bluuebunny/crossref_metadata_2025 huggingface dataset:
Isolated Pancreatic Metastasis From Squamous Cell Lung Cancer Mimicking Primary Pancreatic Ductal Adenocarcinoma on FDG PET/CT
Authors: Zhou Wei , Dong Hui , Dong Aisheng
Published: March 2020

Isolated pancreatic metastasis from lung cancer is rare. We present a case of isolated pancreatic metastasis from squamous cell lung cancer. The pancreatic tumor showed hypovascularity on enhanced MRI and intense FDG uptake on FDG PET/CT mimicking primary pancreatic ductal adenocarcinoma. This case indicates pancreatic metastasis should be considered as a differential diagnosis in patients with a history of extrapancreatic cancer and hypermetabolic pancreatic lesion.
Incidental Breast Carcinoma Detected With 13N-NH3 Cardiac PET Imaging
Authors: Bernsen Marie Louise E. , van der Zant Friso M. , Wondergem Maurits , Broos Wouter A. M. , Knol Remco J. J.
Published: March 2020

A 78-year-old woman with chest pain and a history of pacemaker implantation for arrhythmia underwent myocardial perfusion imaging by means of 13N-NH3 cardiac PET/CT. 13N-NH3 cardiac PET showed no signs of ischemia or infarction. Incidentally, a nodule with increased 13N-NH3 activity was observed in the right breast. Histopathologic examination revealed invasive ductal carcinoma.
Forequarter Amputation and Reconstructive Options
Authors: Tukiainen Erkki , Barner-Rasmussen Ian , Popov Pentscho , Kaarela Outi
Published: March 2020

Objective

This study aimed to present the results of a series of forequarter amputations (FQAs) and to evaluate the reconstructive methods used.

Summary Background Data

Although FQA has become a rare procedure in the era of limb-sparing treatment of extremity malignancies, it is a useful option when resection of a shoulder girdle or proximal upper extremity tumor cannot be performed so as to retain a functional limb.

Methods

Thirty-four patients were treated with FQA in 1989 to 2017. Various reconstructive techniques were used, including free fillet flaps from the amputated extremity.

Results

All patients presented with intractable symptoms such as severe pain, motor or sensory deficit, or limb edema. Seventeen patients were treated with palliative intent. Chest wall resection was performed in 9 patients. Free flap reconstruction was necessary for 15 patients, with 11 free flaps harvested from the amputated extremity. There was no operative mortality, and no free flaps were lost. In curatively treated patients, estimated 5-year disease-specific survival was 60%. Median survival in the palliatively treated group was 13 months (1–35 months).

Conclusions

Limb-sparing treatment is preferable for most shoulder girdle and proximal upper extremity tumors. Sometimes, FQA is the only option enabling curative treatment. In palliative indications, considerable disease-free intervals and relief from disabling symptoms can be achieved. The extensive tissue defects caused by extended FQA can be safely and reliably reconstructed by means of free flaps, preferably harvested from the amputated extremity.
Prepectoral Breast Reconstruction
Authors: Wong Lesley
Published: March 2020

Prepectoral breast reconstruction has rapidly gained attention as a new technique for implant-based breast reconstruction. It is essentially a modernization of an old technique made possible by the use of marketable products, primarily dermal matrices and cohesive silicone gel implants. The rapid dissemination of its benefits, not only to physicians, but also to the general public and referring physicians, leading to widespread adoption, is in part due to a combination of marketing and social media/Internet influences. This review will summarize the recent peer-reviewed literature to provide facts for the reconstructive surgeon to decide whether this technique is a fad or a useful option in implant-based breast reconstruction.
Abdominoplasty With Scarpa Fascia Preservation
Authors: Pisco Andreia , Rebelo Marco , Peres Helena , Costa-Ferreira António
Published: March 2020

Background

Abdominoplasty is becoming increasingly more common, with seroma being the most frequent complication. Suction drains are used very often as a method to prevent seroma formation, and it has been suggested that techniques using Scarpa fascia preservation and closed-suction drains have lower seroma rates than other approaches. However few studies have addressed parameters that may affect drain efficiency. A prospective comparative study was conducted to determine if applying 2 or 3 closed-suction drains, after an abdominoplasty with Scarpa fascia preservation, has any effect on several outcomes.

Methods

This was a single-center study conducted from September 2016 to March 2019. Patients were allocated according to choice to 1 of the 2 surgeons involved in the study, each responsible for 1 group: abdominoplasty with Scarpa fascia preservation with 2 closed-suction drains placed postoperatively (group A) or with 3 closed-suction drains (group B). A comparative analysis of selected variables was done between both groups, including time to drain removal, total and daily drain output, duration of hospital stay, emergency department visit, readmission to the hospital, secondary surgical procedure, and incidence of postoperative local and systemic complications.

Results

A total of 73 abdominoplasties with Scarpa fascia preservation were performed in women (group A, 33 patients; group B, 40 patients). General characteristics of group A and B were similar. There were no statistically significant differences between groups in any of the determined variables, namely, main outcomes (total and daily drain output, time to drain removal) or complications (local or systemic).

Conclusions

Our results suggest that using 3 closed-suction drains postabdominoplasty with Scarpa fascia preservation has no advantages in total and daily drain output, time to drain removal, or complications when compared with the usual 2 drains approach.
Handmade Cranioplasty: An Obsolete Procedure or a Surgery That Is Still Useful?
Authors: Zoli Matteo , Di Gino Marco , Cuoci Andrea , Palandri Giorgio , Acciarri Nicola , Mazzatenta Diego
Published: March 2020

Custom made cranioplasty (CM CPL) represents the gold standard for cranial defect reconstruction, allowing an adequate protection of the brain with good cosmetic results. Nevertheless, it is an expensive procedure, requiring time for preparation of the prothesis. Aim of this study is to evaluate whether and in what cases handmade cranioplasty (HM CPL) still represents a valid alternative to CM CPL.

Therefore, all consecutive cranioplasties in our center from 2013 to 2019 have been analyzed. Size and location of cranial defect have been considered, as the cause of decompression. Morbidity rate and final outcome have been evaluated. Series includes 143 patients (61% males, mean age: 60 years, SD:16). HM CPL was performed in 59 cases (41.2%) and CM in the remaining 84 (58.8%). HM CPL was preferred for smaller cranial defects (p: 0.22), inferior to 100 cm2 (p: 0.01) located in fronto-parietal-occipital area (p: 0.01). Furthermore, HM CPL results in the first choice after removal of infiltrative tumors (p: 0.02). Surgical complications consisted in 14 (9%) infections, 8 hematomas (5.6%), and one cranioplasty displacement (0.7%). At follow-up, in 85.3% of cases the CPL is still in place with satisfactory cosmetic and functional outcome (86.5% of HM CPL, 84.5% of CM CPL).

HM CPL may still represent an effective and economic alternative procedure, when specific patient selection criteria are respected. This technique requires a long learning learning curve and demanding surgical maneuvers. Our handmade reconstruction technique with some hints to improve the esthetic result is presented.
Total Joint Replacement After Condylar Destruction Secondary to Long-Standing Dislocation of the Temporomandibular Joint
Authors: Sarlabous Mathilde , Psutka David J.
Published: March 2020

Background:

To describe the treatment of 2 long-standing chronic dislocation of the temporomandibular joints (TMJs) and 1 chronic recurrent dislocation.

Methods:

This report describes the treatment of 3 patients; 2 with a long-standing chronic dislocation of the TMJ and 1 with a chronic recurrent dislocation. Duration of dislocation and anatomical considerations make the treatment challenging and controversial. The patients presented in this report all developed destruction of their condyles. They were successfully treated with total joint replacement with alloplastic devices.

Results:

All the 3 patients underwent successful surgery and recovery. Mandibular function and pain level were significantly improved.

Conclusion:

Long-standing dislocation of the TMJ is rare. This condition can be successfully treated by resection of the damaged condyles and reconstruction with alloplastic total TMJ replacements.
Applications of Computer-Aided Design/Manufacturing Technology in Treatment of Hemifacial Microsomia
Authors: Sun Yue , Du Wen , Xu Chunwei , Lin Yunfeng , Liu Xian , Luo En
Published: March 2020

Computer-aided surgery has been widely used in treatment of hemifacial microsomia and matured in recent decades. These techniques include the computer-aided design, virtual surgical planning, modeling surgery, rapid prototyping techniques, intraoperative navigation and so on. The purpose of this article is to summarize the current application of computer-aided design/computer-aided manufacturing technology in the treatment for hemifacial microsomia during the last 5 years, as well as the views and discussions on some topics, and finally introduce a method of our team. Our effort is that using the holes predrilled in cutting guides, the pre-bent titanium plates are easily placed. Avoiding potential bone autorotation caused by unfitness between conventional titanium plates and bone surface, which keeps the bone fixation precisely in line with the preoperative virtual plan and reduce the movement of bone segments due to the undesirable stress of the plates.
Ceftriaxone Combined With Metronidazole is Superior to Cefoxitin Alone in the Management of Uncomplicated Appendicitis in Children
Authors: Kashtan Mark A. , Graham Dionne A. , Melvin Patrice , Cameron Danielle B. , Anandalwar Seema P. , Hills-Dunlap Jonathan L. , Rangel Shawn J.
Published: March 2020

Objective:

To compare rates of surgical site infection between the 2 most commonly utilized narrow-spectrum antibiotic regimens in children with uncomplicated appendicitis (ceftriaxone with metronidazole and cefoxitin alone).

Summary of Background Data:

Narrow-spectrum antibiotics have been found to be equivalent to extended-spectrum (antipseudomonal) agents in preventing surgical site infection (SSI) in children with uncomplicated appendicitis. The comparative effectiveness of different narrow-spectrum agents has not been reported.

Methods:

This was a multicenter retrospective cohort study using clinical data from the Pediatric National Surgical Quality Improvement Program Appendectomy Collaborative Pilot database merged with antibiotic utilization data from the Pediatric Health Information System database from January 2013 to June 2015. Multivariable logistic regression was used to compare outcomes between antibiotic treatment groups after adjusting for patient characteristics, surrogate measures of disease severity, and clustering of outcomes within hospitals.

Results:

Eight hundred forty-six patients from 14 hospitals were included in the final study cohort with an overall SSI rate of 1.3%. A total of 56.0% of patients received ceftriaxone with metronidazole (hospital range: 0%–100%) and 44.0% received cefoxitin (range: 0%–100%). In the multivariable model, ceftriaxone with metronidazole was associated with a 90% reduction in the odds of a SSI compared to cefoxitin [0.2% vs 2.7%; odds ratio: 0.10 (95% confidence interval 0.02–0.60); P = 0.01].

Conclusions:

Ceftriaxone combined with metronidazole is superior to cefoxitin alone in preventing SSIs in children with uncomplicated appendicitis.
Prognosis Based Definition of Resectability in Pancreatic Cancer
Authors: Oba Atsushi , Croce Chiara , Hosokawa Patrick , Meguid Cheryl , Torphy Robert J. , Al-Musawi Mohammed H. , Ahrendt Steven , Gleisner Ana , Schulick Richard D. , Del Chiaro Marco
Published: March 2020

Objective:

To identify objective preoperative prognostic factors that are able to predict long-term survival of patients affected by PDAC.

Summary of Background Data:

In the modern era of improved systemic chemotherapy for PDAC, tumor biology, and response to chemotherapy are essential in defining prognosis and an improved approach is needed for classifying resectability beyond purely anatomic features.

Methods:

We queried the National Cancer Database regarding patients diagnosed with PDAC from 2010 to 2016. Cox proportional hazard models were used to select preoperative baseline factors significantly associated with survival; final models for overall survival (OS) were internally validated and formed the basis of the nomogram.

Results:

A total of 7849 patients with PDAC were included with a median follow-up of 19 months. On multivariable analysis, factors significantly associated with OS included carbohydrate antigen 19-9, neoadjuvant treatment, tumor size, age, facility type, Charlson/Deyo score, primary site, and sex; T4 stage was not independently associated with OS. The cumulative score was used to classify patients into 3 groups: good, intermediate, and poor prognosis, respectively. The strength of our model was validated by a highly significant randomization test, Log-rank test, and simple hazard ratio; the concordance index was 0.59.

Conclusion:

This new PDAC nomogram, based solely on preoperative variables, could be a useful tool to patients and counseling physicians in selecting therapy. This model suggests a new concept of resectability that is meant to reflect the biology of the tumor, thus partially overcoming existing definitions, that are mainly based on tumor anatomic features.
Increased Postoperative Use of Computed Tomography Following Emergency Surgery for Ileocaecal Crohn Disease
Authors: Caiazzo Anna , Flashman Karen , Celentano Valerio
Published: March 2020

Introduction:

Multiple imaging modalities are often required for the relapsing nature of Crohn disease (CD). Computed tomography (CT) offers a rapid acquisition of images and shows high specificity and sensitivity. However, CT imaging exposes to a higher dose of ionizing radiation than other abdominal imaging modalities. The aim of this study was to compare the use of preoperative and postoperative CT scan in patients undergoing emergency and elective surgery for CD.

Methods:

All patients undergoing emergency and elective surgery for ileocaecal CD January 2014 to December 2018 were included in this prospective observational study. The study objective was to evaluate the frequency of use of CT scan perioperatively with the number and findings of preoperative and postoperative CT being the primary outcomes. The secondary outcomes were operating time, length of hospital stay, reoperations, and rehospitalization.

Results:

A total of 75 patients were included, 33 in the emergency group (43%) and 44 in the elective group (57%). There was a higher use of preoperative CT scan in the emergency surgery group, with 14 patients (42%) having a CT scan before surgery compared with 2 (5%) in the elective group (P=0.14). Thirteen patients (39.4%) had a postoperative CT scan in the emergency surgery group, compared with 10 patients (23.8%) in the elective surgery group.

Conclusion:

Patients undergoing emergency surgery for CD are at increased risk of exposure to ionizing radiations due to high perioperative use of CT scan.
Heart Transplantation From Brain Dead Donors: A Systematic Review of Animal Models
Authors: See Hoe Louise E. , Wells Matthew A. , Bartnikowski Nicole , Obonyo Nchafatso G. , Millar Jonathan E. , Khoo Aimee , Ki Katrina K. , Shuker Tristan , Ferraioli Alessandro , Colombo Sebastiano M. , Chan Wandy , McGiffin David C. , Suen Jacky Y. , Fraser John F.
Published: March 2020

Despite advances in mechanical circulatory devices and pharmacologic therapies, heart transplantation (HTx) is the definitive and most effective therapy for an important proportion of qualifying patients with end-stage heart failure. However, the demand for donor hearts significantly outweighs the supply. Hearts are sourced from donors following brain death, which exposes donor hearts to substantial pathophysiological perturbations that can influence heart transplant success and recipient survival. Although significant advances in recipient selection, donor and HTx recipient management, immunosuppression, and pretransplant mechanical circulatory support have been achieved, primary graft dysfunction after cardiac transplantation continues to be an important cause of morbidity and mortality. Animal models, when appropriate, can guide/inform medical practice, and fill gaps in knowledge that are unattainable in clinical settings. Consequently, we performed a systematic review of existing animal models that incorporate donor brain death and subsequent HTx and assessed studies for scientific rigor and clinical relevance. Following literature screening via the U.S National Library of Medicine bibliographic database (MEDLINE) and Embase, 29 studies were assessed. Analysis of included studies identified marked heterogeneity in animal models of donor brain death coupled to HTx, with few research groups worldwide identified as utilizing these models. General reporting of important determinants of heart transplant success was mixed, and assessment of posttransplant cardiac function was limited to an invasive technique (pressure-volume analysis), which is limitedly applied in clinical settings. This review highlights translational challenges between available animal models and clinical heart transplant settings that are potentially hindering advancement of this field of investigation.
Molecular Analysis of Renal Allograft Biopsies: Where Do We Stand and Where Are We Going?
Authors: Snijders Malou L. H. , Varol Hilal , van der Zwan Marieke , Becker Jan U. , Hesselink Dennis A. , Baan Carla C. , von der Thüsen Jan H. , Clahsen-van Groningen Marian C.
Published: March 2020

A renal core biopsy for histological evaluation is the gold standard for diagnosing renal transplant pathology. However, renal biopsy interpretation is subjective and can render insufficient precision, making it difficult to apply a targeted therapeutic regimen for the individual patient. This warrants a need for additional methods assessing disease state in the renal transplant. Significant research activity has been focused on the role of molecular analysis in the diagnosis of renal allograft rejection. The identification of specific molecular expression patterns in allograft biopsies related to different types of allograft injury could provide valuable information about the processes underlying renal transplant dysfunction and can be used for the development of molecular classifier scores, which could improve our diagnostic and prognostic ability and could guide treatment. Molecular profiling has the potential to be more precise and objective than histological evaluation and may identify injury even before it becomes visible on histology, making it possible to start treatment at the earliest time possible. Combining conventional diagnostics (histology, serology, and clinical data) and molecular evaluation will most likely offer the best diagnostic approach. We believe that the use of state-of-the-art molecular analysis will have a significant impact in diagnostics after renal transplantation. In this review, we elaborate on the molecular phenotype of both acute and chronic T cell-mediated rejection and antibody-mediated rejection and discuss the additive value of molecular profiling in the setting of diagnosing renal allograft rejection and how this will improve transplant patient care.
A Comparison of the Biomechanical Protection Provided by 2 Cyanoacrylate-Based Skin Protectants
Authors: Lee Jiye , Gibson Daniel J.
Published: March 2020

PURPOSE:

The purpose of this study was to evaluate the in-gel strain and tear reduction provided by 2 skin protectant products that were applied as a liquid and allowed to dry, leaving behind a protective layer.

DESIGN:

Prospective, 3-group comparison cohort study using an in vitro model.

METHODS:

A fragile agar-based gel with an embedded bead was used in a custom device that applied variable interface pressures of 550, 1080, or 1600 Pa, respectively. The device then imparted 216 N of external shear force in 0.625-mm increments. The resulting strain in the gel was measured by digital image correlation. The strain at tearing was determined by observing the images of the gels and calculating the strain at that point. This approach was used to compare untreated gels to gels treated with one of 2 commercially available cyanoacrylate-based skin protectants. The results from the 3 groups were first analyzed by analysis of variance, followed by Tukey's Honestly Significant Difference test when indicated.

RESULTS:

We observed a proportional increase in interface pressure and strain that differed among the 3 groups. Specifically, the gels treated with a mixed polymer skin protectant had less pretearing strain than the control gel at both the 1080-Pa load (−15%, P = 3.64 × 10−4) and 1600 Pa-load (−20%, P = .03). The pure cyanoacrylate-treated gels had less strain than the control at 1080 Pa (−34%, P = 4.25 × 10−7) and 1600 Pa (−48%, P = 1.07 × 10−7); it also had less strain than the mixed polymer product at 1080 Pa (−19%, P = 5.38 × 10−6) and 1600 Pa (−28%, P = 3.88 × 10−3). In terms of protection from tearing, at an interface pressure of 1080 Pa, the control gel tore 80% of the time, the mixed polymer-treated gel tore 100% of the time, and the pure cyanoacrylate-treated gel did not tear (0/5, P = 8.84 × 10−5). Under a load of 1600 Pa, 100% of the control and mixed polymer-treated gels tore while none of the cyanoacrylate-treated gels did (P = 2.54 × 10−24).

CONCLUSION:

The pure cyanoacrylate-based skin protectant provided the most protection, with consistent reductions in both strain and tearing. Both skin protectants reduced the initial in-gel strain; however, only the pure cyanoacrylate-treated product protected the gel from tears under the conditions tested. These results indicate that cyanoacrylate-based skin protectants can reduce shear strain and tearing in fragile elastic materials.
The Price equation and evolutionary epidemiology
Authors: Day Troy , Parsons Todd , Lambert Amaury , Gandon Sylvain
Published: March 2020

The Price equation has found widespread application in many areas of evolutionary biology, including the evolutionary epidemiology of infectious diseases. In this paper, we illustrate the utility of this approach to modelling disease evolution by first deriving a version of Price’s equation that can be applied in continuous time and to populations with overlapping generations. We then show how this version of Price’s equation provides an alternative perspective on pathogen evolution by considering the epidemiological meaning of each of its terms. Finally, we extend these results to the case where population size is small and generates demographic stochasticity. We show that the particular partitioning of evolutionary change given by Price’s equation is also a natural way to partition the evolutionary consequences of demographic stochasticity, and demonstrate how such stochasticity tends to weaken selection on birth rate (e.g. the transmission rate of an infectious disease) and enhance selection on mortality rate (e.g. factors, like virulence, that cause the end of an infection). In the long term, if there is a trade-off between virulence and transmission across parasite strains, the weaker selection on transmission and stronger selection on virulence that arises from demographic stochasticity will tend to drive the evolution of lower levels of virulence.

This article is part of the theme issue ‘Fifty years of the Price equation’.
Price's equation made clear
Authors: Gardner Andy
Published: March 2020

Price's equation provides a very simple—and very general—encapsulation of evolutionary change. It forms the mathematical foundations of several topics in evolutionary biology, and has also been applied outwith evolutionary biology to a wide range of other scientific disciplines. However, the equation's combination of simplicity and generality has led to a number of misapprehensions as to what it is saying and how it is supposed to be used. Here, I give a simple account of what Price's equation is, how it is derived, what it is saying and why this is useful. In particular, I suggest that Price's equation is useful not primarily as a predictor of evolutionary change but because it provides a general theory of selection. As an illustration, I discuss some of the insights Price's equation has brought to the study of social evolution.

This article is part of the theme issue ‘Fifty years of the Price equation’.
The spectrum of antibacterial activity of human defensins and cathelicidin against gram-positive and gram-negative bacterial strains isolated from hospitalized patients
Authors: Bolatchiev Albert
Published: March 2020

Background

To date, there is a spread of resistance of microorganisms to antibiotics. To solve this problem, the search and development of new drugs with antibacterial activity is necessary. Antimicrobial peptides (AMPs) have pronounced antibacterial activity and may be promising candidates for the role of new drugs. Besides, AMPs can be used to overcome conventional antibiotics resistance due to the possible synergistic effect. In this work, the combined effect of some AMPs (human defensins, HNP-1, hBD-1, hBD-3 and cathelicidin, LL-37) with conventional antibiotics (vancomycin and imipenem) against gram-positive (Enterococcus faecalis; Staphylococcus aureus, methicillin-sensitive, MSSA, and methicillin-resistant, MRSA) and gram-negative (Escherichia coli; Klebsiella pneumoniae; Pseudomonas aeruginosa) bacterial strains was investigated.

Methods

Bacterial strains were isolated from hospitalized patients of the intensive care unit. Commercially available AMPs (HNP-1, hBD-1, hBD-3, LL-37 by Cloud-Clone Corp., USA) and antibiotics, vancomycin (Sandoz, Slovenia) and imipenem (Merck Sharp and Dohme, USA) were used. Antibiotic resistance phenotypes of isolated bacterial strains were carried out using the disk diffusion method. The standard checkerboard assays were used to study minimum inhibitory concentrations (MIC) of antimicrobials. The combined microbicidal effect of two substances (AMP+conventional antibiotic) was assessed by the fractional inhibitory concentration index (FICI). If FICI ≤ 0,5, then it was considered that two substances showed synergism of action; if 0.5 < FICI < 4 – no interaction; if FICI > 4 – antagonism.

Results

All studied AMPs had antibacterial activity against the studied strains. hBD-3 showed the lowest MICs compared to other AMPs. MIC of hBD-3 against S. aureus (MSSA and MRSA), E. coli, K. pneumoniae was the same – 0.5 mg/L, and against P. aeruginosa it was 2 mg/L. The combinations HNP-1+vancomycin (against E. faecalis) and hBD-3+imipenem (against E. coli, K. pneumoniae, P. aeruginosa) according to FICI values have shown the synergistic effect. The results of this study can be used to develop novel antibiotics based on AMPs. Also, in some cases, AMPs can help to overcome resistance to conventional antibiotics.
Comparison of severe and non-severe COVID-19 pneumonia: review and meta-analysis
Authors: Ji Weiping , Zhang Jing , Bishnu Gautam , Du Xudong , Chen Xinxin , Xu Hui , Guo Xiaoling , Cai Zhenzhai , Shen Xian
Published: March 2020

Objective

To compare the difference between severe and non-severe COVID-19 pneumonia and figure out the potential symptoms lead to severity.

Methods

Articles from PubMed, Embase, Cochrane database, and google up-to 24 February 2020 were systematically reviewed. Eighteen Literatures were identified with cases of COVID-19 pneumonia. The extracted data includes clinical symptoms, age, gender, sample size and region et al were systematic reviewed and meta analyzed.

Results

14 eligible studies including 1,424 patients were analyzed. Symptoms like fever (89.2%), cough (67.2%), fatigue (43.6%) were common, dizziness, hemoptysis, abdominal pain and conjunctival congestion/conjunctivitis were rare. Polypnea/dyspnea in severe patients were significantly higher than non-severe (42.7% vs.16.3%, P<0.0001). Fever and diarrhea were higher in severe patients(p=0.0374and0.0267). Further meta-analysis showed incidence of fever(OR1.70,95%CI 1.01-2.87), polypnea/dyspnea(OR3.53, 95%CI 1.95-6.38) and diarrhea(OR1.80,95%CI 1.06-3.03) was higher in severe patients, which meant the severe risk of patients with fever, polypnea/dyspnea, diarrhea were 1.70, 3.53, 1.80 times higher than those with no corresponding symptoms.

Conclusions

Fever, cough and fatigue are common symptoms in COVID-19 pneumonia. Compared with non-severe patients, the symptoms as fever, polypnea/dyspnea and diarrhea are potential symptoms lead to severity.
The effect of depth context in the segmentation of the colon in MRI volumes
Authors: Benson Ezenwoko , Rier Lukas , Millican Isawan , Pritchard Sue , Costigan Carolyn , Pound Michael , Major Giles , French Andrew , Gowland Penny , Pridmore Tony , Hoad Caroline
Published: March 2020

Colonic volume content measurements can provide important information about the digestive tract physiology. Development of automated analyses will accelerate the translation of these measurements into clinical practice. In this paper, we test the effect of data dimension on the success of deep learning approaches to segment colons from MRI data. Deep learning network models were developed which used either 2D slices, complete 3D volumes and 2.5D partial volumes. These represent variations in the trade-off between the size and complexity of a network and its training regime, and the limitation of only being able to use a small section of the data at a time: full 3D networks, for example, have more image context available for decision making but require more powerful hardware to implement. For the datasets utilised here, 3D data was found to outperform 2.5D data, which in turn performed better than 2D datasets. The maximum Dice scores achieved by the networks were 0.898, 0.834 and 0.794 respectively. We also considered the effect of ablating varying amounts of data on the ability of the networks to label images correctly. We achieve dice scores of 0.829, 0.827 and 0.389 for 3D single slices ablation, 3D multi-slice ablation and 2.5D middle slice ablation.

In addition, we examined another practical consideration of deep learning, that of how well a network performs on data from another acquisition device. Networks trained on images from a Philips Achieva MRI system yielded Dice scores of up to 0.77 in the 3D case when tested on images captured from a GE Medical Systems HDxt (both 1.5 Tesla) without any retraining. We also considered the effect of single versus multimodal MRI data showing that single modality dice scores can be boosted from 0.825 to 0.898 when adding an extra modality.
Differential B-cell receptor signaling requirement for adhesion of mantle cell lymphoma cells to stromal cells
Authors: Sadeghi Laia , Arvidsson Gustav , Merrien Magali , Wasik Agata M. , Görgens André , Smith C.I. Edvard , Sander Birgitta , Wright Anthony P.
Published: March 2020

Interactions between lymphoma cells and stromal cells play a key role in promoting tumor survival and development of drug resistance. We identified differences in key signaling pathways between the JeKo-1 and REC-1 mantle cell lymphoma (MCL) cell lines, which exhibited different patterns of stromal cell adhesion and chemotactic migration towards stroma-conditioned medium. The identified adhesion-regulated genes reciprocated important aspects of microenvironment-mediated gene modulation in MCL patients. 590 genes were differently regulated between the cell lines upon adhesion to stromal cells, while 32 genes were similarly regulated in both cell lines. Regulation of B-cell Receptor (BCR) signature genes in adherent cells was specific for JeKo-1. Inhibition of BCR signaling by siRNA or clinically approved inhibitors, Ibrutinib and Acalabrutinib, decreased adhesion of JeKo-1 but not REC-1 cells to stromal cells. Cell surface levels of CXCR4 were higher in JeKo-1 cells and CXCR4 was important for migration and adhesion of JeKo-1 but not REC-1 cells. Surface levels of ICAM1 adhesion protein differ for REC-1 and JeKo-1. While ICAM1 plays a positive role in adherence of both cell lines to stromal cells, S1PR1 had an inhibitory effect. The results presented here provide a model framework for further investigation of mechanistic differences in patient-response to new pathway-specific drugs.
Substrate specificity profiling of SARS-CoV-2 main protease enables design of activity-based probes for patient-sample imaging
Authors: Rut Wioletta , Groborz Katarzyna , Zhang Linlin , Sun Xinyuanyuan , Zmudzinski Mikolaj , Pawlik Bartlomiej , Młynarski Wojciech , Hilgenfeld Rolf , Drag Marcin
Published: March 2020

In December 2019, the first cases of infection with a novel coronavirus, SARS-CoV-2, were diagnosed in Wuhan, China. Due to international travel and human-to-human transmission, the virus spread rapidly inside and outside of China. Currently, there is no effective antiviral treatment for coronavirus disease 2019 (COVID-19); therefore, research efforts are focused on the rapid development of vaccines and antiviral drugs. The SARS-CoV-2 main protease constitutes one of the most attractive antiviral drug targets. To address this emerging problem, we have synthesized a combinatorial library of fluorogenic substrates with glutamine in the P1 position. We used it to determine the substrate preferences of the SARS-CoV and SARS-CoV-2 main proteases, using natural and a large panel of unnatural amino acids. On the basis of these findings, we designed and synthesized an inhibitor and two activity-based probes, for one of which we determined the crystal structure of its complex with the SARS-CoV-2 Mpro. Using this approach we visualized SARS-CoV-2 active Mprowithin nasopharyngeal epithelial cells of a patient with active COVID-19 infection. The results of our work provide a structural framework for the design of inhibitors as antiviral agents or diagnostic tests.
Transcranial ultrasound stimulation in humans is associated with an auditory confound that can be effectively masked
Authors: Braun Verena , Blackmore Joseph , Cleveland Robin O. , Butler Christopher R.
Published: March 2020

Background

Transcranial ultrasound stimulation (TUS) is emerging as a potentially powerful, non-invasive technique for focal brain stimulation. Recent animal work suggests, however, that TUS effects may be confounded by indirect stimulation of early auditory pathways.

Objective

We aimed to investigate in human participants whether TUS elicits audible sounds and if these can be masked by an audio signal.

Methods

In 18 healthy participants, T1-weighted magnetic resonance brain imaging was acquired for 3D ultrasound simulations to determine optimal transducer placements and source amplitudes. Thermal simulations ensured that temperature rises were <0.5 °C at the target and <3 °C in the skull. To test for non-specific auditory activation, TUS (500 kHz, 300 ms burst, modulated at 1 kHz with 50% duty cycle) was applied to primary visual cortex and participants were asked to distinguish stimulation from non-stimulation trials. EEG was recorded throughout the task. Furthermore, ex-vivo skull experiments tested for the presence of skull vibrations during TUS.

Results

We found that participants can hear sound during TUS and can distinguish between stimulation and non-stimulation trials. This was corroborated by EEG recordings indicating auditory activation associated with TUS. Delivering an audio waveform to participants through earphones while TUS was applied reduced detection rates to chance level and abolished the TUS-induced auditory EEG signal. Ex vivo skull experiments demonstrated that sound is conducted through the skull at the pulse repetition frequency of the ultrasound.

Conclusion

Future studies using TUS in humans need to take this auditory confound into account and mask stimulation appropriately.
Single-cell transcriptomics of allo-reactive CD4+T cells over time reveals divergent fates during gut GVHD
Authors: Engel Jessica A. , Lee Hyun Jae , Williams Cameron G. , Kuns Rachel , Olver Stuart , Lansink Lianne I. M. , Soon Megan S. F. , Andersen Stacey B. , Powell Joseph E. , Svensson Valentine , Teichmann Sarah A. , Hill Geoffrey R , Varelias Antiopi , Koyama Motoko , Haque Ashraful
Published: March 2020

Acute gastrointestinal Graft-versus-Host-Disease (GVHD) is a primary determinant of mortality after allogeneic hematopoietic stem-cell transplantation (alloSCT). It is mediated by alloreactive donor CD4+T cells that differentiate into pathogenic subsets expressing IFNγ, IL-17A or GM-CSF, and is regulated by subsets expressing IL-10 and/or Foxp3. Developmental relationships between T-helper states during priming in mesenteric lymph nodes (mLN) and effector function in the GI tract remain undefined at genome-scale. We used scRNA-seq and computational modelling to create an atlas of putative differentiation pathways during GVHD. Computational trajectory inference suggested emergence of pathogenic and regulatory states along a single developmental trajectory in mLN. Importantly, we identified an unexpected second trajectory, categorised by little proliferation or cytokine expression, reduced glycolysis, and high TCF1 expression. TCF1hicells upregulated α4β7 prior to gut migration and failed to express cytokines therein. Nevertheless, they demonstrated recall potential and plasticity following secondary transplantation, including cytokine or Foxp3 expression, but reduced TCF1. Thus, scRNA-seq revealed divergence of allo-reactive CD4+T cells into quiescent and effector states during gut GVHD, reflecting putative heterogenous primingin vivo. These findings, the first at a single-cell level during GVHD over time, can now be used to interrogate T cell differentiation in patients undergoing alloSCT.
Real-time Ratiometric Imaging of Micelles Assembly State in a Microfluidic Cancer-on-a-chip
Authors: Feiner-Gracia Natalia , Mares Adrianna Glinkowska , Buzhor Marina , Rodriguez-Trujillo Romen , Samitier Josep , Amir Roey J. , Pujals Silvia , Albertazzi Lorenzo
Published: March 2020

The performance of supramolecular nanocarriers as drug delivery systems depends on their stability in the complex and dynamic biological media. After administration, nanocarriers are challenged by confronting different barriers such as shear stress and proteins present in blood, endothelial wall, extracellular matrix and eventually cancer cell membranes. While early disassembly will result in a premature drug release, extreme stability of the nanocarriers can lead to poor drug release and low efficiency. Therefore, comprehensive understanding of the stability and assembly state of supramolecular carriers in each stage of delivery is a key factor for the rational design of these systems. One of the key challenges is that current 2Din vitromodels do not provide exhaustive information, as they do not fully recapitulate the 3D tumor microenvironment. This deficiency of the 2D models complexity is the main reason for the differences observedin vivowhen testing the performance of supramolecular nanocarriers. Herein, we present a real-time monitoring study of self-assembled micelles stability and extravasation, combining spectral confocal microscopy and a microfluidic tumor-on-a-chip. The combination of advanced imaging and a reliable organ-on-a-chip model allow us to track micelle disassembly by following the spectral properties of the amphiphiles in space and time during the crucial steps of drug delivery. The spectrally active micelles were introduced under flow and their position and conformation followed during the crossing of barriers by spectral imaging, revealing the interplay between carrier structure, micellar stability and extravasation. Integrating the ability of the micelles to change their fluorescent properties when disassembled, spectral confocal imaging and 3D microfluidic tumor blood vessel-on-a-chip, resulted in the establishment of a robust testing platform, suitable for real-time imaging and evaluation of supramolecular drug delivery carrier’s stability.
Robust Production of Uniform Human Cerebral Organoids from Pluripotent Stem Cells
Authors: Sivitilli A. , Gosio J.T. , Ghoshal B. , Evstratova A. , Trcka D. , Ghiasiighorveh P. , Hernandez J. J. , Beaulieu J. M. , Wrana J. L. , Attisano L.
Published: March 2020

Human cerebral organoid (hCO) models offer the opportunity to understand fundamental processes underlying human specific cortical development and pathophysiology in an experimentally tractable system. While diverse methods to generate brain organoids have been developed, a major challenge has been the production of organoids with reproducible cell type heterogeneity and macroscopic morphology. Here, we directly addressed this problem by establishing a robust production pipeline to generate morphologically consistent (ie uniform) hCOs and achieve a success rate of >80%. These hCOs include both a radial glial stem cell compartment and electrophysiologically competent mature neurons. Moreover, we show using immunofluorescence microscopy and single cell profiling, that individual organoids display reproducible cell type compositions that are conserved upon extended culture. We expect that application of this method will provide new insights into brain development and disease processes.
Anatomically precise relationship between specific amygdala connections and selective markers of mental well-being in humans
Authors: Klein-Flügge Miriam C , Jensen Daria EA , Takagi Yu , Verhagen Lennart , Smith Stephen M , Rushworth Matthew FS
Published: March 2020

There has been increasing interest in using neuroimaging measures to predict psychiatric disorders. However, predictions usually rely on large numbers of brain connections and large disorder heterogeneity, thus lacking both anatomical and behavioural specificity, preventing the advancement of targeted interventions. Here, we address both challenges. First, using resting-state functional MRI, we parcellated the amygdala, a region implicated in mood disorders but difficult to image with high fidelity, into seven nuclei. Next, a questionnaire factor analysis provided four sub-clinical latent behaviours frequently found in anxious-depressive individuals, such as negative emotions and sleep problems. Finally, for each latent behaviour, we identified the most predictive connections between individual amygdala nuclei and highly specific regions of interest e.g. dorsal raphe nucleus in the brainstem or medial prefrontal cortical regions. A small number of distinct connections predicted behaviours, providing unprecedented levels of specificity, in humans, for relating mental well-being to precise anatomical connections.
Conjugates of neuroprotective chaperone L-PGDS provide MRI contrast for detection of amyloid β-rich regions in live Alzheimer’s Disease mouse model brain
Authors: Sharma Bhargy , Grandjean Joanes , Phillips Margaret , Kumar Ambrish , Mandino Francesca , Yeow Ling Yun , Nandwana Vikas , Dravid Vinayak P. , Bengang Xing , Lim Sierin , Pervushin Konstantin
Published: March 2020

Endogenous brain proteins can recognize the toxic oligomers of amyloid-β (Aβ) peptides implicated in Alzheimer’s disease (AD) and interact with them to prevent their aggregation. Lipocalin-type Prostaglandin D Synthase (L-PGDS) is a major Aβ-chaperone protein in the human cerebrospinal fluid. Here we demonstrate that L-PGDS detects amyloids in diseased mouse brain. Conjugation of L-PGDS with magnetic nanoparticles enhanced the contrast for magnetic resonance imaging. We conjugated the L-PGDS protein with ferritin nanocages to detect amyloids in the AD mouse model brain. We show here that the conjugates administered through intraventricular injections co-localize with amyloids in the mouse brain. These conjugates can target the brain regions through non-invasive intranasal administration, as shown in healthy mice. These conjugates can inhibit the aggregation of amyloidsin vitroand show potential neuroprotective function by breaking down the mature amyloid fibrils.
Fine-tuning of the AMBER RNA Force Field with a New Term Adjusting Interactions of Terminal Nucleotides
Authors: Mlýnský Vojtěch , Kührová Petra , Kühr Tomáš , Otyepka Michal , Bussi Giovanni , Banáš Pavel , Šponer Jiří
Published: March 2020

Determination of RNA structural-dynamic properties is challenging for experimental methods. Thus atomistic molecular dynamics (MD) simulations represent a helpful technique complementary to experiments. However, contemporary MD methods still suffer from limitations of force fields (ffs), including imbalances in the non-bondedffterms. We have recently demonstrated that some improvement of state-of-the-art AMBER RNAffcan be achieved by adding a new term for H-bonding called gHBfix, which increases tuning flexibility and reduces the risk of side-effects. Still, the first gHBfix version did not fully correct simulations of short RNA tetranucleotides (TNs). TNs are key benchmark systems due to availability of unique NMR data, although giving too much weight on improving TN simulations can easily lead to over-fitting to A-form RNA. Here we combine the gHBfix version with another term called tHBfix, which separately treats H-bond interactions formed by terminal nucleotides. This allows to refine simulations of RNA TNs without affecting simulations of other RNAs. The approach is in line with adopted strategy of current RNAffs, where the terminal nucleotides possess different parameters for the terminal atoms than the internal nucleotides. The combination of gHBfix with tHBfix significantly improves the behavior of RNA TNs during well-converged enhanced-sampling simulations. TNs mostly populate canonical A-form like states while spurious intercalated structures are largely suppressed. Still, simulations of r(AAAA) and r(UUUU) TNs show some residual discrepancies with the primary NMR data which suggests that future tuning of some otherffterms might be useful.