bluuebunny/crossref_metadata_2025 huggingface dataset:
Vascular Complications in Pediatric Pancreatitis: A Case Series
Authors: Dike Chinenye R. , Cress Gretchen , Fishman Douglas S. , Gonska Tanja , Ooi Chee Y. , Perito Emily R. , Troendle David , Tsai Cynthia M. , Lowe Mark E. , Uc Aliye
Published: July 2021

We reviewed INSPPIRE (International Study Group of Pediatric Pancreatitis: In Search for a Cure) database for splanchnic venous thrombosis or arterial pseudoaneurysms to determine the incidence, risk factors and outcomes of peripancreatic vascular complications in children with acute recurrent pancreatitis (ARP) or chronic pancreatitis (CP). Of 410 children with diagnostic imaging studies, vascular complications were reported in five (1.2%); two had ARP, three CP. The vascular events were reported during moderately severe or severe acute pancreatitis (AP) in four, mild AP in one. Venous thrombosis occurred in four, arterial pseudoaneurysm (left gastric artery) in one. Two patients with venous thrombosis were treated with anticoagulant, one achieved recanalization (splenic vein). In two patients who did not receive anticoagulants, one re-canalized. No adverse effects were observed with anticoagulants. The child with pseudoaneurysm underwent aneurysmal coiling. Anti-coagulants appear to be safe in children with acute pancreatitis, their long-term benefit needs to be further investigated.
A Quality Approach to Reducing the Occurrence of Occluded Leukocyte Reduction Filters During Platelet Transfusion
Authors: Wongsa Cory , Ghiyassi Nava , Cornelius Marah , Villamin Colleen , Tomczak Nancy , Bates Tonita
Published: July 2021

Background:

In 2019, an increase in clotted platelet filter occurrences was noted with the implementation of new leukocyte reduction filters through a volumetric pump.

Local Problem:

Occluded platelet filters contribute to delays in platelet transfusions, additional nursing workflows, and potential wastage of platelets, leading to staff and patient dissatisfaction.

Methods:

Direct observation of nursing practice with priming platelet filters identified opportunities for improvement. Education was designed incorporating manufacturer recommendations with results of the observations. Nursing education was disseminated through small group sessions, one-to-one teaching, tip sheets, and an e-learning video.

Results:

Nursing education interventions resulted in a 170% reduction in the reported monthly filter occlusion rate.

Conclusion:

Engagement of nurses in quality improvement processes and collaboration across departments led to a sustained decrease in the clotted platelet filters.
Nursing Interventions Increase Influenza Vaccination Quality Measures for Home Telehealth Patients
Authors: Rand Maxine L.
Published: July 2021

Background:

Influenza vaccinations are a preventive health quality measure. Home telehealth nursing staff interventions can reduce influenza disease burden and complications.

Purpose:

To improve seasonal flu vaccine rates using novel home telehealth clinical and technology interventions.

Methods:

A pre- and postintervention concurrent cohort study for 513 outpatients was conducted. Interventions included automated 2-way patient messaging using remote monitoring equipment, a new note template to record vaccination status in the electronic health record, and flu vaccine patient education.

Results:

Interventions resulted in vaccination rates of 70.4% for Veterans ages 19 to 65 years, and 81.7% for Veterans 66 years and older, exceeding national, regional, and local Veterans Administration targets.

Conclusions:

Two-way messaging and standardized documentation increased rates. Declinations persisted despite education. Reasons included fear of side effects, and rarely leaving home due to the COVID-19 pandemic. Nursing interventions can increase influenza vaccination quality measures for primary care home telehealth patients.
Geographic Distance to Extracorporeal Life Support Centers for Pediatric Patients Within the Continental United States
Authors: Farr Bethany J. , McEvoy L. T. Christian S. , Ross-Li Dan , Rice-Townsend Samuel E. , Ricca Robert L.
Published: July 2021

OBJECTIVES:

Distance to subspecialty surgical care is a known impediment to the delivery of high-quality healthcare. Extracorporeal life support is of benefit to pediatric patients with specific medical conditions. Despite a continued increase in the number of extracorporeal life support centers, not all children have equal access to extracorporeal life support due to geographic constraints, creating a potential disparity in healthcare. We attempted to better define the variation in geographic proximity to extracorporeal life support centers for pediatric patients using the U.S. Decennial Census.

DESIGN:

A publicly available listing of voluntarily reporting extracorporeal life support centers in 2019 and the 2010 Decennial Census were used to calculate straight-line distances between extracorporeal life support zip code centroids and census block centroids. Disparities in distance to care associated with urbanization were analyzed.

SETTING:

United States.

PATIENTS:

None.

INTERVENTIONS:

Large database review.

MEASUREMENTS AND MAIN RESULTS:

There were 136 centers providing pediatric extracorporeal life support in 2019. The distribution varied by state with Texas, California, and Florida having the most centers. Over 16 million children (23% of the pediatric population) live greater than 60 miles from an extracorporeal life support center. Significant disparity exists between urban and rural locations with over 47% of children in a rural setting living greater than 60 miles from an extracorporeal life support center compared with 17% of children living in an urban setting.

CONCLUSIONS:

Disparities in proximity to extracorporeal life support centers were present and persistent across states. Children in rural areas have less access to extracorporeal life support centers based upon geographic distance alone. These findings may affect practice patterns and treatment decisions and are important to the development of regionalization strategies to ensure all children have subspecialty surgical care available to them, including extracorporeal life support.
Communication Patterns During Routine Patient Care in a Pediatric Intensive Care Unit: The Behavioral Impact of In Situ Simulation
Authors: Ulmer Francis F. , Lutz Andrea M. , Müller Fabienne , Riva Thomas , Bütikofer Lukas , Greif Robert
Published: July 2021

Objective

Effective communication minimizes medical errors and leads to improved team performance while treating critically ill patients. Closed-loop communication is routinely applied in high-risk industries but remains underutilized in healthcare. Simulation serves as an educational tool to introduce, practice, and appreciate the efficacy of closed-loop communication.

Methods

This observational before-and-after study investigates behavioral changes in communication among nurses brought on by simulation team training in a pediatric intensive care unit (PICU). The communication patterns of PICU nurses, who had no prior simulation experience, were observed during routine bedside care before and after undergoing in situ simulation.

One month before and 1 and 3 months after simulation (intervention), 2 trained raters recorded nurse communications relative to callouts, uttered by the sender, and callbacks, reciprocated by the recipient. The impact of simulation on communication patterns was analyzed quantitatively.

Results

Among the 15 PICU nurses included in this study, significant changes in communication behavior were observed during patient care after communication-focused in situ simulation. The PICU nurses were significantly less likely to let a callout go unanswered during clinical routine. The effect prevailed both 1 month (P = 0.039) and 3 months (P = 0.033) after the educational exposure.

Conclusions

This observational before-and-after study describes the prevalence and pattern of communication among PICU nurses during routine patient care and documents PICU nurses transferring simulation-acquired communication skills into their clinical environment after a single afternoon of in situ simulation. This successful transfer of simulation-acquired skills has the potential to improve patient safety and outcome.
Late-phase dominance of a single epitope-specific CD8+ T-cell response in passive neutralizing antibody-infused simian immunodeficiency virus controllers
Authors: Kanno Yoshiaki , Hau Trang Thi Thu , Kurokawa Rise , Nomura Takushi , Nishizawa Masako , Matano Tetsuro , Yamamoto Hiroyuki
Published: July 2021

Objective:

Analysis of the quantity and quality of epitope-specific CD8+ T-cell responses is crucial for understanding the mechanism of HIV/simian immunodeficiency virus (SIV) replication control. We have previously shown that acute-phase passive infusion of neutralizing antibodies (NAbs) results in augmented broad T-cell responses and robust SIVmac239 control in rhesus macaques. Analyzing long-term dynamics of CD8+ T-cell responses in these SIV controllers provides important insights into designing lasting anti-HIV immunity.

Design:

We analyzed dynamics and metabolic/functional profiles of SIV-specific CD8+ T-cell responses in rhesus macaques that controlled SIVmac239 replication following acute-phase passive NAb infusion.

Methods:

SIV epitope-specific CD8+ T-cell responses in peripheral blood at multiple chronic-phase time points were investigated in four passive NAb-infused SIV controllers. In particular, expression patterns of Eomesodermin (Eomes), phosphorylated AMP kinase (pAMPK), CD28 and programmed death-1 (PD-1) were examined.

Results:

In the NAb-infused SIV controllers, a single epitope-specific CD8+ T-cell response detected from acute infection and maintaining low levels up to year 1 showed a surge thereafter, up to year 2 postchallenge. Retention of an effector-skewed and unexhausted Eomes-high/pAMPK-low/CD28-negative/PD-1-low subpopulation in these epitope-specific CD8+ T cells implicated their front-line commitment in residual viral replication control.

Conclusion:

In long-term SIV control following acute-phase passive NAb infusion, a single-epitope, high-quality CTL response was dominantly induced in the chronic phase. These results likely describe one favorable pattern of immunodominant epitope-specific CD8+ T-cell preservation and suggest the importance of incorporating metabolic marker signatures for understanding NAb/T-cell synergism-based HIV/SIV control.
A Novel Technique of Negative Pressure Wound Therapy for Pharyngeal Cutaneous Fistulas Around Tracheostomas
Authors: Kashimura Tsutomu , Yoshida Kotoku , Soejima Kazutaka
Published: July 2021

Fistula formation after free jejunal transplantation is relatively common; however, treating esophago-jejunal anastomosis fistulas is difficult. Herein, the authors report a case of esophago-jejunal anastomosis fistula adjacent to the permanent tracheostoma after free jejunal transplantation that was closed using negative pressure wound therapy (NPWT). A 70-year-old man underwent total pharyngo-laryngo-cervical esophagectomy and free jejunal transplantation for hypopharyngeal cancer. After reconstruction, an esophago-jejunal anastomosis fistula developed on the permanent tracheostoma margin. The fistula was sutured, but it recurred. Therefore, NPWT was performed to close the fistula via the bridge method and balloon compression using a tracheal cannula. NPWT requires the maintenance of local negative pressure. However, esophago-jejunal anastomosis fistula formation after free jejunal transplantation makes this difficult because of the unevenness of the permanent tracheostoma and moist surface of the tracheal mucosa. NPWT performed using the bridge method and balloon compression is an effective option for fistula treatment.
High-sensitivity Cardiac Troponin Is Not Associated With Acute Cellular Rejection After Heart Transplantation
Authors: Fitzsimons Sarah J. , Evans Jonathan D. W. , Rassl Doris M. , Lee Kuan Ken , Strachan Fiona E. , Parameshwar Jayan , Mills Nicholas L. , Pettit Stephen J.
Published: July 2021

Background.

Acute cellular rejection (ACR) is common in the first year after cardiac transplantation, and regular surveillance endomyocardial biopsy (EMB) is required. An inexpensive, simple noninvasive diagnostic test would be useful. Prior studies suggest cardiac troponin (cTn) has potential as a “rule-out” test to minimize the use of EMB. Our aim was to determine whether a new high-sensitivity cardiac troponin I (hs-cTnI) assay would have utility as a “rule-out” test for ACR after heart transplantation.

Methods.

Blood samples at patient follow-up visits were collected and stored over a period of 5 y. Serum cTnI concentrations were measured using the ARCHITECT
STAT
hs-cTnI assay and compared with an EMB performed on the same day. Receiver-operator curve analysis based on mixed-effects logistic regression models that account for repeated measurements in individuals was performed to determine a serum troponin level below which ACR could be reliably excluded.

Results.

One hundred seventy patients had 883 serum hs-cTnI results paired to a routine surveillance EMB. Fifty-one (6%) EMB showed significant ACR (grade ≥2R). Receiver-operator curve analysis approximated the null hypothesis area under the curve 0.509 (95% CI, 0.428-0.591). Sub-analysis including repeated hs-cTnI levels in a single individual, and early (<3 mo) EMB also showed no diagnostic utility of hs-cTnI measurement (area under the curve 0.512).

Conclusions.

In the largest published study to date, we found no association between hs-cTnI concentration and the presence of significant ACR on surveillance EMB. Measurement of hs-cTnI may not be a useful technique for diagnosis or exclusion of ACR after heart transplantation.
Ultra-Deep Sequencing Reveals the Mutational Landscape of Classical Hodgkin Lymphoma
Authors: Gomez Felicia , Mosior Matthew , McMichael Joshua , Skidmore Zachary L. , Duncavage Eric J. , Miller Christopher A. , Abel Haley J. , Li Yi-Shan , Krysiak Kilannin , Russler-Germain David A. , Watkins Marcus P. , Ramirez Cody , Schmidt Alina , Rodrigues Fernanda Martins , Trani Lee , Khanna Ajay , Wagner Julia A. , Fulton Robert S. , Fronick Catrina , O’Laughlin Michelle , Schappe Timothy , Cashen Amanda , Mehta-Shah Neha , Kahl Brad S. , Walker Jason , Bartlett Nancy L. , Griffith Malachi , Fehniger Todd A. , Griffith Obi L.
Published: July 2021

The malignant Hodgkin and Reed Sternberg (HRS) cells of classical Hodgkin lymphoma (cHL) are scarce in affected lymph nodes, creating a challenge to detect driver somatic mutations. As an alternative to cell purification techniques, we hypothesized that ultra-deep exome sequencing would allow genomic study of HRS cells, thereby streamlining analysis and avoiding technical pitfalls. To test this, 31 cHL tumor/normal pairs were exome sequenced to ∼1000x median depth of coverage. An orthogonal error-corrected sequencing approach verified >95% of the discovered mutations. We identified mutations in genes novel to cHL including:CDH5andPCDH7;novel mutations inIL4R, and a novel pattern of recurrent mutations in pathways regulating Hippo signaling. This study provides proof-of-principle that ultra-deep exome sequencing can be utilized to identify recurrent mutations in HRS cells, allowing for the analysis for clinically relevant genomic variants in large cohorts of cHL patients.
Evidence of widespread endemic populations of highly multidrug-resistant Klebsiella pneumoniae seen concurrently through the lens of two hospital intensive care units in Vietnam
Authors: Pham My H. , Hoi Le Thi , Beale Mathew A. , Khokhar Fahad , Hoa Nguyen Thi , Musicha Patrick , Blackwell Grace , Long Hoang Bao , Huong Dang Thi , Binh Nguyen Gia , Co Dao Xuan , Giang Tran , Bui Cuong , Tran Hai Ninh , Bryan James , Herrick Archie , Feltwell Theresa , Nadjm Behzad , Parkhill Julian , van Doorn H. Rogier , Trung Nguyen Vu , Van Kinh Nguyen , Estée Török M. , Thomson Nicholas R.
Published: July 2021

Background

Extended spectrum beta-lactamases-producing (ESBL-P) and/or carbapenem-resistant (CR) Klebsiella pneumoniae have severely restricted available treatment options in healthcare settings in Vietnam. Understanding the diversity and transmission mechanisms of ESBL- and carbapenemase-encoding K. pneumoniae is important in both hospital and community settings for patient management.

Methods

We conducted a 6-month prospective cohort study of 69 Intensive care unit (ICU) patients from two hospitals in Hanoi, Vietnam. Longitudinally collected samples from patients and the ICU environment were cultured on selective media, and 357 K. pneumoniae colonies were whole genome sequenced. We performed phylogenetic analyses, and correlated phenotypic antimicrobial susceptibility testing with genotypic features of K. pneumoniae isolates. We constructed transmission networks of patient samples, relating ICU admission times and locations with genetic similarity of infecting K. pneumoniae.

Findings

Despite being geographically and clinically separated, the two hospitals shared closely related strains carrying the same array of antimicrobial resistance genes. Many patients carried the same resistant K. pneumoniae clone from admission to discharge. 45.9% of total isolates carried both ESBL- and carbapenemase-encoding genes, with high minimum inhibitory concentrations. We found a novel co-occurrence of blaKPC-2 and blaNDM-1 in 46. 6% of samples from the globally successful ST15 lineage.

Interpretation

These results highlight the high prevalence of ESBL-positive carbapenem-resistant K. pneumoniae in Vietnamese ICUs. Through studying K. pneumoniae ST15 in detail, we illustrated how important resistance genes are coalescing in stains carried broadly by patients entering the two hospitals directly or through referral.

Funding

This study was supported by the Medical Research Council Newton Fund, United Kingdom (grant MR/N029399/1); the Ministry of Science and Technology, Vietnam (grant HNQT/SPÐP/04.16); This research was funded in whole by the Wellcome Trust (grant 206194). For the purpose of Open Access, the author has applied a CC BY public copyright licence to any Author Accepted Manuscript version arising from this submission.
Awareness regarding Anemia in Antenatal women attending tertiary care hospitals in South India
Authors: Thapar Rekha , Sinha Mehul , Rajendiran Hemasri , Jabeen Noora , Bajaj Vaibhav , Richard Tony
Published: July 2021

Disclaimer statement: The authors have withdrawn this manuscript because proper permission was not taken from the concerned authorities before the submission of this manuscript. Therefore,the authors do not wish this work to be cited as a reference for the project. If you have any questions, please contact the corresponding author.
Importance of epidemic severity and vaccine mode of action and availability for delaying the second vaccine dose
Authors: Berec Luděk , Levínský René , Weiner Jakub , Šmíd Martin , Neruda Roman , Vidnerová Petra , Suchopárová Gabriela
Published: July 2021

Following initial optimism regarding the potential for rapid vaccination, delays and shortages in vaccine supplies have occurred in many countries. Various strategies to counter this gloomy reality and speed up vaccination have been set forth, of which the most popular approach has been to delay the second vaccine dose for a longer period than originally recommended by the manufacturers. Controversy has surrounded this strategy, and overly simplistic models have been developed to shed light on this issue. Here we use three different epidemic models, all accounting for the actual COVID-19 epidemic in the Czech Republic, including the rise and eventual prevalence of the B.1.1.7 variant of SARS-CoV-2 virus and real vaccination rollout strategy, to explore when delaying the second vaccine dose from 21 days to 42 days is advantageous. Using the numbers of COVID-19-related deaths as a quantity for comparing various model scenarios, we find that vaccine mode of action at the beginning of the infection course (preventing contagion and symptom appearance), mild epidemic and sufficient vaccine supply rate call for the original inter-delay scenario of 21 days regardless of vaccine efficacy. On the contrary, for vaccine mode of action at the end of infection course (preventing severe symptoms and death), severe epidemic and low vaccine supply rate, the 42-day inter-dose period is preferable, at any plausible vaccine efficacy.

One sentence summary

We address when delaying the second vaccine dose is advantageous, considering various epidemic severities and various vaccine actions and availabilities.
Human genotype-to-phenotype predictions: boosting accuracy with nonlinear models
Authors: Medvedev Aleksandr , Sharma Satyarth Mishra , Tsatsorin Evgenii , Nabieva Elena , Yarotsky Dmitry
Published: July 2021

Genotype-to-phenotype prediction is a central problem of human genetics. In recent years, it has become possible to construct complex predictive models for phenotypes, thanks to the availability of large genome data sets as well as efficient and scalable machine learning tools. In this paper, we make a three-fold contribution to this problem. First, we ask if state-of-the-art nonlinear predictive models, such as boosted decision trees, can be more efficient for phenotype prediction than conventional linear models. We find that this is indeed the case if model features include a sufficiently rich set of covariates, but probably not otherwise. Second, we ask if the conventional selection of single nucleotide polymorphisms (SNPs) by genome wide association studies (GWAS) can be replaced by a more efficient procedure, taking into account information in previously selected SNPs. We propose such a procedure, based on a sequential feature importance estimation with decision trees, and show that this approach indeed produced informative SNP sets that are much more compact than when selected with GWAS. Finally, we show that the highest prediction accuracy can ultimately be achieved by ensembling individual linear and nonlinear models. To the best of our knowledge, for some of the phenotypes that we consider (asthma, hypothyroidism), our results are a new state-of-the-art.
Disinfection of SARS-CoV-2 using UVC reveals wavelength sensitivity contributes towards rapid virucidal activity
Authors: Mariita Richard M. , Wilson Miller Amy C. , Randive Rajul V. , McKay Lindsay G. A. , Storm Nadia , Griffiths Anthony
Published: July 2021

SARS-CoV-2 can be disinfected using ultraviolet-C (UVC) light. For effective inactivation strategies, design and implementation, knowledge of UVC wavelength sensitivity, and disinfection rate of the relevant pathogen are required. This study aimed to determine the inactivation profile of SARS-CoV-2 using UVC irradiation with different wavelengths. Specifically, the study determined dosage, inactivation levels, and wavelength sensitivity of SARS-CoV-2. Assessment of SARS-CoV-2 (isolate USA/WA1-2020) inactivation at peak wavelengths of 259, 268, 270, 275 and 280 nm was performed using a plaque assay method. A UVC dose of 3.1 mJ/cm2 using 259 and 268 nm arrays yielded log reduction values (LRV) of 2.32 and 2.44, respectively. With a dose of 5 mJ/cm2, arrays of peak wavelengths at 259 and 268 nm obtained similar inactivation levels (LRV 2.97 and 2.80 respectively). The arrays of longer wavelength (270, 275 and 280 nm), demonstrated lower performances (≤LRV 2.0) when applying an irradiation dose of 5 mJ/cm2. Additional study with the 268 nm array revealed that a dose of 6.25 mJ/cm2 is enough to obtain a LRV of 3. These results suggest that 259 and 268 nm are the most efficient wavelengths for SARS-CoV-2 inactivation compared to longer UVC wavelengths, allowing the calculation of disinfection systems efficacy.
FiMAP: A Fast Identity-by-Descent Mapping Test for Biobank-scale Cohorts
Authors: Chen Han , Naseri Ardalan , Zhi Degui
Published: July 2021

Although genome-wide association studies (GWAS) have identified tens of thousands of genetic loci, the genetic architecture is still not fully understood for many complex traits. Most GWAS and sequencing association studies have focused on single nucleotide polymorphisms or copy number variations, including common and rare genetic variants. However, phased haplotype information is often ignored in GWAS or variant set tests for rare variants. Here we leverage the identity-by-descent (IBD) segments inferred from a random projection-based IBD detection algorithm in the mapping of genetic associations with complex traits, to develop a computationally efficient statistical test for IBD mapping in biobank-scale cohorts. We used sparse linear algebra and random matrix algorithms to speed up the computation, and a genome-wide IBD mapping scan of more than 400,000 samples finished within a few hours. Simulation studies showed that our new method had well-controlled type I error rates under the null hypothesis of no genetic association in large biobank-scale cohorts, and outperformed traditional GWAS approaches and variant set tests when the causal variants were untyped and rare, or in the presence of haplotype effects. We also applied our method to IBD mapping of six anthropometric traits using the UK Biobank data and identified a total of 3,442 associations, 2,224 (65%) of which remained significant after conditioning on independent association variants in the ± 3 cM flanking regions from GWAS.
Low dose mRNA-1273 COVID-19 vaccine generates durable T cell memory and antibodies enhanced by pre-existing crossreactive T cell memory
Authors: Mateus Jose , Dan Jennifer M. , Zhang Zeli , Moderbacher Carolyn Rydyznski , Lammers Marshall , Goodwin Benjamin , Sette Alessandro , Crotty Shane , Weiskopf Daniela
Published: July 2021

Understanding human immune responses to SARS-CoV-2 RNA vaccines is of interest for a panoply of reasons. Here we examined vaccine-specific CD4+ T cell, CD8+ T cell, binding antibody, and neutralizing antibody responses to the 25 μg Moderna mRNA-1273 vaccine over 7 months post-immunization, including multiple age groups, with a particular interest in assessing whether pre-existing crossreactive T cell memory impacts vaccine-generated immunity. Low dose (25 μg) mRNA-1273 elicited durable Spike binding antibodies comparable to that of convalescent COVID-19 cases. Vaccine-generated Spike memory CD4+ T cells 6 months post-boost were comparable in quantity and quality to COVID-19 cases, including the presence of TFH cells and IFNγ-expressing cells. Spike CD8+ T cells were generated in 88% of subjects, with equivalent percentages of CD8+ T cell memory responders at 6 months post-boost compared to COVID-19 cases. Lastly, subjects with pre-existing crossreactive CD4+ T cell memory had increased CD4+ T cell and antibody responses to the vaccine, demonstrating a biological relevance of SARS-CoV-2 crossreactive CD4+ T cells.

One-Sentence Summary

The mRNA-1273 vaccine induces a durable and functional T cell and antibody response comparable to natural infection.
Structural connectivity of subthalamic nucleus stimulation for improving freezing of gait
Authors: Strelow Joshua N. , Baldermann Juan C. , Dembek Till A. , Jergas Hannah , Petry-Schmelzer Jan N. , Schott Frederik , Dafsari Haidar , Moll Christian K.E. , Hamel Wolfgang , Gulberti Alessandro , Visser-Vandewalle Veerle , Fink Gereon R. , Pötter-Nerger Monika , Barbe Michael T.
Published: July 2021

Gait impairments such as freezing of gait (FOG) are among the most common and disabling symptoms of Parkinson’s disease (PD). While the efficacy of deep brain stimulation (DBS) of the subthalamic nucleus (STN) in patients with early or advanced PD has been proven in large randomised controlled trials, its effect on gait impairments is still insufficiently understood. Moreover, there is uncertainty about pathways that need to be modulated to improve gait impairments. In this bi-centric study, we investigated how STN-DBS alters FOG in 47 subjects with PD. We assessed freezing prevalence and severity using the Freezing of Gait Questionnaire and Item 14 of the Unified Parkinson’s Disease Rating Scale-II. Using a model of publicly available basal-ganglia pathways we determined a connectivity profile for postoperative changes in FOG. Compared to preoperative baseline, freezing of gait significantly improved six months postoperatively, marked by reduced frequency and duration of freezing episodes. We found that optimal stimulation sites for improving freezing of gait structurally connected to primary and supplementary motor areas, the dorsolateral prefrontal cortex and to the globus pallidus. Stimulation of the lenticular fasciculus was associated with worsening of freezing of gait. Our findings highlight the need for optimal identification and characterisation for network structures that can be implemented in stereotactic planning and can additionally pose a target for postoperative stimulation strategies.
Genome-Wide Association Study of Estradiol Levels, and the Causal Effect of Estradiol on Bone Mineral Density
Authors: Schmitz Daniel , Ek Weronica E. , Berggren Elin , Höglund Julia , Karlsson Torgny , Johansson Åsa
Published: July 2021

Context

Estradiol is the primary female sex hormone and plays an important role for skeletal health in both sexes. Several enzymes are involved in estradiol metabolism but few genome-wide association studies (GWAS) have been performed to characterize the genetic contribution to variation in estrogen levels.

Objective

Identify genetic loci affecting estradiol levels and estimate causal effect of estradiol on bone mineral density (BMD).

Design

We performed GWAS for estradiol in males (N = 147,690) and females (N = 163,985) from UK Biobank (UKB). Estradiol was analyzed as a binary phenotype; above/below detection limit (175 pmol/L). We further estimated the causal effect of estradiol on BMD using Mendelian randomization.

Results

We identified 14 independent loci associated (P<5×10−8) with estradiol levels in males, of which one (CYP3A7) was genome-wide and seven nominally (P<0.05) significant in females. In addition, one female specific locus was identified. Most loci contain functionally relevant genes that have not been discussed in relation to estradiol levels in previous GWAS. For example, SRD5A2, which encodes a steroid 5-alpha reductase that is involved in processing androgens, and UGT3A1 and UGT2B7 which encode enzymes likely to be involved in estradiol elimination. The allele that tags the O blood group, at the ABO locus, was associated with higher estradiol levels. We identified a causal effect of high estradiol levels on increased BMD in both males (P=1.58×10−11) and females (P=7.48×10−6).

Conclusion

Our findings further support the importance of the body’s own estrogen to maintain skeletal health in males and in females.
Adulthood asthma as a consequence of childhood adversity: a systematic review of epigenetically affected genes
Authors: Saygideğer Yasemin , Özkan Hakan , Baydar Oya , Yılmaz Özge
Published: July 2021

There is an accumulating data that shows relation between childhood adversity and vulnerability to chronic diseases as well as epigenetic influences that in turn give rise to these diseases. Asthma is one of the chronic diseases that is influenced from genetic regulation of the inflammatory biomolecules and therefore the hypothesis in this research was childhood adversity might have caused epigenetic differentiation in the asthma related genes in the population who had childhood trauma. To test this hypothesis, the literature was systematically reviewed to extract epigenetically modified gene data of the adults who had childhood adversity, and affected genes were further evaluated for their association with asthma. PRISMA guidelines were adopted and PubMed and Google Scholar were included in the searched databases, to evaluate epigenetic modifications in asthma related genes of physically, emotionally or sexually abused children. After retrieving a total of 12,085 articles, 36 of them were included in the study. Several genes and pathways that may contribute to pathogenesis of asthma development, increased inflammation or response to asthma treatment were found epigenetically affected by childhood traumas. Childhood adversity, causing epigenetic changes in DNA, may lead to asthma development or influence the course of the disease and therefore should be taken into account for the prolonged health consequences.
Simulated Diagnostic Performance of Ultra-Low-Field MRI: Harnessing Open-Access Datasets to Evaluate Novel Devices
Authors: Arnold T. Campbell , Baldassano Steven N. , Litt Brian , Stein Joel M.
Published: July 2021

The purpose of this study is to demonstrate a method for virtually evaluating novel imaging devices using machine learning and open-access datasets, here applied to a new, ultra-low-field strength (ULF), 64mT, portable MRI device. Paired 3T and 64mT brain images were used to develop and validate a transformation converting standard clinical images to ULF-quality images. Separately, 3T images were aggregated from open-source databases spanning four neuropathologies: low-grade glioma (LGG, N=76), high-grade glioma (HGG, N=259), stroke (N=28), and multiple sclerosis (MS, N=20). The transformation method was then applied to the open-source data to generate simulated ULF images for each pathology. Convolutional neural networks (DenseNet-121) were trained to detect pathology in axial slices from either 3T or simulated 64 mT images, and their relative performance was compared to characterize the potential diagnostic capabilities of ULF imaging. Algorithm performance was measured using area under the receiver operating characteristic curve. Across all cohorts, pathology detection was similar between 3T and simulated 64mT images (LGG: 0.97 vs. 0.98; HGG: 0.96 vs. 0.95; stroke: 0.94 vs. 0.94; MS: 0.90 vs 0.87). Pathology detection was further characterized as a function of lesion size, intensity, and contrast. Simulated images showed decreasing sensitivity for lesions smaller than 4 cm2(∼2.25 cm in diameter). While simulations cannot replace prospective trials during the evaluation of medical devices, they can provide guidance and justification for prospective studies. Simulated data derived from open-source imaging databases may facilitate testing and validation of new imaging devices.

Highlights

Ultra-low-field, point-of-care MRI has potential to detect a range of pathologies including brain tumors, strokes, and multiple sclerosis. However, determining the diagnostic capabilities and appropriate use case for such devices requires further prospective studies.

Open-source image datasets provide a powerful tool for accelerating imaging research and enable simulated trials that can guide prospective clinical trials or device development.
Heart Rate Variability as a Prospective Predictor of Early COVID-19 Symptoms
Authors: Ponomarev Alexey , Tyapochkin Konstantin , Surkova Ekaterina , Smorodnikova Evgeniya , Pravdin Pavel
Published: July 2021

Heart rate variability (HRV) is the fluctuation in the time interval between consecutive heartbeats, the measurement of which is a non-invasive method for assessing the autonomic status. The autonomic nervous system plays an important role in physiological situations, and in various pathological processes such as in cardiovascular diseases and viral infections. This study examined the cardiac autonomic responses, as measured by HRV before, after, and during coronavirus disease. In this study, we used beat interval data extracted from the Welltory app from 14 eligible subjects (9 men and 5 women) with a mean age (SD) of 44 (8.7) years. HRV analysis was performed through an assessment of time-domain indices (SDNN and RMSSD). Group analysis did not reveal any statistical difference between HRV metrics before, during, and after COVID-19. However, HRV at the individual level showed a statistically significant individual change during COVID-19 in some users. These data further support the usefulness of using individual-level HRV tracking for the detection of early diseases inclusive of COVID-19.
Anti-spike antibody response to natural SARS-CoV-2 infection in the general population
Authors: Wei Jia , Matthews Philippa C. , Stoesser Nicole , Maddox Thomas , Lorenzi Luke , Studley Ruth , Bell John I , Newton John N , Farrar Jeremy , Diamond Ian , Rourke Emma , Howarth Alison , Marsden Brian D. , Hoosdally Sarah , Jones E Yvonne , Stuart David I , Crook Derrick W. , Peto Tim E. A. , Pouwels Koen B. , Walker A. Sarah , Eyre David W. ,   the COVID-19 Infection Survey team
Published: July 2021

We estimated the duration and determinants of antibody response after SARS-CoV-2 infection in the general population using representative data from 7,256 United Kingdom COVID-19 infection survey participants who had positive swab SARS-CoV-2 PCR tests from 26-April-2020 to 14-June-2021. A latent class model classified 24% of participants as ‘non-responders’ not developing anti-spike antibodies. These seronegative non-responders were older, had higher SARS-CoV-2 cycle threshold values during infection (i.e. lower viral burden), and less frequently reported any symptoms. Among those who seroconverted, using Bayesian linear mixed models, the estimated anti-spike IgG peak level was 7.3-fold higher than the level previously associated with 50% protection against reinfection, with higher peak levels in older participants and those of non-white ethnicity. The estimated anti-spike IgG half-life was 184 days, being longer in females and those of white ethnicity. We estimated antibody levels associated with protection against reinfection likely last 1.5-2 years on average, with levels associated with protection from severe infection present for several years. These estimates could inform planning for vaccination booster strategies.
ERAP1, ERAP2, and two copies of HLA-Aw19 alleles increase the risk for Birdshot Chorioretinopathy in HLA-A29 carriers
Authors: Gelfman Sahar , Monnet Dominique , Ligocki Ann J. , Tabary Thierry , Moscati Arden , Bai Xiaodong , Freudenberg Jan , Cooper Blerta , Kosmicki Jack A. , Wolf Sarah ,   Regeneron Genetics Center, Ferreira Manuel A. R. , Overton John , Weyne Jonathan , Stahl Eli A. , Baras Aris , Romano Carmelo , Cohen Jacques H. M. , Coppola Giovanni , Brézin Antoine
Published: July 2021

Purpose

Birdshot Chorioretinopathy (BSCR) is strongly associated with HLA-A29. This study was designed to elucidate the genetic modifiers of BSCR in HLA-A29 carriers.

Methods

We sequenced the largest BSCR cohort to date, including 286 cases and 108 HLA-A29 positive controls to perform genome wide common and rare variant associations. We further typed the HLA alleles of cases and 45,386 HLA-A29 controls of European ancestry to identify HLA alleles that associate with BSCR risk.

Results

Carrying a second allele that belongs to the HLA-Aw19 broad antigen family (including HLA-A29, A30, A31, and A33) increases the risk for BSCR (OR=4.44, p=2.2e-03). This result was validated by comparing allele frequencies to large HLA-A29-controlled cohorts (n=45,386, OR>2.5, p<1.3e-06). We also confirm that ERAP1 and ERAP2 haplotypes modulate the risk for disease within our HLA-A29 controlled cohort. A meta-analysis with an independent dataset confirmed that ERAP1 and ERAP2 haplotypes modulate the risk for disease at a genome-wide significant level: ERAP1-rs27432 (OR 2.46; 95% CI 1.85-3.26; p=4.07e-10), an eQTL decreasing ERAP1 expression, and ERAP2-rs10044354 (OR 1.95; 95% CI 1.55-2.44; p=6.2e-09), an eQTL increasing ERAP2 expression. Furthermore, ERAP2-rs2248374 that disrupts ERAP2 expression is protective (OR 0.56; 95% CI [0.45-0.70]; p=2.39e-07). BSCR risk is additively increased when combining ERAP1/ERAP2 risk genotypes with two copies of HLA-Aw19 alleles (OR 13.53; 95% CI 3.79-54.77, p=1.17e-05).

Conclusions

The genetic factors increasing BSCR risk demonstrate a pattern of increased processing, as well as increased presentation of ERAP2 specific peptides. This suggests a mechanism in which exceeding a peptide presentation threshold activates the immune response in choroids of A29 carriers.
An executive center for the intake of liquids
Authors: Dempsey Bowen , Sungeelee Selvee , Bokiniec Philip , Chettouh Zoubida , Diem Séverine , Autran Sandra , Harrell Evan R. , Poulet James F.A. , Birchmeier Carmen , Carrey Harry , Genovesio Auguste , McMullan Simon , Goridis Christo , Fortin Gilles , Brunet Jean-François
Published: July 2021

It has long been known that orofacial movements for feeding can be triggered, coordinated, and often rhythmically organized at the level of the brainstem, without input from higher centers. We uncover two nuclei that can organize the movements for ingesting fluids in mammals. These neuronal groups, defined by unique transcriptional codes and developmental origins, IRtPhox2b and Peri5Atoh1, are located, respectively, in the intermediate reticular formation of the medulla and around the motor nucleus of the trigeminal nerve. They are premotor to all jaw-opening and tongue muscles. Stimulation of either, in awake animals, opens the jaw, while IRtPhox2b alone also protracts the tongue. Moreover, stationary stimulation of IRtPhox2b entrains a rhythmic alternation of tongue protraction and retraction, synchronized with jaw opening and closing, that mimics lapping. Finally, fiber photometric recordings show that IRtPhox2b is active during volitional lapping. Our study identifies one of the long hypothesized subcortical nuclei underpinning a stereotyped feeding behavior.
3D printed lung on a chip device with a stretchable nanofibrous membrane for modeling ventilator induced lung injury
Authors: Tas Sinem , Rehnberg Emil , Bölükbas Deniz A. , Beech Jason P. , Kazado Liora Nasi , Svenningsson Isak , Arvidsson Martin , Sandberg Axel , Dahlgren Kajsa A. , Edthofer Alexander , Gustafsson Anna , Isaksson Hanna , Wood Jeffery A. , Tegenfeldt Jonas O. , Wagner Darcy E.
Published: July 2021

Mechanical ventilation is often required in patients with pulmonary disease to maintain adequate gas exchange. Despite improved knowledge regarding the risks of over ventilating the lung, ventilator induced lung injury (VILI) remains a major clinical problem due to inhomogeneities within the diseased lung itself as well as the need to increase pressure or volume of oxygen to the lung as a life-saving measure. VILI is characterized by increased physical forces exerted within the lung, which results in cell death, inflammation and long-term fibrotic remodeling. Animal models can be used to study VILI, but it is challenging to distinguish the contributions of individual cell types in such a setup.In vitromodels, which allow for controlled stretching of specific lung cell types have emerged as a potential option, but these models and the membranes used in them are unable to recapitulate some key features of the lung such as the 3D nanofibrous structure of the alveolar basement membrane while also allowing for cells to be cultured at an air liquid interface (ALI) and undergo increased mechanical stretch that mimics VILI. Here we develop a lung on a chip device with a nanofibrous synthetic membrane to provide ALI conditions and controllable stretching, including injurious stretching mimicking VILI. The lung on a chip device consists of a thin (i.e. ∼20 µm) stretchable poly(caprolactone) (PCL) nanofibrous membrane placed between two channels fabricated in polydimethylsiloxane (PDMS) using 3D printed molds. We demonstrate that this lung on a chip device can be used to induce mechanotrauma in lung epithelial cells due to cyclic pathophysiologic stretch (∼25%) that mimics clinical VILI. Pathophysiologic stretch induces cell injury and subsequently cell death, which results in loss of the epithelial monolayer, a feature mimicking the early stages of VILI. We also validate the potential of our lung on a chip device to be used to explore cellular pathways known to be altered with mechanical stretch and show that pathophysiologic stretch of lung epithelial cells causes nuclear translocation of the mechanotransducers YAP/TAZ. In conclusion, we show that a breathable lung on a chip device with a nanofibrous membrane can be easily fabricated using 3D printing of the lung on a chip molds and that this model can be used to explore pathomechanisms in mechanically induced lung injury.
Quantifying unusual neurological movement phenotypes in collective movement phenotypes
Authors: Owoeye Kehinde , Musolesi Mirco , Hailes Stephen
Published: July 2021

Building models of anomalous behaviour in animals is important for monitoring animal welfare as well as assessing the efficacy of therapeutic interventions in preclinical trials. In this paper, we describe methods that allow for the automatic discrimination of sheep with a genetic mutation that causes Batten disease from an age-matched control group, using GPS movement traces as input. Batten disease is an autosomal recessive lysosomal storage abnormality with symptoms that are likely to affect the way that those with it move and socialise, including loss of vision and dementia. The sheep in this study displayed a full range of symptoms and during the experiment, the sheep were mixed with a large group of younger animals. We used data obtained from bespoke raw data GPS sensors carried by all animals, with a sampling rate of 1 sample/second and a positional accuracy of around 30cm. The distance covered in each ten minute period and, more specifically, outliers in each period, were used as the basis for estimating the abnormal behaviour. Our results show that, despite the variability in the sample, the bulk of the outliers during the period of observation across six days came from the sheep with Batten disease. Our results point towards the potential of using relatively simple movement metrics in identifying the onset of a phenotype in symptomatically similar conditions.
Accurate Automatic Glioma Segmentation in Brain MRI images Based on CapsNet
Authors: Aziz M. Jalili , Zade A. Amiri Tehrani , Farnia P. , Alimohamadi M. , Makkiabadi B. , Ahmadian A. , Alirezaie J.
Published: July 2021

Glioma is a highly invasive type of brain tumor with an irregular morphology and blurred infiltrative borders that may affect different parts of the brain. Therefore, it is a challenging task to identify the exact boundaries of the tumor in an MR image. In recent years, deep learning-based Convolutional Neural Networks (CNNs) have gained popularity in the field of image processing and have been utilized for accurate image segmentation in medical applications. However, due to the inherent constraints of CNNs, tens of thousands of images are required for training, and collecting and annotating such a large number of images poses a serious challenge for their practical implementation. Here, for the first time, we have optimized a network based on the capsule neural network called SegCaps, to achieve accurate glioma segmentation on MR images. We have compared our results with a similar experiment conducted using the commonly utilized U-Net. Both experiments were performed on the BraTS2020 challenging dataset. For U-Net, network training was performed on the entire dataset, whereas a subset containing only 20% of the whole dataset was used for the SegCaps. To evaluate the results of our proposed method, the Dice Similarity Coefficient (DSC) was used. SegCaps and U-Net reached DSC of 87.96% and 85.56% on glioma tumor core segmentation, respectively. The SegCaps uses convolutional layers as the basic components and has the intrinsic capability to generalize novel viewpoints. The network learns the spatial relationship between features using dynamic routing of capsules. These capabilities of the capsule neural network have led to a 3% improvement in results of glioma segmentation with fewer data while it contains 95.4% fewer parameters than U-Net.