bluuebunny/crossref_metadata_2025_split huggingface dataset:
Timing of orchidopexy and its relationship to postoperative testicular atrophy: results from the ORCHESTRA study
Authors:   Paediatric Surgical Trainees Research Network (PSTRN),   Organizing and Writing Group:, Skerritt C , Bradshaw C , Hall N , McCarthy L , Woodward M 
Published: February 2021

Abstract

Background
In 2011 a consensus statement from the British Association of Paediatric Urologists recommended lowering the age at orchidopexy to under 1 year. There are concerns that a younger age at operation may increase postoperative testicular atrophy. The ORCHESTRA study aimed to establish the current age at orchidopexy in a multicentre, international audit and to see whether testicular atrophy was affected by age at operation.

Methods
The study was undertaken over a 3-month period in 28 centres in boys undergoing orchidopexy for unilateral, palpable undescended testes. Data collection was done using a standardized, predetermined protocol. The primary outcome was postoperative testicular atrophy. Secondary outcomes were wound infections, reoperations, and unplanned hospital stays related to anaesthetic events.

Results
A total of 417 patients were included, of whom only 48 (11.5 per cent) underwent orchidopexy before 1 year of age. There was no difference in anaesthetic complications in boys aged less than 1 year versus older patients: 0 of 48 (0 per cent) versus 6 of 369 (1.6 per cent) (P = 0.999). Complete follow-up was available for 331 patients (79.4 per cent). There was no difference in atrophy rate between those aged less than 1 year and older boys: 1 of 37 (3 per cent) versus 9 of 294 (3.1 per cent) (P = 0.999). Reoperation rates were 0 of 37 (0 per cent) and 7 of 294 (2.4 per cent) respectively (P = 1.000). There were more wound infections in boys under 1 year of age: 4 of 37 (11 per cent) versus 7 of 294 (2.4 per cent) (P = 0.025).

Conclusion
Only 11.5 per cent of boys underwent surgery before the age of 1 year. There was no increased risk of postoperative testicular atrophy with early surgery, although there was a higher rate of wound infection. Further study is required to demonstrate that early orchidopexy is not inferior to orchidopexy undertaken in boys aged over 1 year.
Chronic pain as a brain imbalance between pain input and pain suppression
Authors: Vanneste Sven , De Ridder Dirk 
Published: February 2021

Abstract
Chronic pain is pain that persists beyond the expected period of healing. The subjective experience of chronic pain results from pathological brain network interactions, rather than from persisting physiological sensory input of nociceptors. We hypothesize that pain is an imbalance between pain evoking dorsal anterior cingulate cortex and somatosensory cortex and pain suppression (i.e. pregenual anterior cingulate cortex). This imbalance can be measured objectively by current density ratios between pain input and pain inhibition. A balance between areas involved in pain input and pain suppression requires communication, which can be objectively identified by connectivity measures, both functional and effective connectivity. In patients with chronic neuropathic pain, electroencephalography is performed with source localization demonstrating that pain is reflected by an abnormal ratio between the dorsal anterior cingulate cortex, somatosensory cortex and pregenual anterior cingulate cortex. Functional connectivity demonstrates decreased communication between these areas, and effective connectivity puts the culprit at the dorsal anterior cingulate cortex, suggesting that the problem is related to abnormal behavioral relevance attached to the pain. In conclusion, chronic pain can be considered as an imbalance between pain input and pain suppression.
Circadian disruption in mice through chronic jet lag-like conditions modulates molecular profiles of cancer in nucleus accumbens and prefrontal cortex
Authors: Khan Suliman , Yong V Wee , Xue Mengzhou 
Published: February 2021

Abstract
Biological rhythms regulate physiological activities. Shiftwork disrupts normal circadian rhythms and may increase the risk of cancer through unknown mechanisms. To mimic environmental light/dark changes encountered by shift workers, a protocol called ‘chronic jet lag (CJL)’ induced by repeatedly shifting light–dark cycles has been used. Here, we subjected mice to CJL by advancing light–dark cycle by 6 h every 2 days, and conducted RNA sequencing to analyze the expression profile and molecular signature in the brain areas of prefrontal cortex and nucleus accumbens. We also performed positron emission tomography (PET) imaging to monitor changes related to glucose metabolism in brain. Our results reveal systematic reprogramming of gene expression associated with cancer-related pathways and metabolic pathways in prefrontal cortex and nucleus accumbens. PET imaging indicates that glucose uptake level was significantly reduced in whole brain as well as the individual brain regions. Moreover, qPCR analysis describes that the expression levels of cancer-related genes were altered in prefrontal cortex and nucleus accumbens. Overall, these results suggest a molecular and metabolic link with CJL-mediated cancer risk, and generate hypotheses on how CJL increases the susceptibility to cancer.
Cezanne is a critical regulator of pathological arterial remodelling by targeting β-catenin signalling
Authors: An Weiwei , Luong Le A , Bowden Neil P , Yang Mei , Wu Wei , Zhou Xinmiao , Liu Chenxin , Niu Kaiyuan , Luo Jun , Zhang Cheng , Sun Xiaolei , Poston Robin , Zhang Li , Evans Paul C , Xiao Qingzhong 
Published: February 2021

Abstract

Aims
Pathological arterial remodelling including neointimal hyperplasia and atherosclerosis is the main underlying cause for occluding arterial diseases. Cezanne is a novel deubiquitinating enzyme, functioning as a NF-кB negative regulator, and plays a key role in renal inflammatory response and kidney injury induced by ischaemia. Here we attempted to examine its pathological role in vascular smooth muscle cell (VSMC) pathology and arterial remodelling.

Methods and results
Cezanne expression levels were consistently induced by various atherogenic stimuli in VSMCs, and in remodelled arteries upon injury. Functionally, VSMCs over-expressing wild-type Cezanne, but not the mutated catalytically-inactive Cezanne (C209S), had an increased proliferative ability and mobility, while the opposite was observed in VSMCs with Cezanne knockdown. Surprisingly, we observed no significant effects of Cezanne on VSMC apoptosis, NF-κB signalling, or inflammation. RNA-sequencing and biochemical studies showed that Cezanne drives VSMC proliferation by regulating CCN family member 1 (CCN1) by targeting β-catenin for deubiquitination. Importantly, local correction of Cezanne expression in the injured arteries greatly decreased VSMC proliferation, and prevented arterial inward remodelling. Interestingly, global Cezanne gene deletion in mice led to smaller atherosclerotic plaques, but with a lower level of plaque stability. Translating, we observed a similar role for Cezanne in human VSMCs, and higher expression levels of Cezanne in human atherosclerotic lesions.

Conclusion
Cezanne is a key regulator of VSMC proliferation and migration in pathological arterial remodelling. Our findings have important implications for therapeutic targeting Cezanne signalling and VSMC pathology in vascular diseases.
Long-term Safety and Efficacy of the Anti-MAdCAM-1 Monoclonal Antibody Ontamalimab [SHP647] for the Treatment of Ulcerative Colitis: The Open-label Study TURANDOT II
Authors: Reinisch Walter , Sandborn William J , Danese Silvio , Hébuterne Xavier , Kłopocka Maria , Tarabar Dino , Vaňásek Tomáš , Greguš Miloš , Hellstern Paul A , Kim Joo Sung , Sparrow Miles P , Gorelick Kenneth J , Hoy Michael , Goetsch Martina , Bliss Caleb , Gupta Charu , Cataldi Fabio , Vermeire Séverine 
Published: February 2021

Abstract

Background and Aims
Ontamalimab, a fully-human monoclonal antibody targeting MAdCAM-1, induced remission in patients with moderate-to-severe ulcerative colitis [UC] in the TURANDOT study. We aimed to assess long-term safety, tolerability, and efficacy of ontamalimab in TURANDOT II.

Methods
TURANDOT II was a phase 2, multicentre, open-label [OL] study in patients with moderate-to-severe UC who completed TURANDOT on placebo or ontamalimab (NCT01771809). Patients were randomised to 75 mg or 225 mg ontamalimab every 4 weeks for 72 weeks [OL1]. The dosage could be increased to 225 mg from Week 8 at the investigator’s discretion. All patients then received 75 mg every 4 weeks for 72 weeks [OL2], followed by 6-month safety follow-up. The primary objective was safety, measured by adverse events [AEs], serious AEs [SAEs], and AEs leading to withdrawal. Mucosal healing [MH; centrally read endoscopy] was assessed.

Results
Of 330 patients, 180 completed OL1; 94 escalated to 225 mg; 127 completed OL2. Overall, 36.1% experienced drug-related AEs. The most common SAE [10.0%] was worsening/ongoing UC; 5.5% of patients had serious infections, the most common being gastroenteritis [0.9%]. One death and four cancers [all unrelated to ontamalimab] occurred. No PML [progressive multifocal leukoencephalopathy]/lymphoproliferative disorders occurred. Geometric mean high-sensitivity C-reactive protein [hsCRP] and faecal calprotectin decreased across OL1 in both dose groups. The proportion of patients assigned to placebo in TURANDOT achieving MH increased from 8.8% [6/68] at baseline to 35.3% at Week 16 [24/68; non-responder imputation]. The corresponding increase in the ontamalimab group was from 23.3% [61/262] to 26.7% [70/262].

Conclusions
Ontamalimab was well tolerated up to 144 weeks in patients with moderate-to-severe UC, with good safety and efficacy.
Diving into Inflammation: A Pilot Study Exploring the Dynamics of the Immune–Microbiota Axis in Ileal Tissue Layers of Patients with Crohn’s Disease
Authors: Russo Edda , Giudici Francesco , Ricci Federica , Scaringi Stefano , Nannini Giulia , Ficari Ferdinando , Luceri Cristina , Niccolai Elena , Baldi Simone , D’Ambrosio Mario , Ramazzotti Matteo , Amedei Amedeo 
Published: February 2021

AbstractBackground and AimsThe pathogenesis of Crohn’s disease [CD] is still unclear. Disorders in the mucosal immunoregulation and its crosstalk with the microbiota may represent an important component in tissue injury. We aimed to characterize the molecular immune response distribution within the ileal layers and to evaluate the correlated microbiota in pathological/healthy settings comparing first surgery/relapse clinical conditions.MethodsWe enrolled 12 CD patients. A comprehensive analysis of an ileal mucosa, submucosa and serosa broad-spectrum cytokine panel was performed through a multiplex approach. In addition, ileal microbiota composition was assessed through next generation sequencing.ResultsWe observed a distinct profile [of IL1-α, IL-1β, IL-4, IL-8, ICAM-1, E-Selectin, P-Selectin, IP-10, IL 6 and IL 18] across the CD vs healthy ileal layers; and a different distribution of IFN- γ, P-Selectin, IL-27 and IL-21 in first surgery vs relapse patients. In addition, the phylum Tenericutes, the family Ruminococcaceae, and the genera Mesoplasma and Mycoplasma were significantly enriched in the pathological setting. Significant microbiota differences were observed between relapse and first surgery patients regarding the class Bacteroidia, and the genera Prevotella, Flavobacterium, Tepidimonas and Escherichia/Shigella. Finally, the abundance of the genus Mycoplasma was positively correlated with IL-18.ConclusionsWe describe a dissimilarity of cytokine distribution and microbiota composition within CD and adjacent healthy ileal tissue layers and between first operation and surgical relapse. Our results give potential insight into the dynamics of the gut microbiota–immune axis in CD patients, leading to detection of new biomarkers.
Thromboembolic complications in transfemoral aortic valve implantation due to aortic wall thrombus and shaggy aorta syndrome
Authors: Haensig Martin , Kuntze Thomas , Gonzalez-Lopez David , Lapp Harald , Lauten Philipp , Owais Tamer 
Published: February 2021

Abstract

OBJECTIVES
Aortic wall thrombus (AWT) can affect suitability to endovascular repair, while its most aggressive entity is better known as shaggy aorta syndrome. Primary objective was to study the procedural and clinical outcome with regard to atherothrombotic AWT in transfemoral aortic valve implantation.

METHODS
In a retrospective, single-centre analysis, a qualitative 0–10 AWT score classification system was used. The most severely affected aortic area in computed tomography angiography cross-section was assessed for the number of affected segments, thrombus type, thickness, area and circumference. Primary endpoints were 30-day mortality, neurologic, renal and pulmonary events and signs of solid organ infarction.

RESULTS
Between November 2017 and September 2019, 604 patients underwent transfemoral transcatheter aortic valve implantation in our institution. Computed tomography-guided analysis revealed AWT in 11.3% and shaggy aorta syndrome in 6 patients (1.0% with 83.3% male). AWT was mainly present in the descending thoracic and abdominal aorta and was associated with acute renal failure (11.8% vs 3.2%, P ≤ 0.001) and a seven-fold increased rate of disabling peri-interventional stroke (4.4% vs 0.6%, P ≤ 0.001). In all patients with disabling peri-interventional stroke a balloon-expandable prosthesis was used (P ≤ 0.001). In case of shaggy aorta, mortality was more than six-fold increased (2.8% vs 16.7%, P = 0.046).

CONCLUSIONS
Severe and irregular thrombus of the descending thoracic and abdominal aorta has been strongly associated with acute respiratory failure and peri-interventional stroke in transfemoral aortic valve implantation, being more likely using balloon-expandable devices. Our results imply important changes with regard to device design and present international transcatheter aortic valve implantation guidelines.
Incidence, determinants and clinical impact of left ventricular function recovery after surgical treatments for ischaemic cardiomyopathy
Authors: Nakae Masaro , Kainuma Satoshi , Toda Koichi , Miyagawa Shigeru , Yoshikawa Yasushi , Hata Hiroki , Yoshioka Daisuke , Kawamura Takuji , Kawamura Ai , Kashiyama Noriyuki , Komukai Sho , Kitamura Tetsuhisa , Hirayama Atsushi , Ueno Takayoshi , Kuratani Toru , Kondoh Haruhiko , Masai Takafumi , Hiraoka Arudo , Sakaguchi Taichi , Yoshitaka Hidenori , Shirakawa Yukitoshi , Takahashi Toshiki , Taniguchi Kazuhiro , Sawa Yoshiki ,   Osaka Cardiovascular Surgery Research (OSCAR) Group
Published: February 2021

Abstract

OBJECTIVES
This retrospective study aimed to clarify the incidence, determinants and clinical impact of left ventricular (LV) function non-recovery after coronary artery bypass grafting (CABG) in patients with ischaemic cardiomyopathy.

METHODS
A total of 490 patients with ischaemic cardiomyopathy (LV ejection fraction ≤ 40%) undergoing CABG were analysed. Follow-up echocardiography was performed at 1 month, 1 year, and annually thereafter. LV function recovery was defined as ejection fraction (EF) ≥40% at least once during follow-up. LV function non-recovery was defined as EF &lt;40% at any follow-up. The primary and secondary end points were changes in LV function and all-cause mortality, respectively. Clinical follow-up was completed in 461 patients (94.1%; mean follow-up: 64.5 ± 45.5 months).

RESULTS
During follow-up, echocardiographic assessments were performed 1863 times (mean, 3.8 ± 2.4), and 193 patients (39.4%) exhibiting LV function non-recovery were identified. Overall survival was significantly higher in the recovery group (53.9%) than in the non-recovery group (31.4%) at 10 years (P &lt; 0.001). Independent predictors of LV function non-recovery were preoperative LV end-systolic diameter [odds ratio (OR) 1.07, 95% confidence interval (CI) 1.04–1.10; P &lt; 0.001] and bilateral internal thoracic artery grafting (OR 0.61, 95% CI 0.39–0.95; P = 0.028). In a multivariable Cox proportional hazards model, LV function non-recovery was significantly associated with all-cause mortality (hazard ratio 2.14, 95% CI 1.60–2.86; P &lt; 0.001).

CONCLUSIONS
Almost 40% of patients with ischaemic cardiomyopathy undergoing CABG did not achieve LV function recovery and were associated with poor prognosis. To achieve LV function recovery, CABG with bilateral internal thoracic artery may be recommended before excessive LV remodelling occurs.

Clinical trial registration number
Institutional review board of Osaka University Hospital, number 16105.
Suture tie-down forces and cyclic contractile forces after an undersized tricuspid annuloplasty using a 3-dimensional rigid ring in an ovine model
Authors: Lim Jae Hong , Shin Heean , Shin Dong Ah , Kim Dae Hyun , Sohn Suk Ho , Choi Jae Woong , Cho Sungkyu , Kim Hee Chan , Hwang Ho Young 
Published: February 2021

Abstract

OBJECTIVES
This study was conducted to measure suture tie-down forces and evaluate cyclic contractile forces (CCFs) in beating hearts after undersized 3-dimensional (3D) rigid-ring tricuspid valve annuloplasty (TAP).

METHODS
Eight force transducers were attached to the 3D rigid TAP ring. Segments 1 to 8 were attached from the mid-septal to anterior-septal commissural area in a counterclockwise order. Two-sizes-down ring TAPs were performed in 6 sheep. Tie-down forces and CCF were recorded and analysed at the 8 annular segments and at 3 levels of peak right ventricular pressure (RVP: 30, 50 and 70 mmHg).

RESULTS
The overall average tie-down forces and CCF were 4.34 ± 2.26 newtons (N) and 0.23 ± 0.09 N, respectively. The CCF at an RVP of 30 mmHg were higher at 3 commissural areas (segments 3, 5 and 8) than at the other segments. The increases in the CCF following changes in the RVP were statistically significant only at the 3 commissural areas (P = 0.012). However, mean CCFs remained low at all annular positions (ranges of average CCF = 0.06–0.46 N).

CONCLUSIONS
The risk of suture dehiscence after down-sized 3D rigid-ring TAP might be minimal because the absolute forces remained low in all annular positions even in the condition of high RVP. However, careful suturing in the septal annular area and commissures is necessary to prevent an annular tear during a down-sized 3D rigid-ring TAP.
Revisiting the genome-wide significance threshold for common variant GWAS
Authors: Chen Zhongsheng , Boehnke Michael , Wen Xiaoquan , Mukherjee Bhramar 
Published: February 2021

AbstractOver the last decade, GWAS meta-analyses have used a strict P-value threshold of 5 × 10−8 to classify associations as significant. Here, we use our current understanding of frequently studied traits including lipid levels, height, and BMI to revisit this genome-wide significance threshold. We compare the performance of studies using the P = 5 × 10−8 threshold in terms of true and false positive rate to other multiple testing strategies: (1) less stringent P-value thresholds, (2) controlling the FDR with the Benjamini–Hochberg and Benjamini–Yekutieli procedure, and (3) controlling the Bayesian FDR with posterior probabilities. We applied these procedures to re-analyze results from the Global Lipids and GIANT GWAS meta-analysis consortia and supported them with extensive simulation that mimics the empirical data. We observe in simulated studies with sample sizes ∼20,000 and &gt;120,000 that relaxing the P-value threshold to 5 × 10−7 increased discovery at the cost of 18% and 8% of additional loci being false positive results, respectively. FDR and Bayesian FDR are well controlled for both sample sizes with a few exceptions that disappear under a less stringent definition of true positives and the two approaches yield similar results. Our work quantifies the value of using a relaxed P-value threshold in large studies to increase their true positive discovery but also show the excess false positive rates due to such actions in modest-sized studies. These results may guide investigators considering different thresholds in replication studies and downstream work such as gene-set enrichment or pathway analysis. Finally, we demonstrate the viability of FDR-controlling procedures in GWAS.
Toward genetic modification of plant-parasitic nematodes: delivery of macromolecules to adults and expression of exogenous mRNA in second stage juveniles
Authors: Kranse Olaf , Beasley Helen , Adams Sally , Pires-daSilva Andre , Bell Christopher , Lilley Catherine J , Urwin Peter E , Bird David , Miska Eric , Smant Geert , Gheysen Godelieve , Jones John , Viney Mark , Abad Pierre , Maier Thomas R , Baum Thomas J , Siddique Shahid , Williamson Valerie , Akay Alper , Eves-van den Akker Sebastian 
Published: February 2021

Abstract
Plant-parasitic nematodes are a continuing threat to food security, causing an estimated 100 billion USD in crop losses each year. The most problematic are the obligate sedentary endoparasites (primarily root knot nematodes and cyst nematodes). Progress in understanding their biology is held back by a lack of tools for functional genetics: forward genetics is largely restricted to studies of natural variation in populations and reverse genetics is entirely reliant on RNA interference. There is an expectation that the development of functional genetic tools would accelerate the progress of research on plant-parasitic nematodes, and hence the development of novel control solutions. Here, we develop some of the foundational biology required to deliver a functional genetic tool kit in plant-parasitic nematodes. We characterize the gonads of male Heterodera schachtii and Meloidogyne hapla in the context of spermatogenesis. We test and optimize various methods for the delivery, expression, and/or detection of exogenous nucleic acids in plant-parasitic nematodes. We demonstrate that delivery of macromolecules to cyst and root knot nematode male germlines is difficult, but possible. Similarly, we demonstrate the delivery of oligonucleotides to root knot nematode gametes. Finally, we develop a transient expression system in plant-parasitic nematodes by demonstrating the delivery and expression of exogenous mRNA encoding various reporter genes throughout the body of H. schachtii juveniles using lipofectamine-based transfection. We anticipate these developments to be independently useful, will expedite the development of genetic modification tools for plant-parasitic nematodes, and ultimately catalyze research on a group of nematodes that threaten global food security.