bluuebunny/crossref_metadata_2025 huggingface dataset:
UVEITIS AFTER THE BNT162b2 mRNA VACCINATION AGAINST SARS-CoV-2 INFECTION
Authors: Rabinovitch Tamar , Ben-Arie-Weintrob Yael , Hareuveni-Blum Tamar , Shaer Boaz , Vishnevskia-Dai Vicktoria , Shulman Shiri , Newman Hadas , Biadsy Muhammad , Masarwa Dua , Fischer Naomi , Yovel Oren , Goldfeather-Ben Zaken Shalhevet , Habot-Wilner Zohar
Published: August 2021

Purpose:

To describe uveitis cases after the BNT162b2 mRNA SARS-CoV-2 vaccination.

Methods:

This is a multicenter, retrospective study. Vaccine-related uveitis diagnosis was supported by the classification of the World Health Organization Adverse Drug Terminology and the Naranjo criteria.

Results:

Twenty-one patients (23 eyes) with a mean age of 51.3 years (23–78 years) were included. Eight of the 21 patients had a known history of uveitis. The median time from previous to current attack was 1 year (0.5–15 years). There were 21 anterior uveitis cases, two with bilateral inflammation. Eight cases occurred after the first vaccination and 13 after the second vaccination. All but three presented as mild to moderate disease. Two patients developed multiple evanescent white dot syndrome after the second vaccination. The mean time from vaccination to uveitis onset was 7.5 ± 7.3 days (1–30 days). At final follow-up, complete resolution was achieved in all but two eyes, which showed significant improvement. One case of severe anterior uveitis developed vitritis and macular edema after the second vaccination, which completely resolved after an intravitreal dexamethasone injection.

Conclusion:

Uveitis may develop after the administration of the BNT162b2 mRNA vaccine. The most common complication was mild to moderate anterior uveitis, while multiple evanescent white dot syndrome can also occur less frequently.
INTRAOCULAR LENS MALPOSITION AFTER SUTURELESS INTRASCLERAL FIXATION OF INTRAOCULAR LENS
Authors: Byun Zeeyoon , Kong Mingui , Son Gisung
Published: August 2021

Purpose:

To introduce cases of intraocular lens (IOL) malposition after sutureless intrascleral fixation.

Methods:

We retrospectively analyzed the medical records of patients who underwent sutureless intrascleral fixation. Cases with postoperative IOL requiring reoperation were analyzed further.

Results:

Of the 48 eyes that underwent sutureless intrascleral fixation of their IOL, seven eyes had postoperative IOL malposition and underwent reoperation (14.6%). There was no difference in the clinical results between the intravitreal (33 eyes) and intracameral (15 eyes) techniques, but IOL malposition requiring reoperation was more frequent in the latter (2 cases [6.1%] vs. 5 cases [33.3%], P = 0.024). In the 7 eyes that required reoperation, the visual acuity before reoperation was 0.9 ± 0.6 logMAR (20/159), whereas astigmatism was −4.8 ± 3.2 diopters. The visual acuity and cylindrical error improved to 0.1 ± 0.2 logMAR (20/25) and −2.4 ± 2.3 diopters, respectively, at 6 months after the secondary operation.

Conclusion:

In 14.6% of the patients who underwent sutureless intrascleral fixation of the IOL, IOL malposition developed and reoperation was performed. With the intravitreal technique, which uses a wider space than the intracameral technique, the frequency of postoperative IOL malposition could be reduced.
The Profile of Secondary Glaucoma in China: A Study of Over 10,000 Patients
Authors: Gong Haijun , Ren Jiawei , Zheng Bingru , Huang Xiuyi , Liao Yunru , Zhou Yuying , Lin Mingkai
Published: August 2021

Background:

Few studies have investigated the epidemiology of secondary glaucoma (SG) in China. This study analyzed the current profile of admitted patients with SG at the largest ophthalmic center in China.

Methods:

SG cases were retrieved retrospectively by International Classification of Disease-10 clinical coding data from January 2010 to December 2019. Demographic data, etiologies, and the management of SG were analyzed. The ratios of the etiologies were compared with previously reported data from other regions. The etiologies and management between the 2010 to 2014 group and the 2015 to 2019 group were compared.

Results:

A total of 11,730 cases were enrolled. The mean age of the patients with SG was 44.45±19.45 years old. Men (66.94%) were more vulnerable than women (33.06%). The etiologies of SG in 2010 to 2019 were trauma (28%), vascular disease (18%), lens-induced (9%), inflammation (11%), drug-induced (2%), anterior segment surgery (7%), posterior segment surgery (11%), syndrome-associated (4%), and tumors (1%). Compared with other regions, our data have a higher proportion of trauma and vascular disease-associated SG. Compared with 2010 to 2014, trauma-induced SG declined, and drug-induced SG, anterior segment surgery, and syndrome-associated SG increased in 2015 to 2019 (P<0.001). Vascular disease-associated SG cases were older than trauma-induced SCs and had a higher percentage in retired patients (P<0.001), whereas trauma-induced SGs were more prevalent in pediatric patients than vascular disease-related SGs (P<0.001). In addition, the application of drainage device implantation, cataract surgery, and cyclophotocoagulation increased, whereas trabeculectomy and anterior chamber paracentesis and cyclocryotherapy decreased in 2015 to 2019 (P<0.005).

Conclusion:

Although the etiology spectrum has changed during the last 10 years, trauma and vascular disease are still common causes of SG in southern China. Traditional antiglaucoma surgery decreased gradually, and more advanced treatments emerged for its treatment. Up-to-date knowledge of SGs reflects the impact of economic development and ophthalmic service improvement on SGs and is of great value for ophthalmologists to detect SGs early and manage them in a timely manner.
Conditioned pain modulation is more efficient in patients with painful diabetic polyneuropathy than those with nonpainful diabetic polyneuropathy
Authors: Granovsky Yelena , Shafran Topaz Leah , Laycock Helen , Zubiedat Rabab , Crystal Shoshana , Buxbaum Chen , Bosak Noam , Hadad Rafi , Domany Erel , Khamaisi Mogher , Sprecher Elliot , Bennett David L. , Rice Andrew , Yarnitsky David
Published: August 2021

Endogenous pain modulation, as tested by the conditioned pain modulation (CPM) protocol, is typically less efficient in patients with chronic pain compared with healthy controls. We aimed to assess whether CPM is less efficient in patients with painful diabetic polyneuropathy (DPN) compared with those with nonpainful DPN. Characterization of the differences in central pain processing between these 2 groups might provide a central nervous system explanation to the presence or absence of pain in diabetic neuropathy in addition to the peripheral one. Two hundred seventy-one patients with DPN underwent CPM testing and clinical assessment, including quantitative sensory testing. Two modalities of the test stimuli (heat and pressure) conditioned to cold noxious water were assessed and compared between patients with painful and nonpainful DPN. No significant difference was found between the groups for pressure pain CPM; however, patients with painful DPN demonstrated unexpectedly more efficient CPMHEAT (−7.4 ± 1.0 vs −2.3 ± 1.6; P = 0.008). Efficient CPMHEAT was associated with higher clinical pain experienced in the 24 hours before testing (r = −0.15; P = 0.029) and greater loss of mechanical sensation (r = −0.135; P = 0.042). Moreover, patients who had mechanical hypoesthesia demonstrated more efficient CPMHEAT (P = 0.005). More efficient CPM among patients with painful DPN might result from not only central changes in pain modulation but also from altered sensory messages coming from tested affected body sites. This calls for the use of intact sites for proper assessment of pain modulation in patients with neuropathy.
Combination of Tranylcypromine and Mirtazapine in Difficult-to-Treat Depression
Authors: Kavakbasi Erhan , Baune Bernhard T.
Published: August 2021

Background

About one third of depression patients do not respond to the first antidepressant trial. Difficult-to-treat depression was suggested to characterize the often chronic and severe course of disease. Previous data indicate that tranylcypromine is effective in case of treatment-refractory depression. Many antidepressants are contraindicated in combination with tranylcypromine and other monoamine-oxidase inhibitors because of the risk of serotonin syndrome. The combination of tranylcypromine and amitriptyline was reported to be efficacious and safe in patients with electroconvulsive therapy–resistant major depression.

Methods

In this retrospective chart review, we report a series of 3 cases, in which patients with electroconvulsive therapy–resistant depression were treated with the combination of tranylcypromine and mirtazapine. There are no published clinical data on this combination yet. Disease severity and treatment response were retrospectively assessed with the Clinical Global Impression—Severity and Improvement Scales.

Results

All 3 patients had severe difficult-to-treat depression with chronic course of disease and several times of inpatient treatment without achieving remission. The combination treatment was tolerated well, although the patients had somatic comorbidities. One patient developed mild and self-limiting neuroleptic malignant syndrome in the long-term course after dose increase of concomitant aripiprazole. All 3 patients showed either much or very much improvement.

Conclusions

Under tight clinical controls in inpatient setting and after exhausting of alternatives, the combination of tranylcypromine and mirtazapine could be considered in patients, who do not achieve adequate improvement through common treatment options recommended in the guidelines. The combination has to be ceased, if symptoms of possible serotonin syndrome occur.
Head-to-head comparison between 68Ga-PSMA and 18F-FDG-PET/CT in lymphomas: a preliminary analysis
Authors: de Souza Stephan Pinheiro Macedo , Tobar Natalia , Frasson Fernanda , Perini Efrain Araujo , de Souza Carmino A. , Delamain Marcia T. , Ramos Celso Dario
Published: August 2021

Purpose

Isolated case reports mention the uptake of radiolabeled PSMA in lymphoma. However, it is not clear if the intensity of 68Ga-PSMA expression varies among different histological subtypes or if it correlates with 18F-FDG uptake. This study compared both tracers in patients with diverse lymphoma subtypes.

Methods

Ten patients with biopsy-proven-lymphoma underwent 18F-FDG and 68Ga-PSMA-PET/CT (maximum time interval: 6 days). Lymphoma subtypes included Hodgkin’s lymphoma (HL, three patients) and aggressive and indolent non-Hodgkin’s lymphoma (NHL, seven patients). The intensity of PSMA uptake was classified visually as low, intermediate, or high, using blood pool, liver and parotid gland uptake as references. Maximum standardized-uptake value (SUVmax) of each affected site was measured in both sets of images.

Results

FDG detected 59/59 involved sites in 10 patients and PSMA 47/59 sites in nine patients. PSMA uptake was generally low, regardless of the intensity of FDG uptake, but it was classified as intermediate in two patients. The median SUVmax varied from 2.0 (2.0–8.2) to 30.9 for FDG and from 1.7 (1.7–1.7) to 4.4 for PSMA, P < 0.0001. The primary lesion of one patient had a marked intralesional mismatch uptake pattern of the tracers, with areas of higher PSMA expression than FDG uptake, and vice-versa. A brain lesion was more easily identified with PSMA than with FDG images.

Conclusion

HL and several NHL subtypes may present PSMA uptake. The intensity of PSMA expression is generally lower than that of FDG uptake and seems to present less variation among the different histological subtypes of lymphomas.
TP53 Mutation and Extraneural Metastasis of Glioblastoma
Authors: Zhang Xiaoming , Katsakhyan Levon , LiVolsi Virginia A. , Roth Jacquelyn J. , Rassekh Christopher H. , Bagley Stephen J. , Nasrallah MacLean P.
Published: August 2021

Extraneural metastases of glioblastoma (GBM), although rare, are becoming an increasingly recognized occurrence. Currently, the biological mechanism underlying this rare occurrence is not understood. To explore the potential genomic drivers of extraneural metastasis in GBM, we present the molecular features of 4 extraneural metastatic GBMs, along with a comprehensive review and analysis of previously reported cases that had available molecular characterization. In addition to our 4 cases, 42 patients from 35 publications are reviewed. To compare the molecular profiles between GBM cases with extraneural metastasis and the general GBM population, genomic data from GBM samples in The Cancer Genome Atlas (TCGA) database were also analyzed. We found that 64.5% (20/31) of the cases with extraneural metastasis that were tested for TP53 changes had at least 1 TP53 pathogenic variant detected in either 1 or both primary and metastatic tumors. In contrast, TP53 mutation was significantly less frequent in the unselected GBM from TCGA (22.6%, 56/248) (P=0.000). In addition, O-6-methylguanine-DNA methyltransferase (MGMT) promoter methylation was more common in unselected TCGA GBM cases (48.6%, 170/350) than in cases with extraneural metastasis (31.8%, 7/22), although not statistically significant. Although isocitrate dehydrogenase (IDH) mutation is a rare occurrence in high-grade astrocytomas, IDH-mutant grade 4 astrocytomas are at least as likely to metastasize as IDH wild-type GBMs; 3 metastatic cases definitively harbored an IDH1 (p.R132H) mutation in our analysis. Our findings not only provide potential biomarkers for earlier screening of extraneural metastasis, but could also suggest clues to understanding biological mechanisms underlying GBM metastasis, and for the development of therapeutic modalities.
Plasma galectin-9 as a predictor of adverse non-AIDS events in persons with chronic HIV during suppressive antiretroviral therapy
Authors: Premeaux Thomas A. , Moser Carlee B. , McKhann Ashley , Hoenigl Martin , Laws Elizabeth I. , Aquino Draven L. , Lederman Michael M. , Landay Alan L. , Gianella Sara , Ndhlovu Lishomwa C.
Published: August 2021

Background:

People with HIV (PWH) on antiretroviral therapy (ART) still experience an increased risk of morbidity and mortality, presumably driven by chronic inflammation, yet predictors of discrete or combinatorial outcomes remain unclear. Galectin-9 (Gal-9), a driver of both inflammatory and immunosuppressive responses, has been associated with HIV disease progression and multimorbidity.

Objective:

To determine whether plasma Gal-9 levels are associated with the occurrence of specific non-AIDS events (NAEs) in PWH initiating ART.

Design:

We performed a nested case–control study of PWH enrolled from 2001 to 2009 and evaluated pre-ART (66 cases, 97 controls), a year post-ART (112 cases, 211 controls), and immediately preceding an event (89 cases, 162 controls). Events included myocardial infarction/stroke, malignancy, serious bacterial infection, or death.

Methods:

Plasma Gal-9 levels were assessed by ELISA. Conditional logistic regression assessed associations with NAEs and Spearman's correlations compared Gal-9 with other previously assessed biomarkers.

Results:

NAEs occurred at a median of 2.8 years (1.7–4.6) after ART initiation. Higher Gal-9 levels were associated with increased risk of NAEs at year 1 and preevent [odds ratio (OR) per 1 interquartile range = 1.4–1.6; all P < 0.05], specifically myocardial infarction/stroke at year 1 (OR = 1.9; P = 0.029). Gal-9 also correlated with multiple inflammatory and immune activation predictors of NAEs (all timepoints).

Conclusion:

Elevated Gal-9 levels are predictive of deleterious NAEs, particularly cardiovascular complications. Whether the Gal-9 pathway, potentially binding to its putative ligands, is active in the pathogenesis of these outcomes warrants further investigation to determine if targeting Gal-9 may slow or reverse the risk of NAEs.
Conversion to Open Surgery in Laparoscopic Colorectal Cancer Resection: Predictive Factors and its Impact on Long-Term Outcomes. A Case Series Study
Authors: Baixauli Jorge , Cienfuegos Javier A. , Martinez Regueira Fernando , Pastor Carlos , Justicia Carlos S. , Valentí Víctor , Rotellar Fernando , Hernández Lizoáin José L.
Published: August 2021

Background:

Laparoscopic resection is the treatment of choice for colorectal cancer. Rates of conversion to open surgery range between 7% and 30% and controversy exists as to the effect of this on oncologic outcomes. The objective of this study was to analyze what factors are predictive of conversion and what effect they have on oncologic outcomes.

Methods:

From a prospective database of patients undergoing laparoscopic surgery between 2000 and 2018 a univariate and multivariate analyses were made of demographic, pathologic, and surgical variables together with complementary treatments comparing purely laparoscopic resection with conversions to open surgery. Overall and disease-free survival were compared using the Kaplan-Meier method.

Results:

Of a total of 829 patients, 43 (5.18%) converted to open surgery. In the univariate analysis, 12 variables were significantly associated with conversion, of which left-sided resection [odds ratio (OR): 2.908; P=0.02], resection of the rectum (OR: 4.749, P=0.014), and local invasion of the tumor (OR: 6.905, P<0.01) were independently predictive factors in the multiple logistic regression. Female sex was associated with fewer conversions (OR: 0.375, P=0.012). The incidence and pattern of relapses were similar in both groups and there were no significant differences between overall and disease-free survival.

Conclusions:

Left-sided resections, resections of the rectum and tumor invasion of neighboring structures are associated with higher rates of conversion. Female sex is associated with fewer conversions. Conversion to open surgery does not compromise oncologic outcomes at 5 and 10 years.
The Value of Preoperative Ultrasound in the Detection of Contralateral Occult Inguinal Hernia in the Treatment of Symptomatic Inguinal Hernia
Authors: Ozgur Ilker , Karatas Irem , Bozkurt Halil A. , Keskin Metin , Akyuz Ali
Published: August 2021

Background:

The true incidence of contralateral occult inguinal hernia (OIH) is a debate. The repair of contralateral OIH in the treatment context of clinical symptomatic unilateral inguinal hernia (IH) is controversial. This study aimed to assess the effect and clinical benefit of preoperative ultrasound (US) in the diagnosis of contralateral OIH performed before surgery.

Methods:

The retrospective data of 155 consecutive male patients who underwent IH repair between January 2014 and January 2020 were analyzed. The surgical procedures for IH and the clinical outcomes of the US were evaluated.

Results:

Of 155 patients, 29 (18.7%) presented with bilateral IH. Preoperative US was performed in 73 cases of clinical unilateral IH (n=126), and 30 (23.8%) patients were found to have a contralateral OIH. The totally extrapreperitoneal (TEP) or Lichtenstein repair was conducted. Bilateral IH repair was proposed for all, but only 28 agreed and underwent bilateral repair. Patients with clinically bilateral hernia had more complications compared with patients diagnosed to have occult contralateral IH after the US (n=3 vs. n=0). In the overall group, the TEP procedure resulted in shorter hospital stay (P=0.001) and less pain (P=0.021).

Conclusions:

The preoperative US may be recommended to assess the presence of a contralateral OIH as it is a noninvasive, radiation-free, widely available, relatively cheap diagnostic method. The preoperative US may change the surgical approach in up to 1/4 patients with a clinical unilateral IH. Either Lichtenstein repair or TEP repair can be performed with an acceptable complication rate in the case of OIH.
Useful Technique for Creating a Good Liver Parenchymal Visual Transection Plane During Laparoscopic Partial Hepatectomy
Authors: Kawasaki Yota , Iino Satoshi , Yamasaki Yoichi , Hozaka Yuto , Idichi Tetsuya , Kurahara Hiroshi , Mataki Yuko , Ueno Shinichi , Ohtsuka Takao
Published: August 2021

Background:

Creating a good surgical visual field is one of the most important factors for performing a successful surgery. Here, we introduce a useful technique for creating a good liver parenchymal visual transection plane during laparoscopic partial hepatectomy and compare the perioperative outcomes of our current technique with those of conventional techniques.

Methods:

We reviewed the data of patients who underwent laparoscopic partial hepatectomy between July 2016 and December 2020. The current technique for creating transection planes was first applied in our department in April 2019. The patients were divided into conventional (forceps) and current (silicone ring) technique groups, depending on the surgical technique.

Results:

Twenty-eight and 12 patients underwent laparoscopic partial hepatectomy using the conventional and current techniques, respectively, when the difficulty level—as determined by IWATE criteria—was low. Although the tumor size was significantly larger (median: 22.5 vs. 15 mm, P=0.04) in the current technique group, the estimated intraoperative blood loss was significantly lower (median: 50 vs. 100 mL, P=0.01), and the median surgical margin was significantly longer (median: 7 vs. 3 mm, P=0.02). There were no significant between-group differences in surgical time (median: 344 vs. 240 min, P=0.14), postoperative hospital stay duration (median: 11 vs. 9.5 d, P=0.051), and the incidence of complications (P=0.63).

Conclusion:

We believe that the technique involving the use of a silicone ring can result in better surgical outcomes as it provides a good visual hepatic transection plane during laparoscopic partial hepatectomy.
Searching for a “Brain Signature” of Neurodevelopmental Disorders: Event-Related Potentials and the Quest for Biomarkers of Cognition
Authors: Key Alexandra P.
Published: August 2021

This review summarizes main applications of event-related potentials (ERPs) to the study of cognitive processes in persons with neurodevelopmental disorders, for whom traditional behavioral assessments may not be suitable. A brief introduction to the ERPs is followed by a review of empirical studies using passive ERP paradigms to address three main questions: characterizing individual differences, predicting risk for poor developmental outcomes, and documenting treatment effects in persons with neurodevelopmental disorders. Evidence across studies reveals feasibility of ERP methodology in a wide range of clinical populations and notes consistently stronger brain–behavior associations involving ERP measures of higher-order cognition compared with sensory–perceptual processes. The final section describes the current limitations of ERP methodology that need to be addressed before it could be used as a clinical tool and highlights the needed steps toward translating ERPs from group-level research applications to individually interpretable clinical use.
Assessing unused residual Pfizer-BioNTech COVID-19 vaccine: a community observational study
Authors: Hubbard Stephen , Bais Rajlaxmi
Published: August 2021

Worldwide morbidity and mortality associated with Covid-19 are severe and ongoing. The Pfizer-BioNTech vaccine is said to be up to 95% effective against severe disease or death. We were able to demonstrate that an additional 9.8% of COVID-19 vaccine doses could theoretically be given if the residual vaccine within the reconstituted Pfizer vials after six doses are extracted were used. This could be achieved by aseptically combining this excess vaccine from multiple vials to achieve full 0.3ml doses.

Methods

An observational study was conducted in April, 2021, at a mass vaccine site run by a community volunteer organization on Bainbridge Island, Washington. We measured the amount of Pfizer-BioNTech COVID-19 vaccine that was left in 172 vials after six doses had been withdrawn per Centers for Disease Control (CDC) protocol.

Results

A total of 30.68 ml of leftover vaccine was measured and discarded as medical waste. 1,036 doses were given from these vials. An extra 102 doses theoretically could have been given using the residual vaccine in the vials. This would have resulted in 9.8% additional doses of COVID-19 vaccine without requiring new vials.

Conclusion

The ability to combine solution from reconstituted Pfizer vaccine vials to minimize waste and obtain additional doses of vaccine could result in an increase in the number of individuals that could be vaccinated worldwide without additional cost. Further studies to validate our findings are warranted. Clinical trials to study the feasibility, safety and efficacy of protocols using this excess vaccine should be considered.
Rapid expansion of SARS-CoV-2 variants of concern is a result of adaptive epistasis
Authors: Garvin Michael R. , Prates Erica T. , Romero Jonathon , Cliff Ashley , Machado Gazolla Joao Gabriel Felipe , Pickholz Monica , Pavicic Mirko , Jacobson Daniel
Published: August 2021

The SARS-CoV-2 pandemic recently entered an alarming new phase with the emergence of the variants of concern (VOC) and understanding their biology is paramount to predicting future ones. Current efforts mainly focus on mutations in the spike glycoprotein (S), but changes in other regions of the viral proteome are likely key. We analyzed more than 900,000 SARS-CoV-2 genomes with a computational systems biology approach including a haplotype network and protein structural analyses to reveal lineage-defining mutations and their critical functional attributes. Our results indicate that increased transmission is promoted by epistasis, i.e., combinations of mutations in S and other viral proteins. Mutations in the non-S proteins involve immune-antagonism and replication performance, suggesting convergent evolution. Furthermore, adaptive mutations appear in geographically disparate locations, suggesting that either independent, repeat mutation events or recombination among different strains are generating VOC. We demonstrate that recombination is a stronger hypothesis, and may be accelerating the emergence of VOC by bringing together cooperative mutations. This emphasizes the importance of a global response to stop the COVID-19 pandemic.
MFDNN: Multi-channel feature deep neural network algorithm to identify Covid19 chest X-ray images
Authors: Pan Liangrui , Ji Boya , Wang Xiaoqi , Peng Shaolaing
Published: August 2021

The use of chest X-ray images (CXI) to detect Severe Acute Respiratory Syndrome Coronavirus 2 (SARS CoV-2) caused by Coronavirus Disease 2019 (COVID-19) is life-saving important for both patients and doctors. This research proposed a multi-channel feature deep neural network algorithm to screen people infected with COVID-19. The algorithm integrates data oversampling technology and a multi-channel feature deep neural network model to carry out the training process in an end-to-end manner. In the experiment, we used a publicly available CXI database with 10,192 Normal, 6012 Lung Opacity (Non-COVID lung infection), and 1345 Viral Pneumonia images. Compared with traditional deep learning models (Densenet201, ResNet50, VGG19, GoogLeNet), the MFDNN model obtains an average test accuracy of 93.19% in all data. Furthermore, in each type of screening, the precision, recall, and F1 Score of the MFDNN model are also better than traditional deep learning networks. Secondly, compared with the latest CoroDet model, the MFDNN algorithm is 1.91% higher than the CoroDet model in the experiment of detecting the four categories of COVID19 infected persons. Finally, our experimental code will be placed at https://github.com/panliangrui/covid19.
Deconvoluting complex correlates of COVID19 severity with local ancestry inference and viral phylodynamics: Results of a multiomic pandemic tracking strategy
Authors: Parikh Victoria N. , Ioannidis Alexander G. , Jimenez-Morales David , Gorzynski John E. , De Jong Hannah N. , Liu Xiran , Roque Jonasel , Cepeda-Espinoza Victoria P. , Osoegawa Kazutoyo , Hughes Chris , Sutton Shirley C. , Youlton Nathan , Joshi Ruchi , Amar David , Tanigawa Yosuke , Russo Douglas , Wong Justin , Lauzon Jessie T. , Edelson Jacob , Montserrat Daniel Mas , Kwon Yongchan , Rubinacci Simone , Delaneau Olivier , Cappello Lorenzo , Kim Jaehee , Shoura Massa J. , Raja Archana N. , Watson Nathaniel , Hammond Nathan , Spiteri Elizabeth , Mallempati Kalyan C. , Montero-Martín Gonzalo , Christle Jeffrey , Kim Jennifer , Kirillova Anna , Seo Kinya , Huang Yong , Zhao Chunli , Moreno-Grau Sonia , Hershman Steven G. , Dalton Karen P. , Zhen Jimmy , Kamm Jack , Bhatt Karan D. , Isakova Alina , Morri Maurizio , Ranganath Thanmayi , Blish Catherine A. , Rogers Angela J. , Nadeau Kari , Yang Samuel , Blomkalns Andra , O’Hara Ruth , Neff Norma F. , DeBoever Christopher , Szalma Sándor , Wheeler Matthew T. , Farh Kyle , Schroth Gary P. , Febbo Phil , deSouza Francis , Fernandez-Vina Marcelo , Kistler Amy , Palacios Julia , Pinsky Benjamin A. , Bustamante Carlos D. , Rivas Manuel A , Ashley Euan A.
Published: August 2021

The SARS-CoV-2 pandemic has differentially impacted populations of varied race, ethnicity and socioeconomic status. Admixture mapping and local ancestry inference represent powerful tools to examine genetic risk within multi-ancestry genomes independent of these confounding social constructs. Here, we leverage a pandemic tracking strategy in which we sequence viral and host genomes and transcriptomes from 1,327 nasopharyngeal swab residuals and integrate them with digital phenotypes from electronic health records. We demonstrate over-representation of individuals possessing Oceanian and Indigenous American ancestry in SARS-CoV-2 positive populations. Genome-wide-association disaggregated by admixture mapping reveals regions of chromosomes 5 and 14 associated with COVID19 severity within African and Oceanic local ancestries, respectively, independent of overall ancestry fraction. Phylodynamic tracking of consensus viral genomes reveals no association with disease severity or inferred ancestry. We further present summary data from a multi-omic investigation of human-leukocyte-antigen (HLA) typing, nasopharyngeal microbiome and human transcriptomics that reveal metagenomic and HLA associations with severe COVID19 infection. This work demonstrates the power of multi-omic pandemic tracking and genomic analyses to reveal distinct epidemiologic, genetic and biological associations for those at the highest risk.
INDI – Integrated Nanobody Database for Immunoinformatics
Authors: Deszyński Piotr , Młokosiewicz Jakub , Volanakis Adam , Jaszczyszyn Igor , Castellana Natalie , Bonissone Stefano , Ganesan Rajkumar , Krawczyk Konrad
Published: August 2021

Nanobodies, a subclass of antibodies found in camelids, are a versatile molecular binding scaffold composed of a single polypeptide chain. The small size of nanobodies bestows multiple therapeutic advantages (stability, tumor penetration) with the first therapeutic approval in 2018 cementing the clinical viability of this format. Structured data and sequence information of nanobodies will enable the accelerated clinical development of nanobody-based therapeutics. Though the nanobody sequence and structure data are deposited in the public domain at an accelerating pace, the heterogeneity of sources and lack of standardization hampers reliable harvesting of nanobody information. We address this issue by creating the Integrated Database of Nanobodies for Immunoinformatics (INDI, http://research.naturalantibody.com/nanobodies). INDI collates nanobodies from all the major public outlets of biological sequences: patents, GenBank, next-generation sequencing repositories, structures and scientific publications. We equip INDI with powerful nanobody-specific sequence and text search facilitating access to more than 11 million nanobody sequences. INDI should facilitate development of novel nanobody-specific computational protocols helping to deliver on the therapeutic promise of this drug format.
Prevalence and Factors Associated with Behavioural Problems in 5-year-old Children Born with Cleft Lip and/or Palate from the Cleft Collective
Authors: Berman Samantha , Sharp Gemma C , Lewis Sarah J , Blakey Rachel , Davies Amy , Humphries Kerry , Wren Yvonne , Sandy Jonathan R , Stergiakouli Evie
Published: August 2021

Objectives

We determined the prevalence of behavioural problems in 5-year-old children born with Cleft Lip and/or Palate (CL/P) and compared it to the prevalence in general population samples. We also identified risk factors for behavioural problems in children with CL/P.

Design

Observational study using questionnaire data from the Cleft Collective (CC) 5-Year-Old cohort study and three general population samples.

Main Outcome Measure

The Strengths and Difficulties Questionnaire (SDQ) was used to measure behavioural problems.

Participants

A total of 340 children born with CL/P whose mothers had completed the SDQ when their child was 5 years old. Published estimates from three large cohorts were used to approximate general population SDQ scores in the UK and these were used as comparison groups; Millennium Cohort Study (MCS) (n=12,511), Office of National Statistics (ONS) normative school-age SDQ data (n=5,855) and the Avon Longitudinal Study of Parents and Children (ALSPAC) (n=9,386).

Results

An estimated 14.3% of 5-year-old children born with CL/P experienced behavioural problems. There was strong evidence to suggest children with CL/P were more likely to experience difficulties than children in the general population, as measured by SDQ total difficulties scores from all three population cohorts: MCS (OR = 2.07 [95% CI = 1.50-2.85]; P<.001), ONS Norms (OR = 1.53 [95% CI = 1.12-2.11]; P=.008), and ALSPAC (OR = 2.37 [95% CI = 1.72-3.27]; P<.001). The odds of hyperactivity, emotional, prosocial and peer problems were increased among children in the Cleft Collective compared with children in the Millennium Cohort Study. Odds ratios and 95% confidence intervals indicated that children in the Cleft Collective were nearly twice as likely as those in the MCS (OR = 1.91 [95% CI = 1.38-2.65]; P<.001) and three times those in ALSPAC (OR = 3.20 [95% CI = 2.29-4.47]; P<.001) to experience emotional difficulties. The odds of emotional difficulties were higher in boys than girls. Maternal smoking, marital status, younger maternal age at conception, lower maternal education, receiving income support, and measures of poor maternal and familial health showed some evidence of association with behavioural problems in 5-year-old children born with CL/P.

Conclusions

Our findings suggest elevated levels of behavioural problems in children born with CL/P, particularly emotional difficulties in boys, compared to the general population and indicate several factors associated observationally with these difficulties.
Accelerometer-Derived and Genetically Inferred Physical Activity and Human Disease
Authors: Khurshid Shaan , Weng Lu-Chen , Nauffal Victor , Pirruccello James P. , Venn Rachael A. , Al-Alusi Mostafa A. , Benjamin Emelia J. , Ellinor Patrick T. , Lubitz Steven A.
Published: August 2021

Physical activity is favorable to health but the relations with human disease and causal effects are poorly quantified. Previous studies have largely relied on self-reported estimates1–3 which are subject to recall bias, confounding, and reverse causality. Using wrist-worn accelerometer measurements from the UK Biobank, we tested associations between moderate-to-vigorous physical activity (MVPA) – both total MVPA minutes and whether MVPA was above a guideline-based threshold of ≥150 minutes/week4–6 – and incidence of over 1,200 diseases. In 96,466 adults who wore accelerometers for one week (mean age 62±8 years), MVPA was associated with 401 (33%) tested diseases at a false discovery rate of 1% during a median of 6.2 years follow-up. Greater MVPA was overwhelmingly associated with reduced disease risk (98% of associations) with hazard ratios (HRs) ranging from 0.10-0.95 per standard deviation (SD) and associations spanning all 18 disease categories tested. A similar pattern of associations was observed when assessing the guideline-based threshold of ≥150 MVPA minutes/week. We examined a polygenic risk score for MVPA as an instrumental variable for activity within a separate UK Biobank sample (N=392,058, mean age 57±8 years). Greater genetically inferred MVPA was associated with reduced risk of 182 (14%) incident diseases (HR range 0.74-0.97 per 1 SD), and included strong associations conferring reduced risks of obstructive bronchitis, peripheral vascular disease, type 2 diabetes, and gastritis/duodenitis. Objective physical activity is broadly associated with lower disease incidence and many associations are consistent with a causal effect.
Development and utilization of a surrogate SARS-CoV-2 viral neutralization assay to assess mRNA vaccine responses
Authors: Wisnewski Adam V , Liu Jian , Lucas Carolina , Klein Jon , Iwasaki Akiko , Cantley Linda , Fazen Louis , Luna Julian Campillo , Slade Martin , Redlich Carrie A
Published: August 2021

Background

Tests for SARS-CoV-2 immunity are needed to help assess responses to vaccination, which can be heterogeneous and may wane over time. The plaque reduction neutralization test (PRNT) is considered the gold standard for measuring serum neutralizing antibodies but requires high level biosafety, live viral cultures and days to complete. We hypothesized that competitive enzyme linked immunoassays (ELISAs) based on SARS-CoV-2 spike protein’s receptor binding domain (RBD) attachment to its host receptor, the angiotensin converting enzyme 2 receptor (ACE2r), would correlate with PRNT, given the central role of RBD-ACE2r interactions in infection and published studies to date, and enable evaluation of vaccine responses.

Methods and Findings

Configuration and development of a competitive ELISA with plate-bound RBD and soluble biotinylated ACE2r was accomplished using pairs of pre/post vaccine serum. When the competitive ELISA was used to evaluate N=32 samples from COVID-19 patients previously tested by PRNT, excellent correlation in IC50 results were observed (rs= .83, p < 0.0001). When the competitive ELISA was used to evaluate N=41 vaccinated individuals and an additional N=14 unvaccinated recovered COVID-19 patients, significant differences in RBD-ACE2r inhibitory activity were associated with prior history of COVID-19 and type of vaccine received. In longitudinal analyses pre and up to 200 days post vaccine, surrogate neutralizing activity increased markedly after primary and booster vaccine doses, but fell substantially, up to <12% maximal levels within 6 months.

Conclusions

A competitive ELISA based on inhibition of RBD-ACE2r attachment correlates well with PRNT, quantifies significantly higher activity among vaccine recipients with prior COVID (vs. those without), and highlights marked declines in surrogate neutralizing activity over a 6 month period post vaccination. The findings raise concern about the duration of vaccine responses and potential need for booster shots.
Associations of behavioral problems and white matter properties of the cerebellar peduncles in boys and girls born full term and preterm
Authors: Hosoki Machiko , Bruckert Lisa , Borchers Lauren R. , Marchman Virginia A. , Travis Katherine E. , Feldman Heidi M.
Published: August 2021

Accumulating evidence suggests that the role of cerebellum includes regulation of behaviors; Cerebellar impairment may lead to behavioral problems. Behavioral problems differ by sex: internalizing problems are more common in girls, externalizing problems in boys. Behavioral problems are also elevated in children born preterm (PT) compared to children born full-term (FT). The current study examined internalizing and externalizing problems in 8-year-old children in relation to sex, birth-group, FA of the cerebellar peduncles, and interactions among these predictor variables. Participants (N=78) were 44 boys (28 PT) and 34 girls (15 PT). We assessed behavioral problems via standardized parent-reports and FA of the cerebellar peduncles using deterministic tractography. Internalizing problems were higher in children born PT compared to children born FT (p=.032); the interaction of sex and birth-group was significant (p=.044). When considering the contribution of the mean-tract FA of cerebellar peduncles to behavioral problems, there was a significant interaction of sex and mean-tract FA of the ICP with internalizing problems; the slope was negative in girls (p=.020) but not boys. In boys, internalizing problems were only associated with mean-tract FA ICP in those born preterm (p=.010). We found no other significant associations contributing to internalizing or externalizing problems. Thus, we found sexual dimorphism and birth-group differences in the association of white matter metrics of the ICP and internalizing problems in school-aged children. The findings inform theories of the origins of internalizing behavioral problems in middle childhood and may suggest approaches to treatment at school age.
Distribution of rare LOXL1 missense alleles, haplotypes and diplotypes suggests association with reduced risk of glaucoma-related exfoliation syndrome
Authors: Igo Rob P. , Kinzy Tyler G. , Cooke Bailey Jessica N. , Khor Chiea Chuen , Aung Tin , Ritch Robert , Sit Arthur J. , Lee Richard K. , Pericak-Vance Margaret , Kang Jae H. , Haines Jonathan L. , Pasquale Louis R. , Wiggs Janey L.
Published: August 2021

Purpose

Common LOXL1 protein-altering variants are significant genetic risk factors for exfoliation syndrome (XFS) and the related secondary glaucoma (XFG). A rare LOXL1 missense allele has been associated with protective effects in a Japanese cohort, suggesting that other rare alleles may also exhibit protective effects. The goal of this study was to assess the contributions of rare LOXL1 variants to XFS/XFG risk in cases and controls from the United States.

Methods

LOXL1 rare (minor allele frequency less than 1%) variants were identified from Humanexome BeadArray (Illumina) data for 1118 XFS/XFG cases and 3661 controls. Distribution of rare variants, haplotypes (defined using IMPUTE2) and diplotypes were examined using the Fisher’s exact test. Rare variant allele distribution was confirmed in an independent set of primary open angle glaucoma (POAG) controls and multi-ethnic datasets. Correlation of LOXL1 common allele homozygosity with disease risk used data from gnomAD (gnomad.broadinstitute.org/) and an existing multi-ethnic meta-analysis.

Results

Four rare LOXL1 missense alleles were identified, and all were more common in controls (combined P= 7.6E-4), with two of these located in a LOXL1 intrinsic disordered region (IDR) known to be involved in LOXL1 aggregation. Haplotypes that included the rare or minor variants were more common in controls compared to cases (OR= 0.33, P=1.7E-8). Heterozygous diplotypes were significantly associated with reduced risk overall (OR= 0.45 P= 1.7 E-89) with the largest effects observed for diplotypes with more than one heterozygous genotype (OR= 0.05, P= 1.0E-39). A homozygous diplotype was associated with increased disease risk (OR= 6.8, P= 4.7E-157) and homozygosity was correlated with disease risk for common LOXL1 variants across multi-ethnic populations (Pearson= 0.92, P<0.001).

Conclusions

Using exome array data from XFS/XFG cases and controls from the United States, we identify 4 rare protective LOXL1 missense variants and show that the distribution of the corresponding haplotypes and diplotypes are associated with reduced risk of XFS/XFG. The diplotype results also demonstrate that LOXL1 allelic heterozygosity is protective while homozygosity is associated with increased disease risk. These results suggest that LOXL1 minor allele frequency variation among populations, with corresponding variation in genotype heterozgyosity and homozygosity, determines the XFS/XFG association effects and that genotypic effects may also impact protein aggregation involving intrinsic disordered regions.
Evolutionary dynamics of DIRS-like and Ngaro-like retrotransposons in Xenopus laevis and Xenopus tropicalis genomes
Authors: Gazolla Camilla Borges , Ludwig Adriana , de Moura Gama Joana , Bruschi Daniel Pacheco
Published: August 2021

Anuran genomes have a large number and diversity of transposable elements, but are little explored, mainly in relation to their molecular structure and evolutionary dynamics. Here, we investigated the retrotransposons containing tyrosine recombinase (YR) (order DIRS) in the genome of Xenopus tropicalis and Xenopus laevis. These anurans show 2n = 20 and the 2n = 36 karyotypes, respectively. They diverged about 48 million years ago (mya) and X. laevis had an allotetraploid origin (around 17-18 mya). Our investigation is based on the analysis of the molecular structure and the phylogenetic relationships of 95 DIRS families of Xenopus belonging to DIRS-like and Ngaro-like superfamilies. We were able to identify molecular signatures in the 5’ and 3’ non-coding terminal regions, preserved open reading frames (ORFs) and conserved domains that are specific to distinguish each superfamily. We recognize two ancient amplification waves of DIRS-like elements that occurred in the ancestor of both species and a higher density of the old/degenerate copies detected in the X. laevis. X. tropicalis showed more recent amplification waves estimated around 16 mya and 3.2 mya and corroborate with high diversity-level of families in this species and with transcriptional activity evidence. Ngaro-like elements presented less diversity and quantity in the genomes, although potentially active copies were also found. Our findings highlight a differential diversity-level and evolutionary dynamics of the YR retrotransposons in the diploid X. tropicalis and X. laevis species expanding our comprehension of the behavior of these elements in both genomes during the diversification process.
Automated MRI Lung Segmentation and 3D Morphological Features for Quantification of Neonatal Lung Disease
Authors: Mairhörmann Benedikt , Castelblanco Alejandra , Häfner Friederike , Pfahler Vanessa , Haist Lena , Waibel Dominik , Flemmer Andreas , Ehrhardt Harald , Stoecklein Sophia , Dietrich Olaf , Foerster Kai , Hilgendorff Anne , Schubert Benjamin
Published: August 2021

The diagnosis of neonatal respiratory diseases is currently based on clinical criteria. However, lung structural information is generally lacking due to the unavailability of routinely applicable, radiation-free imaging tools as well as the time-consuming, often non-standardized manual analysis of imaging data. Increased efficiency, comparability and accuracy in image quantification is needed in this patient cohort as pulmonary complications determine immediate and long-term survival.

We therefore developed an ensemble of deep convolutional neural networks to perform lung segmentation in magnetic resonance imaging (MRI) sequences obtained in premature infants near term (n=107), with subsequent reconstruction of the 3-dimensional neonatal lung and estimation of MRI lung descriptors for volume, shape, surface, and signal intensity distribution.

Annotation of lung segments in quiet-breathing MRI for infants with and without Bronchopulmonary Dysplasia (BPD) was achieved by development of a deep learning model reaching a volumetric dice score (VDC) of 0.908 and validated in an independent cohort (VDC 0.880), thereby matching expert-level performance while demonstrating transferability, robustness towards technical (low spatial resolution, movement artifacts) and lung disease grades. MRI lung descriptors presented relevant correlations with lung lesion scores and enabled the separation of neonates with and without BPD (AUC 0.92±0.016), mild vs severe BPD (AUC 0.84±0.027), and single level prediction of BPD severity (AUC 0.75±0.013).

Our work demonstrates the potential of AI-supported MRI markers as a diagnostic tool, characterizing changes in lung structure in neonatal respiratory disease while avoiding radiation exposure.