bluuebunny/crossref_metadata_2025 huggingface dataset:
The evolution of alternative splicing in glioblastoma under therapy
Authors: Wang Lin , Shamardani Karin , Babikir Husam , Catalan Francisca , Nejo Takahide , Chang Susan , Phillips Joanna J. , Okada Hideho , Diaz Aaron A.
Published: January 2021

Background

Alternative splicing is a rich source of tumor-specific neoantigen targets for immunotherapy. This holds promise for glioblastomas (GBMs), the most common primary tumors of the adult brain, which are resistant to standard-of-care therapy. Although most clinical trials enroll patients at recurrence, most preclinical studies have been done with specimens from primary disease. There are limited expression data from GBMs at recurrence and surprisingly little is known about the evolution of splicing patterns under therapy.

Result

We profile 37 primary-recurrent paired human GBM specimens via RNA sequencing. We describe the landscape of alternative splicing in GBM at recurrence and contrast that to primary and non-malignant brain-tissue specimens. By screening single-cell atlases, we identify cell-type-specific splicing patterns and novel splicing events in cell-surface proteins that are suitable targets for engineered T cell therapies. We identify recurrent-specific isoforms of mitogen-activated kinase pathway genes that enhance invasiveness and are preferentially expressed by stem-like cells.

Conclusion

These studies shed light on gene expression in recurrent GBM and identify novel targets for therapeutic development.
CRISPRi enables isoform-specific loss-of-function screens and identification of gastric cancer-specific isoform dependencies
Authors: Davies Rebecca , Liu Ling , Taotao Sheng , Tuano Natasha , Chaturvedi Richa , Huang Kie Kyon , Itman Catherine , Mandoli Amit , Qamra Aditi , Hu Changyuan , Powell David , Daly Roger J. , Tan Patrick , Rosenbluh Joseph
Published: January 2021

Introduction

Genes contain multiple promoters that can drive the expression of various transcript isoforms. Although transcript isoforms from the same gene could have diverse and non-overlapping functions, current loss-of-function methodologies are not able to differentiate between isoform-specific phenotypes.

Results

Here, we show that CRISPR interference (CRISPRi) can be adopted for targeting specific promoters within a gene, enabling isoform-specific loss-of-function genetic screens. We use this strategy to test functional dependencies of 820 transcript isoforms that are gained in gastric cancer (GC). We identify a subset of GC-gained transcript isoform dependencies, and of these, we validate CIT kinase as a novel GC dependency. We further show that some genes express isoforms with opposite functions. Specifically, we find that the tumour suppressor ZFHX3 expresses an isoform that has a paradoxical oncogenic role that correlates with poor patient outcome.

Conclusions

Our work finds isoform-specific phenotypes that would not be identified using current loss-of-function approaches that are not designed to target specific transcript isoforms.
The circulating levels of CTRP1 and CTRP5 are associated with obesity indices and carotid intima-media thickness (cIMT) value in patients with type 2 diabetes: a preliminary study
Authors: Majidi Ziba , Emamgholipour Solaleh , Omidifar Abolfazl , Rahmani Fard Soheil , Poustchi Hossein , Shanaki Mehrnoosh
Published: January 2021

Background

There is growing evidence that the C1qTNF-related protein (CTRP) family has a crucial role in the pathophysiology of metabolic disorders such as type 2 diabetes (T2D) and obesity. We sought to identify the association of CTRP1 and CTRP5 circulating levels with various obesity parameters such as visceral adipose tissue (VAT) thickness, visceral adiposity index (VAI), and with carotid intima-media thickness (cIMT) in patients with T2D and controls.

Methods

This preliminary study consisted of men with T2D (n = 42) and men without T2D (n = 42). The measurement of cIMT and VAT thickness was performed using an Accuvix XQ ultrasound. Circulating levels of CTRP1, CTRP5, and adiponectin were measured by enzyme-linked immunosorbent assay (ELISA).

Results

CTRP-1 and CTRP1/CTRP5 ratio were markedly higher in patients with T2D compared to controls (p < 0001 and p = 0004 respectively). Interestingly, binominal logistic regression revealed that a higher circulating level of CTRP1 was associated with the presence of T2D (odds ratio [OR]: 1.009 [95% CI: 1.004–1.015]; P = .001). CTRP1 circulating levels were correlated with WHR, VAT, and HOMA-IR in the whole population study. Also, we observed that the ratio of CTRP1 to CTRP5 in plasma (β = 0.648, P = 0.005) and CTRP5 circulating levels (β = 0.444, P = 0.049) are independently associated with cIMT value.

Conclusions

Our results indicated that CTRP1 and CTRP5 concentrations were correlated with atherosclerosis in men with T2D and these adipokines might have a causal role for cardiometabolic risk in T2D.However, more studies in large sample sizes are required to clarify the role of CTRPs in T2D pathogenesis.
Performance of diabetes screening tests: an evaluation study of Iranian diabetes screening program
Authors: Kianpour Fateme , Fararouei Mohammad , Hassanzadeh Jafar , Mohammadi Mohammadnabi , Dianatinasab Mostafa
Published: January 2021

Background

Type 2 diabetes is a common non-communicable disease that is responsible for about 9% of all deaths and a 25% reduction in life expectancy. However, nearly half of the diabetic patients are not aware of their disease. In this regard, to identify un-known diabetic patients, diabetes screening is of great importance. This study was conducted to evaluate the performance of two commonly used diabetes screening tests that are currently recommended by the Iranian diabetes screening program for (DSP).

Methods

The validity of the two diabetes screening tests were measured among 1057 participants who were older than 30 years of age. The studied screening tests included capillary fasting blood glucose (CBG) and glycated hemoglobin (HbA1c). The golden standard for measuring the validity of the tests was venous fasting plasma glucose (VPG).

Results

According to the results, the sensitivity of CBG and HbA1c tests was 69.01% and 84.5%, and the specificity of the tests were 95.7% and 79.3%, respectively. Positive and negative predictive values were 53.84% and 97.72% for CBG and 22.72% and 98.61% for HbA1c, respectively. The recommended cut points for CBG and HbA1c were 116.5 mg/dl and 7.15%, respectively. Using these values as the new cut points, sensitivity and specificity of CBG and HbA1c changed to 80.30% and 89.10%, and 77.50% and 94.20%, respectively.

Conclusions

Compared to several other countries, the performance of Iranian DSP is relatively better. The Receiver Operating Characteristic Curve suggested new cut points for significantly better performance of DSP.
Israel’s rapid rollout of vaccinations for COVID-19
Authors: Rosen Bruce , Waitzberg Ruth , Israeli Avi
Published: January 2021

As of the end of 2020, the State of Israel, with a population of 9.3 million, had administered more COVID-19 vaccine doses than all countries aside from China, the US, and the UK. Moreover, Israel had administered almost 11.0 doses per 100 population, while the next highest rates were 3.5 (in Bahrain) and 1.4 (in the United Kingdom). All other countries had administered less than 1 dose per 100 population.

While Israel’s rollout of COVID-19 vaccinations was not problem-free, its initial phase had clearly been rapid and effective. A large number of factors contributed to this early success, and they can be divided into three major groups.

The first group of factors consists of long-standing characteristics of Israel which are extrinsic to health care. They include: Israel’s small size (in terms of both area and population), a relatively young population, relatively warm weather in December 2020, a centralized national system of government, and well-developed infrastructure for implementing prompt responses to large-scale national emergencies.

The second group of factors are also long-standing, but they are health-system specific. They include: the organizational, IT and logistical capacities of Israel’s community-based health care providers, the availability of a cadre of well-trained, salaried, community-based nurses who are directly employed by those providers, a tradition of effective cooperation between government, health plans, hospitals, and emergency care providers – particularly during national emergencies; and support tools and decisionmaking frameworks to support vaccination campaigns.

The third group consists of factors that are more recent and are specific to the COVID-19 vaccination effort. They include: the mobilization of special government funding for vaccine purchase and distribution, timely contracting for a large amount of vaccines relative to Israel’s population, the use of simple, clear and easily implementable criteria for determining who had priority for receiving vaccines in the early phases of the distribution process, a creative technical response that addressed the demanding cold storage requirements of the Pfizer-BioNTech COVID-19 vaccine, and well-tailored outreach efforts to encourage Israelis to sign up for vaccinations and then show up to get vaccinated.

While many of these facilitating factors are not unique to Israel, part of what made the Israeli rollout successful was its combination of facilitating factors (as opposed to each factor being unique separately) and the synergies it created among them. Moreover, some high-income countries (including the US, the UK, and Canada) are lacking several of these facilitating factors, apparently contributing to the slower pace of the rollout in those countries.
Trendelenburg maneuver predicts fluid responsiveness in patients on veno-arterial extracorporeal membrane oxygenation
Authors: Luo Jing-chao , Su Ying , Dong Li-li , Hou Jun-yi , Li Xin , Zhang Ying , Ma Guo-guang , Zheng Ji-li , Hao Guang-wei , Wang Huan , Zhang Yi-jie , Luo Zhe , Tu Guo-wei
Published: January 2021

Background

Evaluation of fluid responsiveness during veno-arterial extracorporeal membrane oxygenation (VA-ECMO) support is crucial. The aim of this study was to investigate whether changes in left ventricular outflow tract velocity–time integral (ΔVTI), induced by a Trendelenburg maneuver, could predict fluid responsiveness during VA-ECMO.

Methods

This prospective study was conducted in patients with VA-ECMO support. The protocol included four sequential steps: (1) baseline-1, a supine position with a 15° upward bed angulation; (2) Trendelenburg maneuver, 15° downward bed angulation; (3) baseline-2, the same position as baseline-1, and (4) fluid challenge, administration of 500 mL gelatin over 15 min without postural change. Hemodynamic parameters were recorded at each step. Fluid responsiveness was defined as ΔVTI of 15% or more, after volume expansion.

Results

From June 2018 to December 2019, 22 patients with VA-ECMO were included, and a total of 39 measurements were performed. Of these, 22 measurements (56%) met fluid responsiveness. The R2 of the linear regression was 0.76, between ΔVTIs induced by Trendelenburg maneuver and the fluid challenge. The area under the receiver operating characteristic curve of ΔVTI induced by Trendelenburg maneuver to predict fluid responsiveness was 0.93 [95% confidence interval (CI) 0.81–0.98], with a sensitivity of 82% (95% CI 60–95%), and specificity of 88% (95% CI 64–99%), at a best threshold of 10% (95% CI 6–12%).

Conclusions

Changes in VTI induced by the Trendelenburg maneuver could effectively predict fluid responsiveness in VA-ECMO patients.

Trial registration ClinicalTrials.gov, NCT 03553459 (the TEMPLE study). Registered on May 30, 2018
PRISMA-S: an extension to the PRISMA Statement for Reporting Literature Searches in Systematic Reviews
Authors: Rethlefsen Melissa L. , Kirtley Shona , Waffenschmidt Siw , Ayala Ana Patricia , Moher David , Page Matthew J. , Koffel Jonathan B. ,   PRISMA-S Group, Blunt Heather , Brigham Tara , Chang Steven , Clark Justin , Conway Aislinn , Couban Rachel , de Kock Shelley , Farrah Kelly , Fehrmann Paul , Foster Margaret , Fowler Susan A. , Glanville Julie , Harris Elizabeth , Hoffecker Lilian , Isojarvi Jaana , Kaunelis David , Ket Hans , Levay Paul , Lyon Jennifer , McGowan Jessie , Murad M. Hassan , Nicholson Joey , Pannabecker Virginia , Paynter Robin , Pinotti Rachel , Ross-White Amanda , Sampson Margaret , Shields Tracy , Stevens Adrienne , Sutton Anthea , Weinfurter Elizabeth , Wright Kath , Young Sarah
Published: January 2021

Background

Literature searches underlie the foundations of systematic reviews and related review types. Yet, the literature searching component of systematic reviews and related review types is often poorly reported. Guidance for literature search reporting has been diverse, and, in many cases, does not offer enough detail to authors who need more specific information about reporting search methods and information sources in a clear, reproducible way. This document presents the PRISMA-S (Preferred Reporting Items for Systematic reviews and Meta-Analyses literature search extension) checklist, and explanation and elaboration.

Methods

The checklist was developed using a 3-stage Delphi survey process, followed by a consensus conference and public review process.

Results

The final checklist includes 16 reporting items, each of which is detailed with exemplar reporting and rationale.

Conclusions

The intent of PRISMA-S is to complement the PRISMA Statement and its extensions by providing a checklist that could be used by interdisciplinary authors, editors, and peer reviewers to verify that each component of a search is completely reported and therefore reproducible.
Texture analysis of iodine maps and conventional images for k-nearest neighbor classification of benign and metastatic lung nodules
Authors: Lennartz Simon , Mager Alina , Große Hokamp Nils , Schäfer Sebastian , Zopfs David , Maintz David , Reinhardt Hans Christian , Thomas Roman K. , Caldeira Liliana , Persigehl Thorsten
Published: January 2021

Background

The purpose of this study was to analyze if the use of texture analysis on spectral detector CT (SDCT)-derived iodine maps (IM) in addition to conventional images (CI) improves lung nodule differentiation, when being applied to a k-nearest neighbor (KNN) classifier.

Methods

183 cancer patients who underwent contrast-enhanced, venous phase SDCT of the chest were included: 85 patients with 146 benign lung nodules (BLN) confirmed by either prior/follow-up CT or histopathology and 98 patients with 425 lung metastases (LM) verified by histopathology, 18F-FDG-PET-CT or unequivocal change during treatment. Semi-automatic 3D segmentation of BLN/LM was performed, and volumetric HU attenuation and iodine concentration were acquired. For conventional images and iodine maps, average, standard deviation, entropy, kurtosis, mean of the positive pixels (MPP), skewness, uniformity and uniformity of the positive pixels (UPP) within the volumes of interests were calculated. All acquired parameters were transferred to a KNN classifier.

Results

Differentiation between BLN and LM was most accurate, when using all CI-derived features combined with the most significant IM-derived feature, entropy (Accuracy:0.87; F1/Dice:0.92). However, differentiation accuracy based on the 4 most powerful CI-derived features performed only slightly inferior (Accuracy:0.84; F1/Dice:0.89, p=0.125). Mono-parametric lung nodule differentiation based on either feature alone (i.e. attenuation or iodine concentration) was poor (AUC=0.65, 0.58, respectively).

Conclusions

First-order texture feature analysis of contrast-enhanced staging SDCT scans of the chest yield accurate differentiation between benign and metastatic lung nodules. In our study cohort, the most powerful iodine map-derived feature slightly, yet insignificantly increased classification accuracy  compared to classification based on conventional image features only.
Widespread distribution of radiocesium-bearing microparticles over the greater Kanto Region resulting from the Fukushima nuclear accident
Authors: Abe Yoshinari , Onozaki Seika , Nakai Izumi , Adachi Kouji , Igarashi Yasuhito , Oura Yasuji , Ebihara Mitsuru , Miyasaka Takafumi , Nakamura Hisashi , Sueki Keisuke , Tsuruta Haruo , Moriguchi Yuichi
Published: January 2021

The Fukushima Daiichi Nuclear Power Plant (FDNPP) accident in March 2011 emitted a considerable amount of radioactive materials. This study isolated radiocesium-bearing microparticles (CsMPs), a form of radioactive materials emitted from the FDNPP at the early stage of the accident, from aerosols collected hourly on filter tapes at seven monitoring stations at the greater Kanto Region, including the Tokyo metropolitan area, on 15 March 2011. The aerosols had a spherical shape ~ 1 μm in diameter with activity of less than 1 Bq of 137Cs per particle. Their physical and chemical characteristics, including radioactivity ratio 134Cs/137Cs as well as chemical composition and state, are essentially the same as previously reported CsMPs. This study demonstrated that air parcels containing CsMPs emitted from the FDNPP were widespread over the greater Kanto Region, more than 250 km away from the FDNPP, during the daytime of 15 March. Trajectory analysis indicated that these particles were emitted from the reactor No. 2 of FDNPP between 14 March evening and 15 March early morning. The information obtained on the widespread distribution of CsMPs can be useful for assessing the actual impacts of radioactive contamination from the FDNPP accident on the environment and human health.
A focal extramedullary hematopoiesis of the spleen in a patient with essential thrombocythemia presenting with a complicated postoperative course: a case report
Authors: Hosoda Kiyotaka , Shimizu Akira , Kubota Koji , Notake Tsuyoshi , Sugenoya Shinsuke , Yasukawa Koya , Hayashi Hikaru , Kobayashi Ryoichiro , Soejima Yuji
Published: January 2021

Background

Extramedullary hematopoiesis is a compensatory response occurring secondary to inadequate bone marrow function and is occasionally observed in essential thrombocythemia (ET). This disease usually presents as multifocal masses in the paravertebral or intra-abdominal region; however, formation of a focal mass in the liver or spleen is rare. In addition, ET is characterized by increased platelet count and shows a tendency toward thrombosis and, occasionally, bleeding. Serious bleeding is common in ET patients, caused by the decrease in or abnormalities of von Willebrand factor (vWF) as a consequence of the precipitous rise in platelets. Therefore, strict management of platelet count using medication is crucial in patients with ET who require invasive procedures, especially splenectomy.

Case presentation

A 68-year-old man with ET was found to have an enlargement of a focal splenic tumor. Imaging findings revealed that the tumor was likely a hemangioma or hamartoma; however, the possibility of malignant disease could not be completely ruled out because of short-term tumor enlargement, and we conducted a splenectomy. The surgery was uneventful, but the patient presented with severe polycythemia and vWF abnormalities postoperatively, which resulted in bleeding from the drain insertion site and wound, epistaxis, and hemorrhoidal bleeding. Three months after discharge, polycythemia still persisted and the level of vWF gradually decreased. With a decrease in vWF, the patient suffered from an increased bleeding tendency. Therefore, the patient has been referred for bone marrow transplantation and is currently awaiting a suitable donor.

Conclusions

Extramedullary hematopoiesis should be listed as a differential diagnosis of focal enlarged splenic tumors, especially in patients with myeloproliferative disorders. Additionally, in splenectomy for ET patients, careful perioperative management taking into consideration the conflicting features of a tendency toward thrombus formation and bleeding is necessary.
Correction to: A proposal for a new temperature-corrected formula for the oxygen content of blood
Authors: Hirota Kiichi , Murata Miyahiko , Shingu Koh
Published: January 2021

An amendment to this paper has been published and can be accessed via the original article.
Correction to: Classes of tree-based networks
Authors: Fischer Mareike , Herbst Lina , Galla Michelle , Long Yangjing , Wicke Kristina
Published: January 2021

An amendment to this paper has been published and can be accessed via the original article.
Potassium Concentration in Initial Fluid Therapy and In-Hospital Mortality of Patients with Diabetic Ketoacidosis
Authors: Okada Akira , Yamana Hayato , Morita Kojiro , Sato Yukihito , Yamaguchi Satoko , Kurakawa Kayo Ikeda , Michihata Nobuaki , Matsui Hiroki , Fushimi Kiyohide , Nangaku Masaomi , Yamauchi Toshimasa , Yasunaga Hideo , Kadowaki Takashi
Published: January 2021

Context

Guidelines worldwide recommend potassium replacement of 10 to 40 mmol/L in the initial fluid therapy for patients with diabetic ketoacidosis. However, evidence is lacking as to the association between infused potassium concentration and mortality.

Objective

We aimed to determine the association between infused potassium concentration and in-hospital mortality.

Methods

Using the Japanese Diagnosis Procedure Combination database, we retrospectively identified inpatients admitted for treatment of diabetic ketoacidosis from July 2010 to March 2018. Patients with kidney dysfunction or serum potassium abnormalities were excluded. We evaluated the association of the potassium concentration in the total infused solutions in the first 2 days of hospitalization with 28-day in-hospital mortality using multivariable regression analysis with a cubic spline model. We also assessed the association between potassium concentration and occurrence of hyperkalemia.

Results

We identified 14 216 patients with diabetic ketoacidosis and observed 261 deaths. The quartile cut-points for potassium concentration were 7.7, 11.4, and 16.1 mmol/L. Within the range of approximately 10 to 40 mmol/L, potassium concentration was not associated with occurrence of hyperkalemia or death. Lower potassium concentrations were associated with higher 28-day in-hospital mortality; the odds ratio for patients receiving 8 mmol/L was 1.69 (95% CI, 1.03 to 2.78; reference: 20 mmol/L), and the odds ratio increased monotonically as potassium concentration decreased further.

Conclusion

Patients receiving potassium replacement at concentrations of 10 to 40 mmol/L had similar in-hospital mortality rates, whereas lower concentrations were associated with higher mortality.
Relationship of Preoperative Thyroid Dysfunction to Clinical Outcomes in Pediatric Cardiac Surgery
Authors: Brown Morgan L , Quinonez Luis G , Staffa Steven J , DiNardo James A , Wassner Ari J
Published: January 2021

Context

Thyroid function may be assessed in children before cardiac surgery because of concerns that hypothyroidism or thyrotoxicosis might adversely affect cardiac function perioperatively. However, the relationship between preoperative thyroid dysfunction and surgical outcomes is unknown.

Objective

Determine the relationship between preoperative thyroid dysfunction and outcomes of pediatric cardiac surgery.

Methods

Retrospective cohort study (January 2005 to July 2019).

Setting

Academic pediatric hospital.

Patients

All patients <19 years old who underwent cardiac surgery with cardiopulmonary bypass and had thyrotropin (TSH) measured within 14 days preoperatively. Exclusion criteria included neonates (≤30 days), preoperative extracorporeal life support, salvage operations, or transplantation procedures.

Main Outcome Measures

Subjects were stratified by preoperative TSH concentration (mIU/L): low (<0.5), normal (0.5-5), mildly high (5.01-10), or moderately high (>10). Outcomes were compared among subjects with normal TSH (control) and each group with abnormal TSH concentrations. The primary outcome was 30-day mortality. Secondary outcomes included time to extubation, intensive care unit and hospital length of stay, and operative complications.

Results

Among 592 patients analyzed, preoperative TSH was low in 15 (2.5%), normal in 347 (58.6%), mildly high in 177 (29.9%), and moderately high in 53 (9.0%). Free thyroxine was measured in 77.4% of patients and was low in 0 to 4.4% of subjects, with no differences among TSH groups. Thirty-day mortality was similar among TSH groups. There were no differences in any secondary outcome between patients with abnormal TSH and patients with normal TSH.

Conclusion

Preoperative mild to moderate subclinical hypothyroidism was not associated with adverse postoperative outcomes in children undergoing cardiopulmonary bypass procedures.
Serum Follistatin Is Increased in Thyroid Cancer and Is Associated With Adverse Tumor Characteristics in Humans
Authors: Panagiotou Grigorios , Ghaly Wael , Upadhyay Jagriti , Pazaitou-Panayiotou Kalliopi , Mantzoros Christos S
Published: January 2021

Context

Obesity and classical growth factors are associated with thyroid cancer (TC). However, less is known regarding novel hormones such as follistatins and activins. We hypothesized that serum follistatin but not activins would be increased in TC.

Objective

This work aimed to assess circulating levels of follistatins, activins, and growth factors in patients with a history of TC vs patients with nonmalignant thyroid diseases.

Methods

A hospital-based, unmatched case-control study was conducted with 170 thyroidectomized patients due to well-differentiated TC and 106 thyroidectomized patients without history of malignancy. Anthropometric, biochemical, and histological parameters were recorded. Serum samples were collected in the steady state 45 days after surgery. Multivariate models were used to adjust for baseline differences of the unmatched variables. Serum levels of follistatin (FST), follistatin like-3, activin A, activin B, bioactive insulin-like growth factor-1, and stanniocalcin-2 were assayed with novel, highly specific ELISA kits.

Results

In unmatched univariate models, TC patients had higher FST serum levels compared to cancer-free individuals, independently of histological subtype. In multivariate models adjusting for covariates, individuals in the highest tertile of FST levels were associated with an increased risk for the presence of any type of TC or specific histological subtypes, including papillary, follicular and Hürthle-cell carcinoma, and medullary TC. Higher postoperative FST concentrations were found in patients with vascular invasion and distant metastases and associated with TNM staging at diagnosis.

Conclusion

FST serum levels are increased in TC patients and correlate with advanced tumor aggressiveness. Future longitudinal studies are needed to confirm and extend our observations.
Progress and Challenges in the Biology of FNDC5 and Irisin
Authors: Maak Steffen , Norheim Frode , Drevon Christian A , Erickson Harold P
Published: January 2021

In 2002, a transmembrane protein—now known as FNDC5—was discovered and shown to be expressed in skeletal muscle, heart, and brain. It was virtually ignored for 10 years, until a study in 2012 proposed that, in response to exercise, the ectodomain of skeletal muscle FNDC5 was cleaved, traveled to white adipose tissue, and induced browning. The wasted energy of this browning raised the possibility that this myokine, named irisin, might mediate some beneficial effects of exercise. Since then, more than 1000 papers have been published exploring the roles of irisin. A major interest has been on adipose tissue and metabolism, following up the major proposal from 2012. Many studies correlating plasma irisin levels with physiological conditions have been questioned for using flawed assays for irisin concentration. However, experiments altering irisin levels by injecting recombinant irisin or by gene knockout are more promising. Recent discoveries have suggested potential roles of irisin in bone remodeling and in the brain, with effects potentially related to Alzheimer’s disease. We discuss some discrepancies between research groups and the mechanisms that are yet to be determined. Some important questions raised in the initial discovery of irisin, such as the role of the mutant start codon of human FNDC5 and the mechanism of ectodomain cleavage, remain to be answered. Apart from these specific questions, a promising new tool has been developed—mice with a global or tissue-specific knockout of FNDC5. In this review, we critically examine the current knowledge and delineate potential solutions to resolve existing ambiguities.
First Somatic PRKAR1A Defect Associated With Mosaicism for Another PRKAR1A Mutation in a Patient With Cushing Syndrome
Authors: Kamilaris Crystal D C , Faucz Fabio R , Andriessen Victoria C , Nilubol Naris , Lee Chyi-Chia Richard , Ahlman Mark A , Hannah-Shmouni Fady , Stratakis Constantine A
Published: January 2021

Context

Primary pigmented nodular adrenocortical disease (PPNAD) is a rare cause of ACTH-independent Cushing syndrome (CS) associated mostly with Carney complex (CNC), a rare autosomal dominant multiple neoplasia syndrome. More than two-thirds of familial cases and approximately one-third of sporadic cases of CNC harbor germline inactivating PRKAR1A defects. Increasingly sensitive technologies for the detection of genetic defects such as next-generation sequencing (NGS) have further highlighted the importance of mosaicism in human disease.

Case Description

A 33-year-old woman was diagnosed with ACTH-independent CS with abdominal computed tomography showing bilateral micronodular adrenal hyperplasia with a left adrenal adenoma. She underwent left adrenalectomy with pathology demonstrating PPNAD with a 1.5-cm pigmented adenoma. DNA analysis by Sanger sequencing revealed 2 different PRKAR1A variants in the adenoma that were absent from DNA extracted from blood and saliva: c.682C > T and c.974-2A > G. “Deep” NGS revealed that 0.31% of DNA copies extracted from blood and saliva did in fact carry the c.682C > T variant, suggesting low-level mosaicism for this defect.

Conclusions

We present a case of PPNAD due to low-level mosaicism for a PRKAR1A defect which led to the formation of an adenoma due to a second, adrenal-specific, somatic PRKAR1A mutation. The identification of mosaicism for PRKAR1A, depending on the number and distribution of cells affected has implications for genetic counseling and tumor surveillance. This is the first recorded case of a patient with PRKAR1A mosaicism, PPNAD, and an adenoma forming due to complete inactivation of PRKAR1A in adrenal tissue from a second, somatic-only, PRKAR1A coding sequence mutation.
REsidual Neuromuscular Block Prediction Score Versus Train-of-Four Ratio and Respiratory Outcomes: A Retrospective Cohort Study
Authors: Patrocínio Maria D. , Shay Denys , Rudolph Maíra I. , Santer Peter , Grabitz Stephanie D. , Xu Xinling , Nabel Sarah , Bose Somnath , Eikermann Matthias
Published: January 2021

BACKGROUND:

Residual neuromuscular blockade is associated with an increased incidence of postoperative respiratory complications. The REsidual neuromuscular block Prediction Score (REPS) identifies patients at high risk for residual neuromuscular blockade after surgery.

METHODS:

A total of 101,510 adults undergoing noncardiac surgery under general anesthesia from October 2005 to December 2018 at a tertiary care center in Massachusetts were analyzed for the primary outcome of postoperative respiratory complications (invasive mechanical ventilation requirement within 7 postoperative days or immediate postextubation desaturation [oxygen saturation {Spo
2} <90%] within 10 minutes). The primary objective was to assess the association between the REPS and respiratory complications. The secondary objective was to compare REPS and train-of-four (TOF) ratio <0.90 on the strength of their association with respiratory complications.

RESULTS:

A high REPS (≥4) was associated with an increase in odds of respiratory complications (adjusted odds ratio [OR], 1.13 [95% confidence interval {CI}, 1.06-1.21]; P < .001). In 6224 cases with available TOF ratio measurements, a low TOF ratio (<0.9) was associated with respiratory complications (adjusted OR, 1.43 [95% CI, 1.11-1.85]; P = .006), whereas a high REPS was not (adjusted OR, 0.96 [95% CI, 0.74-1.23]; P = .73) (P = .018 for comparison between ORs).

CONCLUSIONS:

The REPS may be implemented as a screening tool to encourage clinicians to use quantitative neuromuscular monitoring in patients at risk of residual neuromuscular blockade. A positive REPS should be followed by a quantitative assessment of the TOF ratio.
“There Is Nothing Wrong about Being Money Grubbing!” Milton Friedman’s Provocative “Capitalism and the Jews” in Context, 1972–88
Authors: Vallois Nicolas , Chassonnery-Zaïgouche Cléo
Published: January 2021

In 1972, Milton Friedman gave a presidential lecture before the Mont Pèlerin Society titled “Capitalism and the Jews.” The lecture was subsequently published as an essay in the 1980s. This article focuses on Fried-man’s public interventions on the theme of capitalism and the Jews from the 1960s to the 1980s. We take a different perspectives from Jeff Lipkes’s recent paper on the topic, published in this journal. While Lipkes examines the internal content of Friedman’s arguments and their historical rectitude, we argue that “Capitalism and the Jews” shall not be read as a scholarly contribution to Jewish economic history. Flirting with stereotypes, Friedman was not looking to be theoretically sound and correct, but to persuade his audiences of the virtues of the free market. We therefore argue that “Capitalism and the Jews” has to be read within the surrounding political and polemical context of its writing and publication. Our article contributes to recent scholarship on the history of the complex relationships between conservatism and free-market ideas. It also provides a case study in the history of economic thought on discrimination and minorities.
Stabilizing and Strengthening the Affordable Care Act: Opportunities for a New Administration
Authors: McMorrow Stacey
Published: January 2021

For the past decade, the Affordable Care Act (ACA) has successfully reduced uninsurance and improved access to and affordability of health care services for millions of Americans. But the law was weakened when the Trump administration shortened the open enrollment period in the federal Marketplace, reduced outreach and enrollment funding, and revised the public charge rule, among other actions. The Biden administration will have the chance to reverse some of these changes and further strengthen the law to improve health care access and affordability. In this article, the author explores options for expanding access to affordable coverage and care for those who do not qualify for Medicaid or marketplace financial assistance and further discusses opportunities for increasing enrollment among those who are already eligible. The author also examines opportunities for expanding access to specific services, including reproductive health care, among those with insurance. Any attempts to modify or build on the ACA will likely be complicated by the ongoing coronavirus pandemic as well as slim Democratic majorities in the House and Senate, but regulatory solutions will likely be easier to achieve than those that require changes to federal law or state policy.
The Future of the Indispensable Insurer: The Biden Administration and Medicaid
Authors: Rosenbaum Sara
Published: January 2021

Medicaid presents both legislative and regulatory challenges and opportunities. As it moves a legislative agenda forward, the Biden administration also will confront a series of immediate regulatory matters, some of which have been made urgent because of pending judicial action. Chief among these pressing matters are ending Medicaid work requirements and block grant experiments, rescinding the public charge rule, ensuring optimal use of Medicaid's enrollment and renewal simplification tools, rescinding the Title X family planning rule (which has enormous implications for Medicaid beneficiaries), and, when the time comes, preparing states to wind down the “Families First” Medicaid maintenance of effort protection while avoiding erroneous beneficiary disenrollment. The administration could consider encouraging remaining nonexpansion states to pursue §1115 Medicaid expansion experiments; additionally, the administration could pursue Medicaid pandemic recovery demonstrations to support health system recovery during the long period that lies ahead. Thus, while certain advances must await legislation, the administration can move Medicaid forward through executive action.
Neural tube closure requires the endocytic receptor Lrp2 and its functional interaction with intracellular scaffolds
Authors: Kowalczyk Izabela , Lee Chanjae , Schuster Elisabeth , Hoeren Josefine , Trivigno Valentina , Riedel Levin , Görne Jessica , Wallingford John B. , Hammes Annette , Feistel Kerstin
Published: January 2021

Pathogenic mutations in the endocytic receptor LRP2 in humans are associated with severe neural tube closure defects (NTDs) such as anencephaly and spina bifida. Here, we have combined analysis of neural tube closure in mouse and in the African Clawed Frog Xenopus laevis to elucidate the etiology of Lrp2-related NTDs. Lrp2 loss of function impaired neuroepithelial morphogenesis, culminating in NTDs that impeded anterior neural plate folding and neural tube closure in both model organisms. Loss of Lrp2 severely affected apical constriction as well as proper localization of the core planar cell polarity (PCP) protein Vangl2, demonstrating a highly conserved role of the receptor in these processes, which are essential for neural tube formation. In addition, we identified a novel functional interaction of Lrp2 with the intracellular adaptor proteins Shroom3 and Gipc1 in the developing forebrain. Our data suggest that, during neurulation, motifs within the intracellular domain of Lrp2 function as a hub that orchestrates endocytic membrane removal for efficient apical constriction, as well as PCP component trafficking in a temporospatial manner.
Desafios, barreiras e aprendizagens com a remanufatura
Authors: Medeiros Flaviani Souto Bolzan , Simonetto Eugênio de Oliveira , Castro Hélio Cristiano Gomes Alves de
Published: January 2021

Este artigo tem como objetivo identificar os desafios, as barreiras e as aprendizagens com a atividade de remanufatura. Por meio de uma busca realizada na internet foram encontradas empresas de diferentes regiões do país que operam no setor. Desse modo, como procedimento de coleta, foi adotado o estudo de casos múltiplos e, como técnica de coleta, foi utilizada a entrevista semiestruturada, uma vez que a intenção era obter dos entrevistados o relato sobre o seu dia a dia e o seu ambiente de negócio na remanufatura. Os resultados mostraram que a atividade é carente de incentivos por parte do poder público. Outro ponto que prejudica é o custo da logística reversa. Há, ainda, a falta de locais apropriados na fase de descarte dos materiais, cujas condições de reaproveitamento no processo não são mais viáveis. Destarte, o estudo permitiu conhecer um pouco mais da remanufatura por meio do que as empresas contatadas vivenciam no mercado.
Maternal and perinatal Health Research Collaboration, India (MaatHRI): methodology for establishing a hospital-based research platform in a low and middle income country setting
Authors: Nair Manisha , Bezbaruah Babul , Bora Amrit Krishna , Bora Krishnaram , Chhabra Shakuntala , Choudhury Saswati S. , Choudhury Arup , Deka Dipika , Deka Gitanjali , Ismavel Vijay Anand , Kakoty Swapna D. , Koshy Roshine M. , Kumar Pramod , Mahanta Pranabika , Medhi Robin , Nath Pranoy , Rani Anjali , Roy Indrani , Sarma Usha , V Carolin Solomi , Talukdar Ratna Kanta , Zahir Farzana , Hill Michael , Kansal Nimmi , Nakra Reena , Baigent Colin , Knight Marian , Kurinczuk Jenny J.
Published: January 2021

Background: Maternal and perinatal Health Research collaboration, India (MaatHRI) is a research platform that aims to improve evidence-based pregnancy care and outcomes for mothers and babies in India, a country with the second highest burden of maternal and perinatal deaths. The objective of this paper is to describe the methods used to establish and standardise the platform and the results of the process.

Methods: MaatHRI is a hospital-based collaborative research platform. It is adapted from the UK Obstetric Surveillance System (UKOSS) and built on a pilot model (IndOSS-Assam), which has been extensively standardised using the following methods: (i) establishing a network of hospitals; (ii) setting up a secure system for data collection, storage and transfer; (iii) developing a standardised laboratory infrastructure; and (iv) developing and implementing regulatory systems.

Results: MaatHRI was established in September 2018. Fourteen hospitals participate across four states in India – Assam, Meghalaya, Uttar Pradesh and Maharashtra. The research team includes 20 nurses, a project manager, 16 obstetricians, two pathologists, a public health specialist, a general physician and a paediatrician. MaatHRI has advanced standardisation of data and laboratory parameters, real-time monitoring of data and participant safety, and secure transfer of data. Four observational epidemiological studies are presently being undertaken through the platform. MaatHRI has enabled bi-directional capacity building. It is overseen by a steering committee and a data safety and monitoring board, a process that is not normally used, but was found to be highly effective in ensuring data safety and equitable partnerships in the context of low and middle income countries (LMICs).

Conclusion: MaatHRI is the first prototype of UKOSS and other similar platforms in a LMIC setting. The model is built on existing methods but applies new standardisation processes to develop a collaborative research platform that can be replicated in other LMICs.
Human Proteinase 3, an important autoantigen of c-ANCA associated vasculitis, shares cross-reactive epitopes with serine protease allergens from mites: an in silico analysis
Authors: Buendía Emiro , Marlon Múnera , Parra Orlando , Sánchez María , Sánchez Andrés , Sánchez Jorge , Viasus Diego
Published: January 2021

Background: In autoimmune vasculitis, autoantibodies to Human Proteinase 3 (PR3), a human serine protease, seems to have a role on the inception of c-ANCA associated vasculitis. The origin of this autoreactive response remains unclear. However, for several autoreactive responses, molecular mimicry between environmental antigens and human proteins is key to trigger autoantibodies and finally autoimmunity manifestations. Considering that PR3 is a serine protease and house dust mite (HDM) group 3 allergens share this biochemical activity, the aim of this study was to identify cross-reactive epitopes between serine proteases from human and mites using an in silico approach.

Methods: Multi alignment among amino acid sequences of PR3 and HDM group 3 allergens was performed to explore identity and structural homology. ElliPro and BepiPred in silico tools were used to predict B and T cell epitopes. Consurf tool was used to conduct identification of conserved regions in serine proteases family.

Results: PR3 and HDM group 3 allergens shared moderate identity and structural homology (root mean square deviation < 1). One B cell cross reactive epitope among serine proteases was identified (29I, 30V, 31G, 32G, 34E, 36K, 37A, 38L, 39A and 54C) and two T cell epitopes.

Conclusions: PR3 have structural homology and share cross reactive epitopes with HDM group 3 allergens.
Botulism outbreak after the consumption of vegetarian pâté in the south of Viet Nam
Authors: Hung Le Quoc , Tho Vo Ngoc Anh , Khanh Do Thi Ngoc , Hien Vo Thi Thanh , Day Jeremy N. , Sang Nguyen Ngoc , Tam Hua Thoai , Thanh Ho Thi Chi , Ngan Nguyen Thi Thuy
Published: January 2021

Botulism is a potentially life-threatening disease caused by toxins produced by Clostridium botulinum. Here we reported a case series of six patients who presented with botulism following ingestion of commercially made pâté. The key features of presentation were acute onset of bilateral cranial nerve palsies and symmetrical descending weakness in the absence of fever resulting in the need for mechanical ventilation in all six patients. The clinical diagnosis of botulism was confirmed through the identification of C. botulinum from the suspected food source.  Given that botulinum antitoxin was not available in Vietnam at the time, and their severe status, all patients received a trial of plasma exchange therapy, but no clear benefit was seen.

Due to its rarity, diagnosing botulism is a challenge, demanding high clinical suspicion. Successful outcomes depend upon early recognition and rapid initiation of specific treatment with botulinum antitoxin. There is a need to improve global access to antitoxin.  These cases, the first in Viet Nam, serve as a reminder of the need to maintain the highest possible food hygiene and preservation practices.
INDUCTION OF MICROTUBING OF NEW PROMISING POTATO VARIETIES IN ASEPTIC CULTURE
Authors: Oves Elena , Gaitova Natal'ya , Shishkina Ol'ga
Published: January 2021

The studies were carried out with the aim of optimizing microtubing of promising potato varieties in aseptic culture. The experiments studied such factors as the use of vessels of various sizes (test tubes with a diameter of 25 mm and plastic containers 18x18 cm, into which 10 ml of agar and 400 ml of liquid nutrient medium, respectively, were poured, respectively), the density of planting plants in containers (40, 60 and 80 stem explants), the composition of the nutrient medium during ontogenesis, cultivation of mini-tubers from in vitro microplants (control) and microtubers (≥ 0.9 cm and 0.5 ... 0.9 cm in size). When studying the possibility of modifying the nutrient medium based on the Murashige-Skoog recipe to induce tuberization in one variant, the sucrose concentration during growth was changed from 2% before the formation of four internodes by 8% after this phase, the kinetin content during the entire observation period was 0.5 mg/l. In the second variant, microplants were kept on a medium with 6% sucrose and 0.25 mg/l kinetin throughout ontogenesis. The highest yield of microtubers of the standard fraction (27 ... 94%) with a multiplication factor of 0.8 ... 2.7 pcs/plant was noted in the variant with 60 cuttings placed in a container. When grown in test tubes with a change of medium, 1.0 ... 1.5 microtubers were collected per plant with a standard fraction yield of 64 ... 78%. The use of container technology with a similar alternation of nutrient media increased the yield of the standard fraction in most of the studied varieties to 75 ... 86%. In variants with a constant sucrose content in the nutrient medium (6%), a very low multiplication factor was noted, which did not compensate for a sufficiently high yield of the standard fraction, regardless of the laboratory vessel used. The multiplication factor of test tube microplants during planting in the ground was higher than when planting microtubers, with a high yield of the standard fraction
INFLUENCE OF AGROCHEMICAL SOIL PROPERTIES ON YIELD AND CHEMICAL COMPOSITION OF RAUSHAN BARLEY GRAIN
Authors: Fatykhov Ildus , Islamova Chulpan , Borisov Boris , Korepanova Elena , Goreeva Vera , Tihonova Ol'ga
Published: January 2021

The productivity of barley Raushan 24.9-53.1 tons per hectare on the farm (SKHPK) them. Michurin, Vavozhsky district of the Udmurt Republic for 2013-2019 had a positive average correlation (r = 0,46) with the pH of the arable layer, a positive weak correlation with the content in the arable layer of mobile phosphorus (r = 0,26), exchange potassium (r = 0.12) and humus (r = 0,12). The crop of 2017, had more potassium, sulfur, phosphorus, magnesium, silicon, calcium, sodium, manganese, tin, iron, rubidium, strontium, barium, zirconium, copper, zinc, titanium, selenium, nickel, vanadium, gadolinium, lithium, germanium, cobalt, tungsten, beryllium, cadmium, than their content in the grain of the 2018 crop. In 2018, the yield was lower by 14,2 centner per hectare of the 2017 crop, and barley kernels contained more bromine, aluminum, boron, molybdenum, thorium, chromium, cerium, lanthanum, niobium, tantalum, gallium