modulate immune responses; however, the impact of the common plant‐derived flavonoid myricetin on T lymphocyte function has not been investigated. We show that myricetin inhibited mouse T lymphocyte activation by bead‐immobilized anti‐CD3 and anti‐CD28 monoclonal antibodies, as indicated by a dose‐dependent reduction in cell proliferation and decreased synthesis of interferon‐γ, interleukin (IL)‐2, IL‐4, and IL‐17 associated with different T helper cell subsets. This effect was attributed to myricetin‐induced reactive oxygen species (ROS) since myricetin caused hydrogen peroxide (H2O2) to accumulate in cell‐free culture medium and H2O2 inhibited T cell proliferation and cytokine synthesis. In addition, the antioxidant N‐acetyl cysteine restored the ability of myricetin‐treated T lymphocytes to proliferate in response to a mitogenic stimulus. The presence of dendritic cells or bone marrow‐derived macrophages negated the inhibitory effect of myricetin on T cell activation, and H2O2 in T cell cultures that were treated with exogenous H2O2 was reduced when antigen‐presenting cells were also present. These findings suggest that antioxidant molecules produced by dendritic cells and macrophages protected T cells from myricetin‐induced oxidative stress, and underscore the importance of considering immune cell interactions when evaluating the immunomodulatory activity of ROS‐generating phytochemicals.