bluuebunny/crossref_metadata_2025 huggingface dataset:
Intratumoral heterogeneity of oxygen metabolism and neovascularization uncovers 2 survival-relevant subgroups of IDH1 wild-type glioblastoma
Authors: Stadlbauer Andreas , Zimmermann Max , Doerfler Arnd , Oberndorfer Stefan , Buchfelder Michael , Coras Roland , Kitzwögerer Melitta , Roessler Karl
Published: April 2018

Background

The intratumoral heterogeneity of oxygen metabolism in combination with variable patterns of neovascularization (NV) as well as reprogramming of energy metabolism affects the landscape of tumor microenvironments (TMEs) in glioblastoma. Knowledge of the hypoxic and perivascular niches within the TME is essential for understanding treatment failure.

Methods

Fifty-two patients with untreated glioblastoma (isocitrate dehydrogenase 1 wild type [IDH1wt]) were examined with a physiological MRI protocol including a multiparametric quantitative blood oxygen level dependent (qBOLD) approach and vascular architecture mapping (VAM). Imaging biomarker information about oxygen metabolism (mitochondrial oxygen tension) and neovascularization (microvascular density and type) were fused for classification of 6 different TMEs: necrosis, hypoxia with/without neovascularization, oxidative phosphorylation (OxPhos), and glycolysis with/without neovascularization. Association of the different TME volume fractions with progression-free survival (PFS) was assessed using Kaplan–Meier analysis and Cox proportional hazards models.

Results

A common spatial structure of TMEs was detected: central necrosis surrounded by tumor hypoxia (with defective and functional neovasculature) and different TMEs with a predominance of OxPhos and glycolysis for energy production, respectively. The percentage of the different TMEs on the total tumor volume uncovered 2 clearly different subtypes of glioblastoma IDH1wt: a glycolytic dominated phenotype with predominantly functional neovasculature and a necrotic/hypoxic dominated phenotype with approximately 50% of defective neovasculature. Patients with a necrotic/hypoxic dominated phenotype showed significantly shorter PFS (P = 0.035).

Conclusions

Our non-invasive mapping approach allows for classification of the TME and detection of tumor-supportive niches in glioblastoma which may be helpful for both clinical patient management and research.
Taxonomic Repositioning of Xanthomonas campestris pv. viticola (Nayudu 1972) Dye 1978 as Xanthomonas citri pv. viticola (Nayudu 1972) Dye 1978 comb. nov. and Emendation of the Description of Xanthomonas citri pv. anacardii to Include Pigmented Isolates Pathogenic to Cashew Plant
Authors: da Gama Marco Aurélio Siqueira , Mariano Rosa de Lima Ramos , da Silva Júnior Wilson José , de Farias Antônio Roberto Gomes , Barbosa Maria Angélica Guimarães , Ferreira Marisa Álvares da Silva Velloso , Costa Júnior César Raimundo Lima , Santos Liliana Andréa , de Souza Elineide Barbosa
Published: April 2018

Grapevine bacterial canker, which is caused by Xanthomonas campestris pv. viticola, is one of the most important grapevine diseases in the northeastern region of Brazil. This disease causes severe damage and represents a high potential risk to the development of Brazilian viticulture. In turn, pigmented isolates pathogenic to cashew plant, making cashew fruit unfit for sale, also have been detected in Northeastern Brazil. Given that the taxonomic position of these bacteria is unclear, the multilocus sequence analysis (MLSA) technique, average nucleotide identity (ANI) values and tetranucleotide frequency correlation coefficients (TETRA) were used to analyze their phylogenetic relationship in relation to other Xanthomonas species. X. campestris pv. viticola was closely related to X. citri pv. mangiferaeindicae (repetitive-polymerase chain reaction [rep-PCR], MLSA, and ANI) and X. citri subsp. citri (MLSA and ANI). Pigmented isolates pathogenic to cashew plant were closely related to X. citri pv. anacardii (rep-PCR, MLSA, ANI, and TETRA). The results obtained in this study support the emendation of the description of X. citri pv. anacardii to include pigmented isolates of Xanthomonas pathogenic to cashew plant. In addition, the reclassification of X. campestris pv. viticola as X. citri pv. viticola comb. nov. is suggested.
A Systematic Review of the Processes Underlying the Main and the Buffering Effect of Social Support on the Experience of Pain
Authors: Che Xianwei , Cash Robin , Ng Sin Ki , Fitzgerald Paul , Fitzgibbon Bernadette M.
Published: April 2018

Objective:

This review aimed to explore the processes that underlie the main and the buffering effect of social support on decreased pain experience.

Materials and Methods:

The systematic review was conducted according to the PRISMA guidelines. Online databases of PubMed and PsycINFO were searched for peer-reviewed articles using keywords (“social support,” OR “interpersonal,” OR “social presence,” OR “spouse,” OR “couple,” OR “marriage”) AND “pain”). Articles were included if they examined the cognitive or behavioral processes linking social support to any aspects of reduced pain experience.

Results:

The database search identified 38 studies, of which 33 were cognitive-behavioral studies and 5 were neurobiological. Cognitive-behavioral studies generated a total of 57 findings of the analgesic influence of social support. This effect was further categorized as social support decreasing the adverse influence of pain-related stress (28/44 findings), reappraising pain-related stress (7/9 findings), and facilitating coping attempts (2/4 findings). Of the 5 neurobiological studies, the influence of social support on pain reduction was associated with reduced neural and physiological stress systems in response to painful stimuli.

Discussion:

This review presents evidence that the stress-buffering effect is more often able to account for the relationship between social support and pain experience. Moreover, findings suggest the critical significance of stress appraisal and attenuated stress systems in linking social support to aspects of reduced pain experience. Findings implicate the role of integrating perceived support and intimacy in support-oriented interventional trials for chronic pain.
Perioperative Complications After Surgery for Thoracic Ossification of Posterior Longitudinal Ligament
Authors: Imagama Shiro , Ando Kei , Takeuchi Kazuhiro , Kato Satoshi , Murakami Hideki , Aizawa Toshimi , Ozawa Hiroshi , Hasegawa Tomohiko , Matsuyama Yukihiro , Koda Masao , Yamazaki Masashi , Chikuda Hirotaka , Shindo Shigeo , Nakagawa Yukihiro , Kimura Atsushi , Takeshita Katsushi , Wada Kanichiro , Katoh Hiroyuki , Watanabe Masahiko , Yamada Kei , Furuya Takeo , Tsuji Takashi , Fujibayashi Shunsuke , Mori Kanji , Kawaguchi Yoshiharu , Watanabe Kota , Matsumoto Morio , Yoshii Toshitaka , Okawa Atsushi
Published: April 2018

Study Design.

Prospective, multicenter, nationwide study.

Objective.

To investigate perioperative complications and risk factors in surgery for thoracic ossification of the posterior longitudinal ligament (T-OPLL) using data from the registry of the Japanese Multicenter Research Organization for Ossification of the Spinal Ligament.

Summary of Background Data.

There is no prospective multicenter study of surgical complications and risk factors for T-OPLL, and previous multicenter retrospective studies have lacked details.

Methods.

Surgical methods, preoperative radiographic findings, pre- and postoperative thoracic myelopathy (Japanese Orthopaedic Association [JOA] score), prone and supine position test (PST), intraoperative ultrasonography, and intraoperative neurophysiological monitoring (IONM) were investigated prospectively in 115 cases (males: 55, females: 60, average age 53.1 y). Factors related to perioperative complications and risk factors for postoperative motor palsy were identified.

Results.

Posterior decompression and fusion with instrumentation with or without dekyphosis was performed in 85 cases (74%). The JOA recovery rate at 1 year after surgery in all cases was 55%. Motor palsy occurred postoperatively in 37 cases (32.2%), with a mean recovery period of 2.7 months. A long recovery period for postoperative motor palsy was significantly associated with a high number of T-OPLL levels (P < 0.0001), lower preoperative JOA score (P < 0.05), and greater estimated blood loss (P < 0.05). Perioperative complications or postoperative motor palsy were significantly related to a higher number of T-OPLL levels, comorbid ossification of ligamentum flavum rate, lower preoperative JOA score, higher preoperative positive PST rate, more surgical invasiveness, a lower rate of intraoperative spinal cord floating in ultrasonography, and higher rate of deterioration of IONM.

Conclusion.

This study firstly demonstrated the perioperative complications with high postoperative motor palsy rate in a nationwide multicenter prospective study. Surgical outcomes for T-OPLL should be improved by identifying and preventing perioperative complications with significant risk factors.

Level of Evidence: 3
Keratoacanthomatous Changes: Unifying the Histologic Spectrum of Actinic Granuloma
Authors: Harb Jennifer N. , Kalen Jessica E. , Hsu Sylvia , Diwan Abdul Hafeez , Calame Antoanella , Motaparthi Kiran
Published: April 2018

Actinic granuloma (AG) manifests as annular plaques on sun-damaged skin. There remains no universal consensus on the nosology, etiology, or clinicopathologic criteria of AG as a distinct entity. Broadly, AG is characterized by granulomatous inflammation, multinucleated giant cells, elastophagocytosis, and the absence of mucin and necrobiosis. It is not uncommon, however, to encounter overlapping histological features of other granulomas, such as granuloma annulare and necrobiosis lipoidica, confounding the diagnosis of this controversial entity. Herein, we describe 2 cases of AG with features of granuloma annulare and necrobiosis lipoidica, supporting the concept of AG as a histologic spectrum. These 2 cases displayed dilated follicular infundibula and pseudoepitheliomatous hyperplasia analogous to changes in keratoacanthomas. These unique epithelial changes, in tandem with characteristic elastin alterations and clinical findings, are helpful and unifying features that permit accurate diagnosis of this controversial entity.
Tilianin-loaded Reactive Oxygen Species-Scavenging Nano-Micelles Protect H9c2 Cardiomyocyte Against Hypoxia/Reoxygenation-Induced Injury
Authors: Wang Yanfang , Wang Ying , Wang Xinchun , Hu Ping
Published: April 2018

Previous studies have shown that tilianin alleviates ischemia-reperfusion-induced cardiomyocyte injury. However, its clinical translation has been hampered because of its insolubility in water. Tilianin-based nano-micelles that may overcome this critical issue are presented. A polyethylene glycol compound was covalently attached to propylene sulfide-formed amphiphilic diblock polymers. In the aqueous solution, tilianin is encapsulated in a hydrophobic shell to form nano-micelles. The Ph-PPS-PEG self-assembled into nanoscale micelles with a size of approximately 70 nm, termed “tilianin-loaded micelles” (TLMs). TLMs are highly efficient hydrogen peroxide scavengers and the activity of caspase-3 inhibition, thereby protecting cells from H/R-induced cytotoxicity. In addition, TLMs decreased levels of MDA, IL-1 and tumor necrosis factor (TNF-α), inhibited apoptosis, TLR4 and nuclear transcription factor (NF-κB p65) protein expression in hypoxia-reoxygenation (H/R) model. Taken together, the study suggests that TLMs may be of clinical value for the protective effects of cardiomyocytes by inhibiting Inflammation and oxidative stress during myocardial ischemia-reperfusion injury.
Perioperative Management of the Gynecologic Patient on Long-term Anticoagulation
Authors: FAGER AMMON M. , DEANS ELIZABETH , JAMES ANDRA H.
Published: April 2018

The perioperative management of patients taking antithrombotic or antiplatelet medications is based on an assessment of the individual patient’s risk for thrombosis or bleeding, the specific medication involved, and the nature of the planned procedure. This article describes specific strategies for whether and how these medications should be interrupted before gynecologic procedures, when they can be restarted following the procedure, and whether bridging therapy should be considered.
Patients with chronic pain exhibit a complex relationship triad between pain, resilience, and within- and cross-network functional connectivity of the default mode network
Authors: Hemington Kasey S. , Rogachov Anton , Cheng Joshua C. , Bosma Rachael L. , Kim Junseok Andrew , Osborne Natalie R. , Inman Robert D. , Davis Karen D.
Published: April 2018

Resilience is a psychological trait that strongly predicts chronic pain–related health outcomes. The neural correlates of both pain and trait resilience are critical to understand the brain–behaviour relationship in chronic pain; yet, neural correlates of resilience in chronic pain states are unknown. However, measures of pain perception and a wide range of psychological health measures have been linked to function of the default mode network (DMN). Thus, we aimed to determine the relationships between resilience, pain perception, and functional connectivity (FC) within the DMN and between the DMN and other brain networks. Resting-state functional magnetic resonance imaging data were acquired from 51 chronic pain patients with a form of spondylarthritis (ankylosing spondylitis) and 51 healthy control participants. Participants completed a questionnaire on their individual trait resilience (the Resilience Scale), and patients reported their clinical pain. In healthy controls, we found within-DMN FC to be stronger in less resilient individuals. In patients with chronic pain, individual resilience was negatively correlated with pain and disease activity. Cross-network FC between the DMN and the sensorimotor network was abnormally high in patients with high clinical pain scores on the day of the study. Finally, there was an interaction between within-DMN FC and clinical pain report in patients: In patients reporting greater pain, the relationship between within-DMN connectivity and resilience was atypical. Thus, our findings reveal different neural representations of resilience and pain. The way in which these behavioural measures interact provides insight into understanding the neural correlates of chronic pain.
Successful Cholecystectomy After Endoscopic Ultrasound Gallbladder Drainage Compared With Percutaneous Cholecystostomy, Can it Be Done?
Authors: Saumoy Monica , Tyberg Amy , Brown Elizabeth , Eachempati Soumitra R. , Lieberman Michael , Afaneh Cheguevara , Kunda Rastislav , Cosgrove Natalie , Siddiqui Ali , Gaidhane Monica , Kahaleh Michel
Published: April 2018

Background:

Endoscopic ultrasound–guided gallbladder drainage (EGBD) with a lumen apposing metal stent is becoming a widely accepted alternative to percutaneous gallbladder drainage (PTGD) for patients who are not candidates for cholecystectomy (CCY). In some patients, medical comorbidites can improve, allowing them to undergo CCY. We compare feasibility and outcomes of interval CCY after EGBD versus PTGD.

Methods:

We conducted a multicentered international cohort study of patients who underwent EGBD or PTGD and then underwent interval CCY. Baseline patient demographics, procedural details, and follow-up data were recorded and compared.

Results:

In total, 34 patients were included. Thirteen patients underwent EGBD followed by CCY (mean age, 53.77±17.27, 46.15% male), and 21 patients underwent PTGD followed by CCY (mean age, 62.14±13.06, 61.9% male). There was no statistically significant difference in mean Charlson Comorbidity Index (P=0.12) or etiology of cholecystitis (P=0.85) between the 2 groups. All patients had a technically successful CCY. There was no difference between rates of open versus laparoscopic CCY (P=1). In addition, there was no difference in postsurgical adverse events (P=0.23).

Conclusions:

Surgical CCY after EGBD with lumen apposing metal stent is safe and feasible for the management of cholecystitis. If patient’s underlying medical conditions improve, previous EUS-GLB drainage should not preclude patients from undergoing CCY as part of standard of care.
Large Volume Fluid Resuscitation for Severe Acute Pancreatitis is Associated With Reduced Mortality
Authors: Yamashita Takahiro , Horibe Masayasu , Sanui Masamitsu , Sasaki Mitsuhito , Sawano Hirotaka , Goto Takashi , Ikeura Tsukasa , Hamada Tsuyoshi , Oda Takuya , Yasuda Hideto , Ogura Yuki , Miyazaki Dai , Hirose Kaoru , Kitamura Katsuya , Chiba Nobutaka , Ozaki Tetsu , Koinuma Toshitaka , Oshima Taku , Yamamoto Tomonori , Hirota Morihisa , Masuda Yukiko , Tokuhira Natsuko , Kobayashi Mioko , Saito Shinjiro , Izai Junko , Lefor Alan K. , Iwasaki Eisuke , Kanai Takanori , Mayumi Toshihiko
Published: April 2018

Background and Aims:

Although fluid resuscitation is critical in acute pancreatitis, the optimal fluid volume is unknown. The aim of this study is to evaluate the association between the volume of fluid administered and clinical outcomes in patients with severe acute pancreatitis (SAP).

Methods:

We conducted a multicenter retrospective study at 44 institutions in Japan. Inclusion criteria were age 18 years or older, and diagnosed with SAP from 2009 to 2013. Patients were stratified into 2 groups: administered fluid volume <6000 and ≥6000 mL in the first 24 hours. We evaluated the association between the 2 groups and clinical outcomes using multivariable logistic regression analysis. The primary outcome was in-hospital mortality. Secondary outcomes included the incidence of pancreatic infection and the need for surgical intervention.

Results:

We analyzed 1097 patients, and the mean fluid volume administered was 5618±3018 mL (mean±SD), with 708 and 389 patients stratified into the fluid <6000 mL and fluid ≥6000 mL groups, respectively. Overall in-hospital mortality was 12.3%. The fluid ≥6000 mL group had significantly higher mortality than the fluid <6000 mL group (univariable analysis, 15.9% vs. 10.3%;P<0.05). In multivariable logistic regression analysis, administration of ≥6000 mL of fluid within the first 24 hours was significantly associated with reduced mortality (odds ratio, 0.58;P<0.05). No significant association was found between the administered fluid volume and pancreatic infection, or between the volume administered and the need for surgical intervention.

Conclusions:

In patients with SAP, administration of a large fluid volume within the first 24 hours is associated with decreased mortality.
Association of clinical and inflammatory markers with small bowel capsule endoscopy findings in Crohn’s disease
Authors: Mitselos Ioannis V. , Katsanos Konstantinos H. , Tatsioni Athina , Skamnelos Alexandros , Eliakim Rami , Tsianos Epameinondas V. , Christodoulou Dimitrios K.
Published: April 2018

Background

Mucosal healing is an established treatment endpoint in Crohn’s disease (CD). Still, clinical indices and inflammatory markers are used widely in CD surveillance.

Aim

The aim of this study was to investigate the diagnostic performance as well as the relationship of C-reactive protein (CRP) and Crohn’s Disease Activity Index (CDAI) with small bowel capsule endoscopy’s (SBCE) inflammation scoring index, the Lewis Score (LS).

Patients and methods

CDAI, CRP, and SBCE findings of 30 CD patients with isolated small bowel disease were retrieved from our academic institution patient records and were analyzed statistically.

Results

SBCE showed significant mucosal inflammation [mean (SD) LS: 1599 (1380)], in nine (60.0%) of 15 patients who were in both clinical and biochemical remission. CDAI and CRP showed a weak and moderate correlation with LS (r=0.317, P=0.088 and r=0.516, P=0.004, respectively). The diagnostic performance of CDAI and CRP in predicting mucosal inflammation was as follows: sensitivity 23.8 and 52.4%; specificity 100 and 66.7%; positive predictive value 100 and 78.6%; and negative predictive value 36.0 and 37.5%. The area under the curve toward endoscopic activity prediction was 0.70 and 0.69, respectively.

Conclusion

Both CDAI and CRP underestimated endoscopic activity as expressed by the LS in a significant proportion of patients with quiescent disease.
Cohesin in haematopoiesis and leukaemia
Authors: Galeev Roman , Larsson Jonas
Published: April 2018

Purpose of review

Disturbance of the delicate balance between self-renewal and differentiation in haematopoietic stem cells (HSCs) can lead to both leukaemia and bone marrow failure. The regulation of this balance in HSC biology has been intensely investigated in several model systems, and lately the importance of epigenetic modifications as well as the organization and architecture of chromatin has become increasingly recognized. In this review, we will focus on the role of the chromatin organizing protein complex cohesin in regulation of normal and malignant haematopoiesis.

Recent findings

Several functional studies in both mouse and human systems have implicated cohesin as a critical regulator of self-renewal and differentiation in HSCs. Together with the discovery of recurrent mutations of cohesin genes in myeloid malignancies, this points towards a direct role of perturbed cohesin function in leukemogenesis.

The work reviewed here provides new insights about the role of the cohesin complex and chromatin architecture in normal and malignant HSCs, and indicates how cohesin may be specifically targeted for therapeutic benefit in the future.
Acid-suppressing Drugs and a Low 1 Level of Antithrombin as Risk Factors for l-Asparaginase-associated Pancreatitis: A Case-control Study in the Japan Association of Childhood Leukemia Study (JACLS)
Authors: Hashii Yoshiko , Yoshida Makoto , Hara Junichi , Nishimura Shinichiro , Yumura-Yagi Keiko , Horibe Keizo , Nakahata Tatsutoshi
Published: April 2018

l-Asparaginase has significantly improved outcome for children with acute lymphoblastic leukemia and has become an essential component of multiagent chemotherapy. However, there are many adverse events due to l-asparaginase, including acute pancreatitis. The pathology of l-asparaginase-associated pancreatitis (AAP) remains unclear. We compared patients who developed AAP (n=29) and random matched controls (n=36) who had been enrolled in the Japan Association of Childhood Leukemia Study of the ALL-02 protocol. AAP and control patients were matched for age, sex, treatment, and protocol risk. We examined correlations between AAP development and clinical symptoms, laboratory data, and concomitant medication. Abdominal pain and nausea were common presenting symptoms for AAP. There was an increased risk of AAP in patients using gastric acid-suppressing agents and antithrombin (AT) supplementation. Mean fibrinogen and AT levels before the onset of AAP were lower in AAP patients than in controls. Decreased AT and fibrinogen levels resulting from the strong suppression of protein synthesis by l-asparaginase were predictive signs for AAP. Our epidemiological approach should prove clinically useful for the diagnosis the AAP as early as possible.
Reduction in Blood Glutamate Levels Combined With the Genetic Inactivation of A2AR Significantly Alleviate Traumatic Brain Injury-Induced Acute Lung Injury
Authors: Bai Wei , Li Ping , Ning Ya-Lei , Jiang Yu-Lin , Yang Nan , Chen Xing , Zhou Yuan-Guo
Published: April 2018

Traumatic brain injury-induced acute lung injury (TBI-ALI) is a serious complication of traumatic brain injury (TBI). Our previous clinical study found that high levels of blood glutamate after TBI were closely related to the occurrence and severity of TBI-ALI, while it remains unknown whether a high concentration of blood glutamate directly causes or aggravates TBI-ALI. We found that inhibition of the adenosine A2A receptor (A2AR) after brain injury alleviated the TBI-ALI; however, it is unknown whether lowering blood glutamate levels in combination with inhibiting the A2AR would lead to better effects. Using mouse models of moderate and severe TBI, we found that intravenous administration of L-glutamate greatly increased the lung water content, lung-body index, level of inflammatory markers in bronchoalveolar lavage fluid and acute lung injury score and significantly decreased the PaO2/FiO2 ratio. Moreover, the incidence of TBI-ALI and the mortality rate were significantly increased, and the combined administration of A2AR activator and exogenous glutamate further exacerbated the above damaging effects. Conversely, lowering the blood glutamate level through peritoneal dialysis or intravenous administration of oxaloacetate notably improved the above parameters, and a further improvement was seen with concurrent A2AR genetic inactivation. These data suggest that A2AR activation aggravates the damaging effect of high blood glutamate concentrations on the lung and that combined treatment targeting both A2AR and blood glutamate may be an effective way to prevent and treat TBI-ALI.
Objective Evidence of Reflux Control After Magnetic Sphincter Augmentation
Authors: Louie Brian E. , Smith C. Daniel , Smith Christopher C. , Bell Reginald C. W. , Gillian George Kevin , Mandel Jeffrey S. , Perry Kyle A. , Birkenhagen Walter Kurt , Taiganides Paul A. , Dunst Christy M. , McCollister Howard M. , Lipham John C. , Khaitan Leena K. , Tsuda Shawn T. , Jobe Blair A. , Kothari Shanu N. , Gould Jon C.
Published: April 2018

Objective:

To report 1-year results from a 5-year mandated study.

Summary Background Data:

In 2012, the United States Food and Drug Administration approved magnetic sphincter augmentation (MSA) with the LINX Reflux Management System (Torax Medical, Shoreview, MN), a novel device for the surgical treatment of gastroesophageal reflux disease (GERD). Continued assessment of safety and effectiveness has been monitored in a Post Approval Study.

Methods:

Multicenter, prospective study of patients with pathologic acid reflux confirmed by esophageal pH testing undergoing MSA. Predefined clinical outcomes were assessed at the annual visit including a validated, disease-specific questionnaire, esophagogastricduodenoscopy and esophageal pH monitoring, and use of proton pump inhibitors.

Results:

A total of 200 patients (102 males, 98 females) with a mean age of 48.5 years (range 19.7–71.6) were treated with MSA between March 2013 and August 2015. At 1 year, the mean total acid exposure time decreased from 10.0% at baseline to 3.6%, and 74.4% of patients had normal esophageal acid exposure time (% time pH<4 ≤5.3%). GERD Health-Related Quality of Life scores improved from a median score of 26.0 at baseline to 4.0 at 1 year, with 84% of patients meeting the predefined success criteria of at least a 50% reduction in total GERD Health-Related Quality of Life score compared with baseline. The device removal rate at 1 year was 2.5%. One erosion and no serious adverse events were reported.

Conclusions:

Safety and effectiveness of magnetic sphincter augmentation has been demonstrated outside of an investigational setting to further confirm MSA as treatment for GERD.
No Surgical Innovation Without Evaluation
Authors: Hirst Allison , Philippou Yiannis , Blazeby Jane , Campbell Bruce , Campbell Marion , Feinberg Joshua , Rovers Maroeska , Blencowe Natalie , Pennell Christopher , Quinn Tom , Rogers Wendy , Cook Jonathan , Kolias Angelos G. , Agha Riaz , Dahm Philipp , Sedrakyan Art , McCulloch Peter
Published: April 2018

Objective:

To update, clarify, and extend IDEAL concepts and recommendations.

Background:

New surgical procedures, devices, and other complex interventions need robust evaluation for safety, efficacy, and effectiveness. Unlike new medicines, there is no internationally agreed evaluation pathway for generating and analyzing data throughout the life cycle of surgical innovations. The IDEAL Framework and Recommendations were designed to provide this pathway and they have been used increasingly since their introduction in 2009. Based on a Delphi survey, expert workshop and major discussions during IDEAL conferences held in Oxford (2016) and New York (2017), this article updates and extends the IDEAL Recommendations, identifies areas for future research, and discusses the ethical problems faced by investigators at each IDEAL stage.

Methods:

The IDEAL Framework describes 5 stages of evolution for new surgical therapeutic interventions—Idea, Development, Exploration, Assessment, and Long-term Study. This comprehensive update proposes several modifications. First, a “Pre-IDEAL” stage describing preclinical studies has been added. Second we discuss potential adaptations to expand the scope of IDEAL (originally designed for surgical procedures) to accommodate therapeutic devices, through an IDEAL-D variant. Third, we explicitly recognise the value of comprehensive data collection through registries at all stages in the Framework and fourth, we examine the ethical issues that arise at each stage of IDEAL and underpin the recommendations. The Recommendations for each stage are reviewed, clarified and additional detail added.

Conclusions:

The intention of this article is to widen the practical use of IDEAL by clarifying the rationale for and practical details of the Recommendations. Additional research based on the experience of implementing these Recommendations is needed to further improve them.
Modified Blumgart Mattress Suture Versus Conventional Interrupted Suture in Pancreaticojejunostomy During Pancreaticoduodenectomy
Authors: Hirono Seiko , Kawai Manabu , Okada Ken-Ichi , Miyazawa Motoki , Kitahata Yuji , Hayami Shinya , Ueno Masaki , Yamaue Hiroki
Published: April 2018

Objective:

This study used a randomized controlled trial (RCT) to evaluate whether mattress suture of pancreatic parenchyma and the seromuscular layer of jejunum (modified Blumgart method) during pancreaticojejunostomy (PJ) decreases the incidence of clinically relevant postoperative pancreatic fistula (POPF) after pancreaticoduodenectomy (PD).

Background:

Several studies reported that mattress suture of Blumgart anastomosis in PJ could reduce POPF rate. This, however, is the first RCT.

Methods:

Between June, 2013 and May, 2017, 224 patients scheduled for PD were enrolled in this study in Wakayama Medical University Hospital. Enrolled patients were randomized to either interrupted suture or modified Blumgart mattress suture. The primary endpoint was the incidence of grade B/C POPF based on the International Study Group on Pancreatic Fistula criteria. This RCT was registered with ClinicalTrials.gov (NCT01898780).

Results:

Patients were randomized to either interrupted suture (103 patients) or modified Blumgart mattress suture (107 patients) and were analyzed by intention-to-treat. Grade B/C POPF occurred in 7 patients (6.8%) in the interrupted suture group and 11 (10.3%) in the mattress suture group (P = 0.367). Mortality within 90 days was 0 in both groups. There were no significant differences in all postoperative complications between the interrupted suture group and the modified Blumgart mattress suture group.

Conclusions:

Mattress suture of pancreatic parenchyma and the jejunal seromuscular layer during PJ (modified Blumgart technique) did not reduce clinically relevant POPF compared with interrupted suture.
Self-organization: the fundament of cell biology
Authors: Wedlich-Söldner Roland , Betz Timo
Published: April 2018

Self-organization refers to the emergence of an overall order in time and space of a given system that results from the collective interactions of its individual components. This concept has been widely recognized as a core principle in pattern formation for multi-component systems of the physical, chemical and biological world. It can be distinguished from self-assembly by the constant input of energy required to maintain order—and self-organization therefore typically occurs in non-equilibrium or dissipative systems. Cells, with their constant energy consumption and myriads of local interactions between distinct proteins, lipids, carbohydrates and nucleic acids, represent the perfect playground for self-organization. It therefore comes as no surprise that many properties and features of self-organized systems, such as spontaneous formation of patterns, nonlinear coupling of reactions, bi-stable switches, waves and oscillations, are found in all aspects of modern cell biology. Ultimately, self-organization lies at the heart of the robustness and adaptability found in cellular and organismal organization, and hence constitutes a fundamental basis for natural selection and evolution.

This article is part of the theme issue ‘Self-organization in cell biology’.
Reverse and forward engineering of protein pattern formation
Authors: Kretschmer Simon , Harrington Leon , Schwille Petra
Published: April 2018

Living systems employ protein pattern formation to regulate important life processes in space and time. Although pattern-forming protein networks have been identified in various prokaryotes and eukaryotes, their systematic experimental characterization is challenging owing to the complex environment of living cells. In turn, cell-free systems are ideally suited for this goal, as they offer defined molecular environments that can be precisely controlled and manipulated. Towards revealing the molecular basis of protein pattern formation, we outline two complementary approaches: the biochemical reverse engineering of reconstituted networks and the de novo design, or forward engineering, of artificial self-organizing systems. We first illustrate the reverse engineering approach by the example of the
Escherichia coli
Min system, a model system for protein self-organization based on the reversible and energy-dependent interaction of the ATPase MinD and its activating protein MinE with a lipid membrane. By reconstituting MinE mutants impaired in ATPase stimulation, we demonstrate how large-scale Min protein patterns are modulated by MinE activity and concentration. We then provide a perspective on the de novo design of self-organizing protein networks. Tightly integrated reverse and forward engineering approaches will be key to understanding and engineering the intriguing phenomenon of protein pattern formation.

This article is part of the theme issue ‘Self-organization in cell biology’.
The Min-protein oscillations in
Escherichia coli
: an example of self-organized cellular protein waves
Authors: Wettmann Lukas , Kruse Karsten
Published: April 2018

In the rod-shaped bacterium
Escherichia coli
, selection of the cell centre as the division site involves pole-to-pole oscillations of the proteins MinC, MinD and MinE. This spatio-temporal pattern emerges from interactions among the Min proteins and with the cytoplasmic membrane. Combining experimental studies
in vivo
and
in vitro
together with theoretical analysis has led to a fairly good understanding of Min-protein self-organization. In different geometries, the system can, in addition to standing waves, also produce travelling planar and spiral waves as well as coexisting stable stationary distributions. Today it stands as one of the best-studied examples of cellular self-organization of proteins.

This article is part of the theme issue ‘Self-organization in cell biology’.
Autotransporter secretion exploits the bacterial actin-homologue
Authors: Ashawesh Mahmoud M. , Markus Robert , Penfold Christopher N. , Hardie Kim R.
Published: April 2018

Bacterial infection of humans, animals and plants relies heavily on secreted proteases that degrade host defences or activate bacterial toxins. The largest family of proteins secreted by Gram-negative pathogenic bacteria, the Autotransporters (ATs), includes key proteolytic virulence factors. There remains uncertainty about the mechanistic steps of the pathway ATs share to exit bacteria, and how it is energetically driven. This study set out to shed light on the AT secretion pathway with the ultimate aim of uncovering novel antimicrobial targets that would be unlikely to trigger the development of resistance mechanisms in bacteria. To do this, two AT virulence factors with distinct proteolytic functions, EspC (secreted from EnteropathogenicEscherichia coli) and AaaA (tethered to the extracellular surface ofPseudomonas aeruginosa) were chosen. EspC and AaaA were fluorescently labelled using two separate methods to establish the localization patterns of ATs as they are secreted from a bacterial cell. Super resolution microscopy revealed that localization of ATs occurs via a helical route along the bacterial cytoskeleton. In addition to requiring the conserved C-terminal β-barrel translocator domain of the AT, we present the first evidence that secretion is dependent on a dynamic interaction with a structure reliant upon the actin homologue MreB and the Sec translocon. These findings provide a step forward in the mechanistic understanding of the secretion of this widely distributed family of proteins that have pivotal roles in bacterial pathogenesis and conserved structural properties that could serve as novel broad-range antimicrobial targets.

Significance

Secreted bacterial proteases facilitate the infection of human, animal and plant hosts by degrading host defences or activating bacterial toxins. The autotransporter family is the largest family of proteins secreted from Gram-negative bacteria, and includes proteolytic virulence factors crucial to bacterial infection. Precisely how autotransporters migrate from the inside to the outside of the cell, and how this movement is energetically driven is a mystery. We demonstrate a spiral pathway of autotransporter secretion, presenting evidence that it involves a dynamic interaction with the actin homologue MreB that comprises the bacterial cytoskeleton. Our findings open the way to unravelling the mechanism of autotransporter secretion and offer the possibility to identify novel antimicrobial targets unlikely to trigger the development of antimicrobial resistance.
Improved estimation of cancer dependencies from large-scale RNAi screens using model-based normalization and data integration
Authors: McFarland James M , Ho Zandra V , Kugener Guillaume , Dempster Joshua M , Montgomery Phillip G , Bryan Jordan G , Krill-Burger John M , Green Thomas M , Vazquez Francisca , Boehm Jesse S , Golub Todd R , Hahn William C , Root David E , Tsherniak Aviad
Published: April 2018

The availability of multiple datasets together comprising hundreds of genome-scale RNAi viability screens across a diverse range of cancer cell lines presents new opportunities for understanding cancer vulnerabilities. Integrated analyses of these data to assess differential dependency across genes and cell lines are challenging due to confounding factors such as batch effects and variable screen quality, as well as difficulty assessing gene dependency on an absolute scale. To address these issues, we incorporated estimation of cell line screen quality parameters and hierarchical Bayesian inference into an analytical framework for analyzing RNAi screens (DEMETER2; https://depmap.org/R2-D2). We applied this model to individual large-scale datasets and show that it substantially improves estimates of gene dependency across a range of performance measures, including identification of gold-standard essential genes as well as agreement with CRISPR-Cas9-based viability screens. This model also allows us to effectively integrate information across three large RNAi screening datasets, providing a unified resource representing the most extensive compilation of cancer cell line genetic dependencies to date.
Modulation of Secretory Lysosomes During NK Cell Education Leads to Accumulation of Granzyme B and Enhanced Functional Potential
Authors: Goodridge Jodie P. , Jacobs Benedikt , Saetersmoen Michelle L. , Clement Dennis , Clancy Trevor , Skarpen Ellen , Brech Andreas , Landskron Johannes , Grimm Christian , Pfefferle Aline , Meza-Zepeda Leonardo , Lorenz Susanne , Wiiger Merete Thune , Louch William E. , Ask Eivind Heggernes , Liu Lisa L. , Sheng Oei Vincent Yi , Kjällquist Una , Linnarsson Sten , Patel Sandip , Taskén Kjetil , Stenmark Harald , Malmberg Karl-Johan
Published: April 2018

Inhibitory signaling during natural killer (NK) cell education translates into increased responsiveness to activation; however the intracellular mechanism for functional tuning by inhibitory receptors remains unclear. We found that educated NK cells expressing self-MHC specific inhibitory killer cell immunoglobulin-like receptors (KIR) show accumulation of granzyme B, localized in dense-core secretory lysosomes, converged close to the centrosome. This discrete morphological phenotype persists in self-KIR+NK cells independently of transcriptional programs that regulate effector function, metabolism and lysosomal biogenesis. The granzymeB dense, large secretory lysosomes in self-KIR+NK cells were efficiently released upon target cell recognition, contributing to their enhanced cytotoxic capacity. Secretory lysosomes are part of the acidic lysosomal compartment, which has been shown to channel calcium and mediate intracellular signalling in several cell types. Interference of signaling from acidic Ca2+stores in primary NK cells reduced both target-specific Ca2+-flux, degranulation and cytokine production. Furthermore, inhibition of PI(3,5)P2synthesis or genetic silencing of the PI(3,5)P2-regulated lysosomal Ca2+-channel TRPML1 led to increased levels of granzyme B and enhanced functional potential. These results indicate an intrinsic role for lysosomal homeostasis in NK cell education.
A common statistical misunderstanding in Psychology and Neuroscience: Do we need normally distributed independent or dependent variables for linear regression to work?
Authors: Habeck Christian G. , Brickman Adam M.
Published: April 2018

Our ability to draw conclusions from experiments often relies on the application of inferential statistics, such as those included within the general-linear-modeling framework. The purpose of this commentary is to direct attention a common fallacy that can be observed in paper reviews and professional exchanges in the field of Psychology and Neuroscience pertaining to multiple regression analysis. The fallacy concerns the confusion of the requirements on theresidualsof a linear-regression model with requirements on thedependent or independent variablesthemselves. A simple thought experiment, algebraic demonstration, and simulation study can demonstrate this misconception. It is our hope that consideration of the fallacy may help clarify distinctions between technical statistical issues and conceptual interpretation of research findings.
Geometric morphometrics of nested symmetries: Hierarchical INTER- AND INTRA-INDIVIDUAL VARIATION IN BIOLOGICAL SHAPES
Authors: Savriama Yoland , Gerber Sylvain
Published: April 2018

Symmetry is a pervasive feature of organismal shape and the focus of a large body of research in Biology. Here, we consider complex patterns of symmetry where a phenotype exhibits a hierarchically structured combination of symmetries. We extend the Procrustes ANOVA for the analysis of nested symmetries and the decomposition of the overall morphological variation into components of symmetry (among-individual variation) and asymmetry (directional and fluctuating asymmetry). We illustrate its use with the Aristotle’s lantern, the masticatory apparatus of ‘regular’ sea urchins, a complex organ displaying bilateral symmetry nested within five-fold rotational symmetry. Our results highlight the importance of characterising the full symmetry of a structure with nested symmetries. Higher order rotational symmetry appears strongly constrained and developmentally stable compared to lower level bilateral symmetry. This contrast between higher and lower levels of asymmetry is discussed in relation to the spatial pattern of the lantern morphogenesis. This extended framework is applicable to any biological object exhibiting nested symmetries, regardless of their type (e.g., bilateral, rotational, translational). Such cases are extremely widespread in animals and plants, from arthropod segmentation to angiosperm inflorescence and corolla shape. The method therefore widens the research scope on developmental instability, canalization, developmental modularity and morphological integration.
A direct proof that sole actin dynamics drive membrane deformations
Authors: Simon Camille , Kusters Rémy , Caorsi Valentina , Allard Antoine , Abou-Ghali Majdouline , Manzi John , Di Cicco Aurélie , Lévy Daniel , Lenz Martin , Joanny Jean-François , Campillo Clément , Plastino Julie , Sens Pierre , Sykes Cécile
Published: April 2018

Cell membrane deformations are crucial for proper cell function. Specialized protein assemblies initiate inward or outward membrane deformations that turn into, for example, filopodia or endocytic intermediates. Actin dynamics and actin-binding proteins are involved in this process, although their detailed role remains controversial. We show here that a dynamic, branched actin network is sufficient, in absence of any membrane-associated proteins, to initiate both inward and outward membrane deformation. With actin polymerization triggered at the membrane of liposomes, we produce inward filopodia-like structures at low tension, while outward endocytosis-like structures are robustly generated regardless of tension. Our results are reminiscent of endocytosis in mammalian cells, where actin polymerization forces are required when membrane tension is increased, and in yeast, where they are always required to overcome the opposing turgor pressure. By combining experimental observations with physical modeling, we propose a mechanism for actin-driven endocytosis under high tension or high pressure conditions.
HIV Peptidome-Wide Association Study Reveals Patient-Specific Epitope Repertoires Associated with HIV Control
Authors: Arora Jatin , McLaren Paul J. , Chaturvedi Nimisha , Carrington Mary , Fellay Jacques , Lenz Tobias L.
Published: April 2018

Genetic variation in the peptide-binding groove of the highly polymorphic human leukocyte antigen (HLA) class I molecules has repeatedly been associated with HIV-1 control and progression to AIDS, accounting for up to 12% of the variation in HIV-1 set point viral load (spVL). This suggests a key role in disease control for HLA presentation of HIV-1 epitopes to cytotoxic T cells. However, a comprehensive understanding of the relevant HLA-bound HIV epitopes is still elusive. Here we developed a peptidome-wide association study (PepWAS) approach that integrates HLA genotypes and spVL data from 6,311 HIV-infected patients to interrogate the entire HIV-1 proteome (3,252 unique peptides) for disease-relevant peptides. This PepWAS approach revealed a core set of epitopes associated with spVL, including previously characterized epitopes but also several novel disease-relevant peptides. More importantly, each patient presents only 16 (±7) and 6 (±6) of these core epitopes through their individual HLA-B and HLA-A variants, respectively. Differences in these patient-specific epitope repertoires account for almost all the variation in spVL previously associated with HLA genetic variation. PepWAS thus enables a comprehensive functional interpretation of the robust but little understood association between HLA and HIV-1 control, prioritizing a short and targetable list of disease-associated epitopes for personalized immunotherapy.