bluuebunny/crossref_metadata_2025 huggingface dataset:
Optimizing Reconstruction in Craniosynostosis: Review of Nonsyndromic Patients Treated With a Novel Technique
Authors: Rudy Hayeem L. , Herman Sean , Stern Carrie S. , Staffenberg David A. , Dowling Kamilah , Goodrich James T. , Tepper Oren M.
Published: June 2020

Purpose:

Open cranial vault remodeling (CVR) with autologous split calvarial bone grafts redistributes and recontours an abnormal calvarium to create an expanded cranial vault in patients with craniosynostosis. We report a 12-year retrospective review of 162 nonsyndromic patients who underwent operative repair using our previously-described technique which portends excellent surgical outcomes and can be applied to patients of any age group and with any variety of suture fusion.

Methods:

Data was gathered on patients who underwent CVR from 2005 to 2016. Surgical records for each patient were analyzed and included operative time, estimated blood loss, and intraoperative transfusion volumes. Intraoperative and postoperative complications, the need for revision surgery, postoperative length of stay, and follow-up records were also reviewed. Syndromic patients were excluded, as well as patients with incomplete data sets. Patients who underwent either anterior or posterior vault remodeling were compared.

Results:

A total of 162 patients were included in this case series. Patients undergoing anterior CVR were significantly older than those undergoing posterior CVR (13.3 versus 11.0 months, P < 0.015) and also had significantly greater intraoperative red blood transfusion volumes (20.3 versus 15.3cc/kg, P < 0.0207) and longer operative time than posterior CVR patients (274.9 versus 216.7 minutes, P < 0.0001). No patients required reoperation for resorption or recurrence or persistent contour irregularities. There were no visual or neurological complications. Calvarial bone was successfully split in 100% of cases.

Conclusions:

This surgical approach to CVR results in good surgical outcomes with a low recurrence rate, while also maximizing operative efficiency, and minimizing total blood loss and transfusion volume. This technique can be applied to any affected suture in a patient with craniosynostosis and in patients of any age group.
Validation of the Adapted Clavien-Dindo in Trauma (ACDiT) Classifications in Medical and Surgical Management of Acute Diverticulitis
Authors: Wei Shuyan , Radwan Aiat , Mueck Krislynn M. , Wan Charlie , Wan David Q. , Millas Stefanos G. , Ko Tien C. , Holcomb John B. , Wade Charles E. , Naumann David N. , Kao Lillian S.
Published: June 2020

Objectives:

To validate the adapted Clavien-Dindo in trauma (ACDiT) tool as a novel outcome measure for patients with acute diverticulitis managed both operatively and nonoperatively.

Background:

Complications following diverticulitis are difficult to classify because no traditional tools address patients managed both operatively and nonoperatively. The ACDiT grading system—graded from 0 to 5b—is applied in this manner but has not yet been validated for this patient group.

Methods:

We performed a 5-year observational study of patients with acute diverticulitis at a safety-net hospital. Baseline demographics and hospitalization data were collected. ACDiT scores were assigned, and validation was undertaken by comparing scores with hospital-free days, and verifying that higher scores were associated with known risk factors for poor outcomes. Inverse probability weighted propensity scores were assigned for surgical management, and inverse probability weighted regression analysis was used to determine factors associated with ACDiT ≥ grade 2.

Results:

Of 260 patients, 188 (72%) were managed nonoperatively. Eighty (31%) developed a complication; 73 (91%) were grades 1 to 3b. Higher grades correlated inversely with hospital-free days (rs = −0.67, P < 0.0001) for all patients and for nonoperative (rs = −0.63, P < 0.0001) and operative (rs = −0.62, P < 0.0001) patients. Hinchey 2 to 3 and initial operative management had higher odds of having a complication of ACDiT ≥ grade 2.

Conclusion:

The ACDiT tool was successfully applied to acute diverticulitis patients managed operatively and nonoperatively, is associated with known risk factors for adverse outcomes. ACDiT may be considered a meaningful outcome measure for comparing strategies for acute diverticulitis.
A Prospective Audit of 805 Consecutive Patients With Penetrating Abdominal Trauma
Authors: Sander Anthony , Spence Richard T. , McPherson Deidre , Edu Sorin , Nicol Andrew , Navsaria Pradeep
Published: June 2020

Background:

Global trends of penetrating abdominal trauma (PAT) have seen a shift toward a selectively conservative management strategy. However, its widespread adoption for gunshot injuries has been sluggish. The purpose of this study is to compare the injury mechanisms of gunshot (GSW) and stab wounds (SW) to the abdomen in presentation, management, and outcomes.

Methods:

Prospective cohort study, set in Cape Town, South Africa, over 2 years. All patients presenting to the center with PAT during this time were included. Presentation, management, and outcomes were compared by injury mechanism, with a focus on the operative strategy (operative vs nonoperative).

Results:

During the study period, 805 patients (SW 37.6%; GSW 62.4%) with PAT were managed. Immediate laparotomies were performed in 119 (39.3%) SW and 355 (70.7%) GSW, with a therapeutic laparotomy rate of 85.7% and 91.8% for SW and GSW, respectively. Nonoperative management (NOM) was implemented in 184 SW (60.7%) and 147 GSW (29.3%) (P < 0.001), with a 92.9% and 92.5% success rate for SW and GSW, respectively. The therapeutic laparotomy rate for the delayed laparotomies (DOM) was 69.2% for SW, and 90.9% for GSW. The accuracy of clinical assessment (with adjuncts) in determining the need for laparotomy was: GSW—92% and SW—91%. Univariate analysis revealed the mechanism not to be associated with DOM. The overall mortality rate was 7.2%, and nonfatal morbidities 22.2%.

Conclusion:

Although GSW is a more morbid and often fatal injury, the general principles of selective conservatism hold true for both GSW and SW, equally.
Abdominal Surgery in Patients With COVID-19
Authors: Safari Saeed , Keyvani Hossein , Malekpour Alamdari Nasser , Dehghanian Amin , Razavi Hashemi Melika , Nemati Honar Behzad , Aminian Ali
Published: June 2020

Multiple tissue samples were obtained during emergent abdominal surgery in 4 patients with coronavirus disease 2019 (COVID-19) to examine for tissue involvement by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The first patient underwent a laparoscopic cholecystectomy for gallbladder empyema and died from severe respiratory failure. The second patient with Crohn disease underwent emergent laparotomy for a perforation in the terminal ileum and recovered. The third patient underwent an open appendectomy and recovered. The fourth patient underwent emergent laparotomy for a perforated peptic ulcer and died from sepsis. Although the SARS-CoV-2 RNA was found in the feces of 3 patients and in the duodenal wall of the patient with perforated peptic ulcer, real time reverse transcriptase polymerase chain reaction (RT-PCR) examination of abdominal fluid was negative for the virus. The RT-PCR did not detect viral RNA in the wall of small intestine, appendix, gallbladder, bile, liver, and urine. Visceral fat (omentum) and abdominal subcutaneous fat of 4 patients were also not infected with the SARS-CoV-2. Although this limited experience did not show direct involvement of abdominal fluid and omentum, assessment in large series is suggested to provide answers about the safety of abdominal surgery in patients with COVID-19.
Navigating the Maze of Dietary Supplements
Authors: O'Dwyer Darla Daniel , Vegiraju Sujatha
Published: June 2020

Dietary supplement companies must adopt Current Good Manufacturing Practices (cGMPs) to ensure that procedures are in place in order to verify the identity, strength, purity, and composition of supplement ingredients. In addition to the Food and Drug Administration enforcement, independent regulatory agencies exist to verify cGMP compliance. Supplement companies must follow regulations governing claims, labeling, advertising, and packaging. The safety record of dietary supplements and resources to assess drug nutrient interactions are discussed. Understanding the regulatory and safety issues surrounding dietary supplements will help nutrition professionals have more confidence when recommending them as an adjunct to diet and lifestyle.
Assessment of Calcium and Vitamin D Intake in an Outpatient Gastroenterology and Hepatology Clinic
Authors: Heitman Kristen , Nahikian-Nelms Marcia , Roberts Kristen
Published: June 2020

Rates of metabolic bone disease (MBD) in patients with gastrointestinal (GI) and hepatic disease exceed 65% of the population. Decreased dietary intake of calcium and vitamin D–rich foods in addition to impaired digestion, absorption, and metabolism likely contributes to a high prevalence of MBD. The aim of this research is to elucidate dietary patterns in patients at high risk for MBD. An online food frequency questionnaire was offered to patients at an outpatient GI/hepatology clinic. Average Healthy Eating Index score was 61.0 ± 13.9. Total calcium and vitamin D intake varied 100003
Parietal Peritoneum as a Novel Substitute for Middle Hepatic Vein Reconstruction During Living Donor Liver Transplantation
Authors: Hong Suk Kyun , Yi Nam-Joon , Cho Jae-Hyung , Lee Jeong-Moo , Hong Kwangpyo , Han Eui Soo , Lee Kwang-Woong , Suh Kyung-Suk
Published: June 2020

Background.

Although autologous, cryopreserved, or artificial vascular grafts can be used as interpositional vascular substitutes for middle hepatic vein (MHV) reconstruction during living donor liver transplantation (LDLT), they are not always available, are limited in size and length, and are associated with risks of infection. This study aimed to evaluate the parietal peritoneum as a novel substitute for MHV reconstruction during LDLT.

Methods.

Prospectively collected data of 15 patients who underwent LDLT using the right liver with reconstruction of MHV using the recipients’ own parietal peritoneum graft were retrospectively reviewed.

Results.

The 1-, 2-, 3-, and 5-mo patency rates were 57.1%, 57.1%, 57.1%, and 28.6%, respectively. Among the 15 cases assessed, the most recent 6 cases showed patent graft flow until discharge with 1-, 2-, 3-, and 5-mo patency rates of 80.0%, 80.0%, 80.0%, and 20.0%, respectively. All patients survived with tolerable liver function tests. There were no significant congestion-related problems, except for 1 patient who experienced MHV thrombosis requiring aspiration thrombectomy and stent insertion. There were no infection-related complications. All patients survived to the final follow-up, with a minimum follow-up duration of 8 mo. When comparing the latter 6 cases of peritoneal grafts and the recent 28 cases of conventional polytetrafluorethylene graft, the overall patency rate of the polytetrafluorethylene group was higher (P = 0.002). There were no major differences other than long-term patency rate.

Conclusions.

Parietal peritoneum may be a novel autologous substitute for MHV reconstruction during LDLT.
Type 2 diabetes prevalence in Pakistan: what is driving this? Clues from subgroup analysis of normal weight individuals in diabetes prevalence survey of Pakistan
Authors: Aamir Azizul Hasan , Ul-Haq Zia , Fazid Sheraz , Shah Basharat Hussain , Raza Abbas , Jawa Ali , Mahar Saeed A. , Ahmad Ibrar , Qureshi Faisal Masood , Heald Adrian H.
Published: June 2020

Background

Type 2 diabetes mellitus (T2DM) is a global health tissue. We determined factors relating to the likelihood of developing T2DM in normal BMI individuals.

Methodology

This was a cross-sectional community-based representative survey, of people aged ≥20 years in Pakistan, using HBA1c as the screening tool. The prevalence of T2DM/prediabetes in people having normal BMI together with associated risk factors was estimated.

Results

Of 6824 normal BMI individuals, there was still a high prevalence of T2DM 14.92% and in underweight at 10.14% (overall prevalence 16.96%). Corresponding rates for prediabetes for the normal BMI category: 9.79% and underweight 8.99%. Multivariate logistic regression modeling for normal BMI individuals, showed a significantly increased risk of T2DM with increasing age (odds ratio [OR] 2.1, 3.3, 4.5 and 4.8, P < 0.001 for 31–40, 41–50, 51–60 and 61 years and above respectively, compared to age decade 20–30 years). Similarly, there was a significantly high risk of T2DM with lower education level [OR for no vs graduate 2.4, 95% confidence interval (CI) 1.5–3.8]. There was a significantly increased risk of T2DM in individuals having a positive family history [OR 4.3 (95% CI 7.0–11.5)]. Overall the influence of overweight/obese on T2DM occurrence (20% increased risk) was much less than in other regions of the world.

Conclusion

There are higher than expected rates of T2DM/prediabetes in Pakistani ethnicity normal BMI individuals. Targeted screening of older individuals with historical lack of educational opportunity, with a family history of T2DM even if of normal BMI may result in a significant benefit in the Pakistan population.
Genetic diversity of Agrobacterium species isolated from nodules of common bean and soybean in Brazil, Mexico, Ecuador and Mozambique, and description of the new species Agrobacterium fabacearum sp. nov.
Authors: Delamuta Jakeline Renata Marçon , Scherer Anderson José , Ribeiro Renan Augusto , Hungria Mariangela
Published: June 2020

Agrobacterium

strains are associated with soil, plants and animals, and known mainly by their pathogenicity. We studied 14 strains isolated from nodules of healthy soybean and common bean plants in Brazil, Mexico, Ecuador and Mozambique. Sequence analysis of the 16S rRNA gene positioned the strains as

Agrobacterium

, but with low phylogenetic resolution. Multilocus sequence analysis (MLSA) of three partial housekeeping genes (glnII, gyrB and recA) positioned the strains in four distinct clades, with

Agrobacterium pusense

, Agrobacterium deltaense,

Agrobacterium radiobacter

and

Agrobacterium

sp. genomospecies G1. Analysis by BOX-PCR revealed high intraspecies diversity. Genomic analysis of representative strains of the three clades indicated that they carry the protelomerase telA gene, and MLSA analysis with six complete housekeeping genes (atpD, glnII, gyrB, recA, rpoB and thrC), as well as average nucleotide identity (less than 90 % with closest species) and digital DNA–DNA hybridization (less than 41 % with closest species) revealed that strain CNPSo 675T and

Agrobacterium

sp. genomospecies G1 compose a new species. Other phenotypic and genotypic characteristics were determined for the new clade. Although not able to re-nodulate the host, we hypothesize that several strains of

Agrobacterium

are endophytes in legume nodules, where they might contribute to plant growth. Our data support the description of the CNPSo 675T and

Agrobacterium

sp. genomospecies G1 strains as a new species, for which the name Agrobacterium fabacearum is proposed. The type strain is CNPSo 675T (=UMR 1457T=LMG 31642T) and is also deposited in other culture collections.
An interpretable mortality prediction model for COVID-19 patients – alternative approach
Authors: Gemmar Peter
Published: June 2020

The pandemic spread of coronavirus leads to increased burden on healthcare services worldwide. Experience shows that required medical treatment can reach limits at local clinics and fast and secure clinical assessment of the disease severity becomes vital. In [1] a model is presented for predicting the mortality of COVID-19 patients from their biomarkers. Three biomarkers have been selected by ranking with a supervised Multi-tree XGBoost classifier. The prediction model is built up as a binary decision tree with depth three and achieves AUC scores of up to 97.84±0.37 and 95.06± 2.21 for training and external test data sets, resp.

In human assessment and decision making influencing parameters usually aren’t considered as sharp numbers but rather as Fuzzy terms [2], and inferencing primarily yields Fuzzy terms or continuous grades rather than binary decisions. Therefore, I examined a Sugenotype Fuzzy classifier [3] for disease assessment and decision support. In addition, I used an artificial neural network (SOM, [4]) for selecting the biomarkers. Modelling and validation was done with the identical data base provided by [1]. With the complete training and test data sets, the Fuzzy prediction model achieves improved AUC scores of up to 98.59 or 95.12 The improvements with the Fuzzy classifier obviously become clear as physicians can interpret output grades to belong to positive or negative class more or less strongly. An extension of the Fuzzy model, which takes into account the trend in key features over time, provides excellent results with the training data, which, however, could not be finally verified due to the lack of suitable test data. The generation and training of the Fuzzy models was fully automatic and without additional adjustment with the help of ANFIS from Matlab©.
Perinatal Granulopoiesis and Risk of Pediatric Asthma
Authors: Turturice Benjamin A. , Theorell Juliana , Koenig Mary Dawn , Tussing-Humphreys Lisa , Gold Diane R. , Litonjua Augusto A. , Oken Emily , Rifas-Shiman Sheryl L. , Perkins David L. , Finn Patricia W.
Published: June 2020

Many perinatal characteristics are associated with risk for pediatric asthma. Identification of biologic processes influenced by these characteristics could facilitate risk stratification or new therapeutic targets. Using publicly available transcriptomic data from CBMCs, transcription of genes involved in myeloid differentiation were inversely associated with pediatric asthma risk stratification based on gestational age at birth, sex, birthweight, and maternal pre-pregnancy BMI. This gene signature was validated in an independent cohort and was specifically associated with genes localizing to neutrophil specific granules. Changes in these genes correlated with changes in protein abundance in serum. CBMC serum levels of PGLYRP-1, a specific granule protein, and sIL6Rα, a membrane protein, were tested for association with pulmonary outcomes. PGLYRP-1 concentration was inversely associated with mid-childhood current asthma and early-teen FEV1/FVC×100. Thus, variation in neutrophil specific granule abundance at birth is associated with individual risk for pediatric asthma and reduced pulmonary function in adolescence.
Transcriptomic profiling of disease severity in patients with COVID-19 reveals role of blood clotting and vasculature related genes
Authors: Masood Kiran Iqbal , Mahmood Syed Faisal , Shahid Saba , Nasir Nosheen , Ghanchi Najia , Nasir Asghar , Jamil Bushra , Khanum Iffat , Razzak Safina , Kanji Akbar , Hasan Zahra
Published: June 2020

COVID-19 caused by SARS-CoV-2 manifests as a range of symptoms. Understanding the molecular mechanisms responsible for immuno-pathogenesis of disease is important for treatment and management of COVID-19. We examined host transcriptomes in moderate and severe COVID-19 cases with a view to identifying pathways that affect its progression. RNA extracted from whole blood of COVID-19 cases was analysed by microarray analysis. Moderate and severe cases were compared with healthy controls and differentially regulated genes (DEGs) categorized into cellular pathways.

DEGs in COVID-19 cases were mostly related to host immune activation and cytokine signaling, pathogen uptake, host defenses, blood and vasculature genes, and SARS-CoV-2- and other virus-affected pathways. The DEGs in these pathways were increased in severe compared with moderate cases. In a severe COVID-19 patient with an unfavourable outcome we observed dysregulation of genes in platelet homeostasis and cardiac conduction and fibrin clotting with disease progression.

COVID-19 morbidity is associated with cytokine activation, cardiovascular risk and thrombosis. We identified DEGs related to dysregulation of blood clotting and homeostasis, platelet activation pathways and to be associated with disease progression. These can be biomarkers of disease progression and also potential targets for treatment interventions in COVID-19.
Rapid inactivation of SARS-CoV-2 with LED irradiation of visible spectrum wavelenghts
Authors: De Santis R. , Luca V. , Faggioni G. , Fillo S. , Stefanelli P. , Rezza G. , Lista F.
Published: June 2020

The COVID-19 pandemic has caused a global health crisis. The difficulty to control the viral spread due to the absence of vaccines and prophylactics measures has raised concerns about prevention and control of SARS-CoV-2. Therefore, it becomes more and more crucial the reduction of environmental risk factors through viral inactivation of aerosols and fomites. Photodynamic inactivation of microorganisms by light energy emitted in the visible spectrum region (VIS), not harmful for mammalian cells and safe for humans, has recently been described. A LED-device emitting a special combination of frequencies in the visible light spectrum was tested on SARS-CoV-2 infected cell surnatant dilutions in order to evaluate the antiviral efficacy. This preliminary in vitro study showed for the first time the ability to inactivate SARS-CoV-2 through LED irradiation of visible spectrum wavelengths. If further and more extensive studies will confirm these data, the usage of this LED could potentially have a big impact on the sanitization of virtually all human environments.
Genetic diversity among SARS-CoV2 strains in South America may impact performance of Molecular detection
Authors: Ramírez Juan David , Muñoz Marina , Hernández Carolina , Florez Carolina , Gomez Sergio , Rico Angelica , Pardo Lisseth , Barrios Esther C. , Paniz-Mondolfi Alberto
Published: June 2020

Since its emergence in Wuhan (China) on December 2019 the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has rapidly spread worldwide. After its arrival in South America in February 2020 the virus has expanded throughout the region infecting over 900,000 individuals with approximately 41,000 reported deaths to date. In response to the rapidly growing number of cases, a number of different primer-probe sets have been developed. However, despite being highly specific most of these primer-probe sets are known to exhibit variable sensitivity.

Currently, there are more than 700 SARS-CoV2 whole genome sequences deposited in databases from Brazil, Chile, Ecuador, Colombia, Uruguay, Peru and Argentina. To test how regional viral diversity may impact oligo binding sites and affect test performance, we reviewed all available primer-probe sets targeting the E, N and RdRp genes against available South American SARS-CoV-2 genomes checking for nucleotide variations in annealing sites. Results from this in silico analysis showed no nucleotide variations on the E-gene target region, in contrast to the N and RdRp genes which showed massive nucleotide variations within oligo binding sites. In lines with previous data, our results suggest that E-gene stands as the most conserved and reliable target when considering single-gene target testing for molecular diagnosis of SARS-CoV-2 in South America.
Naturalistic coding of working memory in primate prefrontal cortex
Authors: Roussy Megan , Luna Rogelio , Duong Lyndon , Corrigan Benjamin , Gulli Roberto A. , Nogueira Ramon , Moreno-Bote Ruben , Sachs Adam J. , Palaniyappan Lena , Martinez-Trujillo Julio C.
Published: June 2020

The primate lateral prefrontal cortex (LPFC) is considered fundamental for temporarily maintaining and manipulating mental representations that serve behavior, a cognitive function known as working memory1. Studies in non-human primates have shown that LPFC lesions impair working memory2and that LPFC neuronal activity encodes working memory representations3. However, such studies have used simple displays and constrained gaze while subjects held information in working memory3, which put into question their ethological validity4,5. Currently, it remains unclear whether LPFC microcircuits can support working memory function during natural behavior. We tested macaque monkeys in a working memory navigation task in a life-like virtual environment while their gaze was unconstrained. We show that LPFC neuronal populations robustly encode working memory representations in these conditions. Furthermore, low doses of the NMDA receptor antagonist, ketamine, impaired working memory performance while sparing perceptual and motor skills. Ketamine decreased the firing of narrow spiking inhibitory interneurons and increased the firing of broad spiking cells reducing population decoding accuracy for remembered locations. Our results show that primate LPFC generates robust neural codes for working memory in naturalistic settings and that such codes rely upon a fine balance between the activation of excitatory and inhibitory neurons.
Machine Learning to Predict Neonatal Mortality Using Public Health Data from São Paulo - Brazil
Authors: Beluzo Carlos Eduardo , Alves Luciana Correia , Silva Everton , Bresan Rodrigo , Arruda Natália , Carvalho Tiago
Published: June 2020

Infant mortality is one of the most important socioeconomic and health quality indicators in the world. In Brazil, neonatal mortality accounts to 70% of the infant mortality. Despite its importance, neonatal mortality shows increasing signals, which causes concerns about the necessity of efficient and effective methods able to help reducing it. In this paper a new approach is proposed to classify newborns that may be susceptible to neonatal mortality by applying supervised machine learning methods on public health features. The approach is evaluated in a sample of 15,858 records extracted from SPNeoDeath dataset, which were created on this paper, from SINASC and SIM databases from São Paulo city (Brazil) for this paper intent. As a results an average AUC of 0.96 was achieved in classifying samples as susceptible to death or not with SVM, XGBoost, Logistic Regression and Random Forests machine learning algorithms. Furthermore the SHAP method was used to understand the features that mostly influenced the algorithms output.
Low-cost measurement of facemask efficacy for filtering expelled droplets during speech
Authors: Fischer Emma P. , Fischer Martin C. , Grass David , Henrion Isaac , Warren Warren S. , Westman Eric
Published: June 2020

Mandates for mask use in public during the recent COVID-19 pandemic, worsened by global shortage of commercial supplies, have led to widespread use of homemade masks and mask alternatives. It is assumed that wearing such masks reduces the likelihood for an infected person to spread the disease, but many of these mask designs have not been tested in practice. We have applied a simple optical measurement method to evaluate the efficacy of masks to reduce the transmission of respiratory droplets during regular speech. We compare a variety of commonly available mask types and observe that some mask types approach the performance of standard surgical masks, while some mask alternatives, such as neck fleece or bandanas, offer very little protection. Our measurement setup is inexpensive and can be built and operated by non-experts, allowing for rapid evaluation of mask performance during speech, sneezing, or coughing.
Nationwide incidence of sarcomas and connective tissue tumors of intermediate malignancy over four years using an expert pathology review network
Authors: de Pinieux Gonzague , Karanian-Philippe Marie , Loarer Francois Le , Guellec Sophie Le , Chabaud Sylvie , Terrier Philippe , Bouvier Corinne , Battistella Maxime , Neuville Agnès , Robin Yves-Marie , Emile Jean-Francois , Moreau Anne , Larousserie Frederique , Leroux Agnes , Stock Nathalie , Lae Marick , Collin Francoise , Weinbreck Nicolas , Aubert Sebastien , Mishellany Florence , Charon-Barra Céline , Croce Sabrina , Doucet Laurent , Quintin-Rouet Isabelle , Chateau Marie-Christine , Bazille Celine , Valo Isabelle , Chetaille Bruno , Ortonne Nicolas , Gomez-Brouchet Anne , Rochaix Philippe , Muret Anne De , Ghnassia Jean-Pierre , Mescam-Mancini Lenaig , Macagno Nicolas , Birtwisle-Peyrottes Isabelle , Delfour Christophe , Angot Emilie , Pommepuy Isabelle , Ranchere-Vince Dominique , Chemin-Airiau Claire , Jean-Denis Myriam , Fayet Yohan , Courrèges Jean-Baptiste , Mesli Nouria , Berchoud Juliane , Toulmonde Maud , Italiano Antoine , Cesne Axel Le , Penel Nicolas , Ducimetiere Francoise , Gouin Francois , Coindre Jean-Michel , Blay Jean-Yves
Published: June 2020

Background

Since 2010, NETSARC and RREPS collected and reviewed prospectively all cases of sarcomas and tumors of intermediate malignancy (TIM) nationwide.

Methods

The nationwide incidence of sarcoma or TIM (2013-2016), confirmed by expert pathologists using WHO classification are presented. Yearly variations and correlation with published clinical trials was analyzed.

Results

139 histological subtypes are reported among the 25172 patients with sarcomas (n=18710, 64%) or TIM (n=6460, 36%), respectively n=5838, n=6153, n=6654, and n=6527 yearly from 2013 to 2016. Over these 4 years, the yearly incidence of sarcomas and TIM was therefore 79.7, 24.9 and 95.1/106/year, above that previously reported. GIST, liposarcoma, leiomyosarcomas, undifferentiated sarcomas represented 13%, 13%, 11% and 11% of tumors. Only GIST, as a single entity had a yearly incidence above 10/million/year. There were respectively 30, 63 and 66 different histological subtypes of sarcomas or TIM with an incidence ranging from 10 to 1/106, 1-0.1/106, or < 0.1/106/year respectively. The 2 later “incidence groups” included 21% of the patients. The incidence of 8 histotypes varied significantly over this 4 years. Patients with tumors with an incidence above 1/106per year have significantly higher numbers of dedicated published phase III and phase II clinical trials (p<10−6).

Conclusions

This nationwide registry of sarcoma patients with histology reviewed by sarcoma experts shows that the incidence of sarcoma and TIM is higher than reported, and that tumors with an incidence<106/year have a much lower access to clinical trials.
A path towards SARS-CoV-2 attenuation: metabolic pressure on CTP synthesis rules the virus evolution
Authors: Ou Zhihua , Ouzounis Christos , Wang Daxi , Sun Wanying , Li Junhua , Chen Weijun , Marlière Philippe , Danchin Antoine
Published: June 2020

Fighting the COVID-19 epidemic summons deep understanding of the way SARS-CoV-2 taps into its host cell metabolic resources. We describe here the singular metabolic background that creates a bottleneck constraining coronaviruses to evolve towards likely attenuation in the long term. Cytidine triphosphate (CTP) is at the crossroad of the biosynthetic processes that allow the virus to multiply. This is because CTP is in demand for three essential steps. It is a building block of the virus genome, it is required for synthesis of the cytosine-based liponucleotide precursors of the viral envelope and, finally, it is a critical building block of the host transfer RNAs synthesis. The CCA 3’-end of all the transfer RNAs required to translate the RNA genome and further transcripts into the proteins used to build active virus copies is not coded in the human genome. It must be synthesized de novo from CTP and ATP. Furthermore, intermediary metabolism is built on compulsory steps of synthesis and salvage of cytosine-based metabolites via uridine triphosphate (UTP) that keep limiting CTP availability. As a consequence, accidental replication errors tend to replace cytosine by uracil in the genome, unless recombination events allow the sequence to return to its ancestral sequences. We document some of the consequences of this situation in the function of viral proteins. We also highlight and provide araison d’êtreto viperin, an enzyme of innate antiviral immunity, which synthesizes 3’-deoxy-3′,4’-didehydro-CTP (ddhCTP) as an extremely efficient antiviral nucleotide.
Detection of hard and soft selective sweeps fromDrosophila melanogasterpopulation genomic data
Authors: Garud Nandita , Messer Philipp W. , Petrov Dmitri
Published: June 2020

Whether hard sweeps or soft sweeps dominate adaptation has been a matter of much debate. Recently, we developed haplotype homozygosity statistics that (i) can detect both hard and soft sweeps with similar power and (ii) can classify the detected sweeps as hard or soft. The application of our method to population genomic data from a natural population ofDrosophila melanogaster(DGRP) allowed us to rediscover three known cases of adaptation at the lociAce,Cyp6g1, andCHKov1known to be driven by soft sweeps, and detected additional candidate loci for recent and strong sweeps. Surprisingly, all of the top 50 candidates showed patterns much more consistent with soft rather than hard sweeps. Recently, Harriset al.2018 criticized this work, suggesting that all the candidate loci detected by our haplotype statistics, including the positive controls, are unlikely to be sweeps at all and instead these haplotype patterns can be more easily explained by complex neutral demographic models. They also claim, confusingly, that these neutral non-sweeps are likely to be hard instead of soft sweeps. Here, we reanalyze the DGRP data using a range of complex admixture demographic models and reconfirm our original published results suggesting that the majority of recent and strong sweeps inD. melanogasterare first likely to be true sweeps, and second, that they do appear to be soft. Furthermore, we discuss ways to take this work forward given that the demographic models employed in such analyses are generally necessarily too simple to capture the full demographic complexity, while more realistic models are unlikely to be inferred correctly because they require fitting a very large number of free parameters.
Comparison of COVID-19 case and death counts in the United States reported by four online trackers: January 22-May 31, 2020
Authors: Smith Jinkinson
Published: June 2020

The first purpose of this study is to describe a project focused on comparing the numbers of COVID-19 cases and deaths in the United States reported by four different online trackers, namely, those maintained by USAFacts, the New York Times, Johns Hopkins University, and the COVID Tracking Project. The second purpose of this study is to present results from the first five months of 2020 (January 22-May 31, 2020). This project is ongoing, so it will be updated regularly as new data from each of these trackers become available. Based on the time period included, the NYT has reported more cases than any of the other three trackers since late March/early April, and COVID Tracking Project has reported fewer deaths than any of the other three trackers since mid-March. It is hoped that the discrepancies identified by this project will provide avenues for research on their causes.
Neurotrophic Factor-Laden Acellular Chondroitin Sulfate Scaffolds Promote Chronic Functional Recovery After Severe Traumatic Brain Injury
Authors: Latchoumane Charles-Francois V. , Betancur Martha I. , Simchick Gregory A. , Sun Min Kyoung , Forghani Rameen , Lenear Christopher E. , Ahmed Aws , Mohankumar Ramya , Balaji Nivedha , Mason Hannah D. , Holmes Philip V. , Zhao Qun , Bellamkonda Ravi V. , Karumbaiah Lohitash
Published: June 2020

Severe traumatic brain injury (sTBI) survivors experience permanent functional disabilities due to significant volume loss and the brain’s poor capacity to regenerate. Chondroitin sulfate glycosaminoglycans (CS-GAGs) are key regulators of growth factor signaling and neural stem cell homeostasis in the brain. However, the efficacy of engineered CS (eCS) matrices in mediating structural and functional recovery after sTBI has not been investigated. We report that neurotrophic factor functionalized acellular eCS matrices implanted into the rat M1 region acutely post-sTBI, significantly enhanced cellular repair and gross motor function recovery when compared to controls, 20 weeks post-sTBI. Animals subjected to M2 region injuries followed by eCS matrix implantations, demonstrated the significant recovery of ‘reach-to-grasp’ function. This was attributed to enhanced volumetric vascularization, activity-regulated cytoskeleton (Arc) protein expression, and perilesional sensorimotor connectivity. These findings indicate that eCS matrices implanted acutely post-sTBI can support complex cellular, vascular, and neuronal circuit repair, chronically after sTBI.
Dihydroxyacetone phosphate signals glucose availability to mTORC1
Authors: Orozco Jose M. , Krawczyk Patrycja A. , Scaria Sonia M. , Cangelosi Andrew L. , Chan Sze Ham , Kunchok Tenzin , Lewis Caroline A. , Sabatini David M.
Published: June 2020

In response to nutrients, the mTOR complex 1 (mTORC1) kinase regulates cell growth by setting the balance between anabolic and catabolic processes. To be active, mTORC1 requires the environmental presence of amino acids and glucose, which provide the building blocks for the biosynthesis of most macromolecules. While a mechanistic understanding of amino acid sensing by mTORC1 is emerging, how glucose activates mTORC1 remains mysterious. Here, we used metabolically engineered human cells to identify glucose-derived metabolites required to activate mTORC1. We find that mTORC1 senses a metabolite downstream of the aldolase and upstream of the glyceraldehyde 3-phosphate dehydrogenase steps of glycolysis and pinpoint dihydroxyacetone phosphate (DHAP) as the key molecule. In cells expressing a triose kinase, the synthesis of DHAP from dihydroxyacetone is sufficient to activate mTORC1 even in the absence of glucose. Genetic perturbations in the GATOR-Rag signaling axis abrogate glucose sensing by mTORC1. DHAP is the glycolytic metabolite along with glyceraldehyde 3-phosphate (GAP) that has the greatest fold-change between cells in high and low glucose. DHAP is a precursor for lipid synthesis, a process under the control of mTORC1, which provides a potential rationale for the sensing of DHAP by mTORC1.
Development of zygotic and germline gene drives in mice
Authors: Pfitzner Chandran , Hughes James , White Melissa , Scherer Michaela , Piltz Sandra , Thomas Paul
Published: June 2020

CRISPR-based synthetic gene drives have the potential to deliver a more effective and humane method of invasive vertebrate pest control than current strategies. Relatively efficient CRISPR gene drives have been developed in insects and yeast but not in mammals. Here we investigated the efficiency of CRISPR/Cas9-based gene drives in Mus musculus by constructing “split drive” systems with Cas9 under the control of zygotic (CAG) or germline (Vasa) promoters. While both systems generated double stranded breaks at their intended target site in vivo, no homing was detectable. Our data indicate that robust and specific Cas9 expression during meiosis is a critical requirement for the generation of efficient CRISPR-based synthetic gene drives in rodents.
Non-selective cation permeation in an AMPA-type glutamate receptor
Authors: Biedermann Johann , Braunbeck Sebastian , Plested Andrew J. R. , Sun Han
Published: June 2020

Fast excitatory synaptic transmission in the central nervous system relies on the AMPA-type glutamate receptor (AMPAR). This receptor incorporates a non-selective cation channel which is opened by the binding of glutamate. Although the open pore structure has recently became available from cryo-electron microscopy (Cryo-EM), the molecular mechanisms governing cation permeability in AMPA receptors are not understood. Here, we combined microsecond molecular dynamics (MD) simulations on a putative open state structure of GluA2 with electrophysiology on cloned channels to elucidate ion permeation mechanisms. Na+, K+and Cs+permeated at physiological rates, consistent with a structure that represents a true open state. A single major ion binding site for Na+and K+in the pore represents the simplest selectivity filter (SF) structure for any tetrameric cation channel of known structure. The minimal SF comprised only Q586 and Q587, and other residues on the cytoplasmic side formed a cone- shaped void that lacked major interactions with ions. We observed Cl-invasion of the upper pore, explaining anion permeation in the edited form of GluA2. A permissive architecture of the SF accommodated different alkali metals in distinct solvation states to allow rapid, non-selective cation permeation, and co-permeation by water. Simulations suggested Cs+uses two equally populated ion binding sites in the filter and we confirmed with electrophysiology of GluA2 that Cs+is more permeant than Na+, consistent with serial binding sites preferentially driving selectivity.

Significance Statement

AMPA-type glutamate receptors (AMPARs) are key actors in neurotransmission, making the final step in a relay of excitability from one brain cell to another. The receptor contains an integral ion channel, which, when opened by neurotransmitter binding, permits sodium and other cations to cross the cell membrane. We investigated permeation of sodium, potassium and caesium in an AMPAR at the atomistic level using a computational molecular dynamics approach on a structure with the ion channel pore in a presumably open state. We determined that the region selecting between cations is the simplest of any channel of this type. Distinct from ion channels that select single ion species, cations are never fully dehydrated and have only one major ion binding site in the filter. Simulations suggested two similar binding sites for caesium, and studies of AMPARs in mammalian cell membranes showed that this makes caesium more permeant than sodium.
RNA-Dependent RNA Polymerase From SARS-CoV-2. Mechanism Of Reaction And Inhibition By Remdesivir
Authors: Aranda Juan , Orozco Modesto
Published: June 2020

We combine sequence analysis, molecular dynamics and hybrid quantum mechanics/molecular mechanics simulations to obtain the first description of the mechanism of reaction of SARS-CoV-2 RNA-dependent RNA polymerase (RdRp) and of the inhibition of the enzyme by Remdesivir. Despite its evolutionary youth, the enzyme is highly optimized to have good fidelity in nucleotide incorporation and a good catalytic efficiency. Our simulations strongly suggest that Remdesivir triphosphate (the active form of drug) is incorporated into the nascent RNA replacing ATP, leading to a duplex RNA which is structurally very similar to an unmodified one. We did not detect any reason to explain the inhibitory activity of Remdesivir at the active site. Displacement of the nascent Remdesivir-containing RNA duplex along the exit channel of the enzyme can occur without evident steric clashes which would justify delayed inhibition. However, after the incorporation of three more nucleotides we found a hydrated Serine which is placed in a perfect arrangement to react through a Pinner’s reaction with the nitrile group of Remdesivir. Kinetic barriers for crosslinking and polymerization are similar suggesting a competition between polymerization and inhibition. Analysis of SARS-CoV-2 mutational landscape and structural analysis of polymerases across different species support the proposed mechanism and suggest that virus has not explored yet resistance to Remdesivir inhibition.
3D reconstruction of odontoblast processes of the mouse molar and incisor
Authors: Shuhaibar Ninna , Hand Arthur R. , Terasaki Mark
Published: June 2020

Odontoblast processes are thin cytoplasmic projections that extend from the cell body at the periphery of the pulp toward the dentin-enamel junction. The odontoblast processes function in the secretion and assembly of dentin during development, participate in mechanosensation, and aid in dentin repair in mature teeth. Because they are small and densely arranged, their three-dimensional organization is not well documented. To gain further insight into how odontoblast processes contribute to odontogenesis, we used serial section electron microscopy to examine these processes in the predentin region of mouse molars and incisors. In molars, the odontoblast processes are tubular with a diameter of ~1.8 μm. The odontoblast processes near the incisor tip are similarly shaped, but those midway between the tip and apex are shaped like plates. The plates are radially aligned and longitudinally oriented with respect to the growth axis of the incisor. The thickness of the plates is approximately the same as the diameter of molar odontoblast processes. The plates have an irregular edge; the average ratio of width (midway in the predentin) to thickness is 2.3 on the labial side and 3.6 on the lingual side. The plate geometry seems likely to be related to the continuous growth of the incisor and may provide a clue as to the mechanisms by which the odontoblast processes are involved in tooth development.
Statistical Pitfalls in Brain Age Analyses
Authors: Butler Ellyn R. , Chen Andrew , Ramadan Rabie , Le Trang T. , Ruparel Kosha , Moore Tyler M. , Satterthwaite Theodore D. , Zhang Fengqing , Shou Haochang , Gur Ruben C. , Nichols Thomas E. , Shinohara Russell T.
Published: June 2020

Over the past decade, there has been an abundance of research on the difference between age and age predicted using brain features, which is commonly referred to as the “brain age gap”. Researchers have identified that the brain age gap, as a linear transformation of an out-of-sample residual, is dependent on age. As such, any group differences on the brain age gap could simply be due to group differences on age. To mitigate the brain age gap’s dependence on age, it has been proposed that age be regressed out of the brain age gap. If this modified brain age gap (MBAG) is treated as a corrected deviation from age, model accuracy statistics such asR2will be artificially inflated. Given the limitations of proposed brain age analyses, further theoretical work is warranted to determine the best way to quantify deviation from normality.

Highlights

The brain age gap is an out-of-sample residual, and as such varies as a function of age.

A recently proposed modification of the brain age gap, designed to mitigate the dependence on age, results in inflated model accuracy statistics if used incorrectly.

Given these limitations, we suggest that new methods should be developed to quantify deviation from normal developmental and aging trajectories.