bluuebunny/crossref_metadata_2025 huggingface dataset:
Reconstruction of the adductor chamber and predicted bite force in pterodactyloids (Pterosauria)
Authors: Pêgas Rodrigo V , Costa Fabiana R , Kellner Alexander W A
Published: November 2020

The reconstruction of jaw muscles is critical in establishing potential cranial functions; however, myological studies of extinct groups that have no descendants are difficult to perform and test. This is particularly true for pterosaurs, a group of extinct flying reptiles that present a plethora of cranial morphologies, suggesting different functions and feeding habits. Here we present a first attempt to reconstruct the adductor musculature of the pterodactyloid skull in detail, using osteological correlates and the extant phylogenetic bracketing method. Using these reconstructions, we estimate bite force for nine selected species and investigate implications for potential dietary habits.
Three-dimensional characterization of first instar horse and rhinoceros stomach bot fly larvae (Oestridae: Gasterophilinae:Gasterophilus,Gyrostigma): novel morphology and evolutionary implications
Authors: Li Xin-Yu , Pape Thomas , Colwell Doug , Dewhurst Charles , Zhang Dong
Published: November 2020

Larval characters are of importance in systematic and evolutionary studies of Diptera but lag behind characters of adults due to difficulties in obtaining relevant information. Larvae of stomach bot flies are obligate parasites completing development exclusively in the alimentary tract of equids and rhinoceroses. They possess diversified morphological adaptations, providing remarkable examples to further our understanding of larval evolution. Herein, three-dimensional structures of first instar Gasterophilus pecorum and Gyrostigma rhinocerontis are compared using confocal laser scanning microscopy (CLSM) and scanning electron microscopy (SEM). We suggest CLSM has a large potential for exploiting cryptic character systems of micro fly larvae, as spectral range and intensity of autofluorescence emitted by sclerotized structures and soft tissues are distinct, presenting a high-contrast mechanism for multistructural visualization with non-destructive sample preparation. Five new potential synapomorphies are proposed to corroborate the sister-group Gasterophilus and Gyrostigma. The upward curving mouth-hooks of first instar Gasterophilus and Gyrostigma are distinctive in Cyclorrhapha and possibly serve to facilitate the larval subcutaneous migration within the host. Three types of mouthhooks are recognized in first instar Oestridae, with the gently curved and gradually tapered type optimized as the ancestral state, from which the gasterophiline and hypodermatine types evolved independently.
Identification of Major Quantitative Trait Loci Controlling Field Resistance to Downy Mildew in Cultivated Lettuce (Lactuca sativa)
Authors: Parra Lorena , Simko Ivan , Michelmore Richard W.
Published: November 2020

Lettuce downy mildew, caused by Bremia lactucae Regel, is the most economically important foliar disease of lettuce (Lactuca sativa L.). The deployment of resistant cultivars carrying dominant resistance genes (Dm genes) plays a crucial role in integrated downy mildew disease management; however, high variability in pathogen populations leads to the defeat of plant resistance conferred by Dm genes. Some lettuce cultivars exhibit field resistance that is only manifested in adult plants. Two populations of recombinant inbred lines (RILs), originating from crosses between the field resistant cultivars Grand Rapids and Iceberg and susceptible cultivars Salinas and PI491224, were evaluated for downy mildew resistance under field conditions. In all, 160 RILs from the Iceberg × PI491224 and 88 RILs from the Grand Rapids × Salinas populations were genotyped using genotyping by sequencing, which generated 906 and 746 high-quality markers, respectively, that were used for quantitative trait locus (QTL) analysis. We found a QTL in chromosome 4 that is present in both Grand Rapids × Salinas and Iceberg × PI491224 populations that has a major effect on field resistance. We also found two additional significant QTLs in chromosomes 2 and 5 in the Iceberg × PI491224 RIL population. Marker-assisted gene pyramiding of multiple Dm genes in combination with QTLs for field resistance provide the opportunity to develop cultivars with more durable resistance to B. lactucae.
Sacrectomy for Recurrent Rectal Cancer Using the Transanal Total Mesorectum Excision Technique
Authors: Kimura Kei , Ikeda Masataka , Kataoka Kozo , Beppu Naohito , Uchino Motoi , Yamano Tomoki , Ikeuchi Hiroki , Tomita Naohiro
Published: November 2020

INTRODUCTION:

In high sacrectomy, it is difficult to secure the lateral surgical margin and prevent severe postoperative complications. In this report, we present our unique surgical procedure using transanal total mesorectal excision for locally recurrent rectal cancer.

TECHNIQUE:

A 49-year-old woman was diagnosed with locally rerecurrent rectal cancer, which was located at the height of the S3 vertebra by preoperative imaging, and posterior pelvic exenteration concomitant with high sacrectomy below the S2 vertebra was planned. A multiaccess transperineal platform was placed to secure the lateral surgical margin using transperineal minimally invasive surgery during the perineal and sacral side procedure. Transperineal minimally invasive surgery has several clinical benefits over the conventional approach. For the perineal approach, a 2-team laparoscopic approach was performed. This surgical intervention with laparoscopic perineal assistance contributed to the completion of the dissection of the planned lateral surgical margin, such as the distal piriformis muscles and the sacrotuberous and sacrospinous ligaments, which are the most difficult areas to access in the lithotomy position. Regarding the sacral approach, it facilitated the dissection of the dorsal space of the sacrum; therefore, only a 7-cm transverse skin incision was required during sacrectomy. Small skin incisions and minimal dissection may reduce surgical site infections.

RESULTS:

The operative time was 933 minutes, with 80 mL of blood loss. There were no major complications, and pathologically confirmed curative resection was achieved.

CONCLUSIONS:

Our new technique utilizing transanal total mesorectum excision is feasible to secure the lateral surgical margin with minimal skin incision and dissection and may prevent severe postoperative complications.
Customizing TMS Applications in Traumatic Brain Injury Using Neuroimaging
Authors: Herrold Amy A. , Siddiqi Shan H. , Livengood Sherri L. , Bender Pape Theresa L. , Higgins James P. , Adamson Maheen Mausoof , Leung Albert , Raij Tommi
Published: November 2020

Optimizing transcranial magnetic stimulation (TMS) treatments in traumatic brain injury (TBI) and co-occurring conditions may benefit from neuroimaging-based customization.

Participants:

Our total sample (N = 97) included 58 individuals with TBI (49 mild, 8 moderate, and 1 severe in a state of disordered consciousness), of which 24 had co-occurring conditions (depression in 14 and alcohol use disorder in 10). Of those without TBI, 6 individuals had alcohol use disorder and 33 were healthy controls. Of our total sample, 54 were veterans and 43 were civilians.

Design:

Proof-of-concept study incorporating data from 5 analyses/studies that used multimodal approaches to integrate neuroimaging with TMS.

Main Measures:

Multimodal neuroimaging methods including structural magnetic resonance imaging (MRI), MRI-guided TMS navigation, functional MRI, diffusion MRI, and TMS-induced electric fields. Outcomes included symptom scales, neuropsychological tests, and physiological measures.

Results:

It is feasible to use multimodal neuroimaging data to customize TMS targets and understand brain-based changes in targeted networks among people with TBI.

Conclusions:

TBI is an anatomically heterogeneous disorder. Preliminary evidence from the 5 studies suggests that using multimodal neuroimaging approaches to customize TMS treatment is feasible. To test whether this will lead to increased clinical efficacy, studies that integrate neuroimaging and TMS targeting data with outcomes are needed.
Use of Repetitive Transcranial Magnetic Stimulation in the Treatment of Neuropsychiatric and Neurocognitive Symptoms Associated With Concussion in Military Populations
Authors: Oberman Lindsay M. , Exley Shannon , Philip Noah S. , Siddiqi Shan H. , Adamson Maheen M. , Brody David L.
Published: November 2020

Background:

Since the year 2000, over 342 000 military service members have experienced a concussion, often associated with chronic neuropsychiatric and neurocognitive symptoms. Repetitive transcranial magnetic stimulation (rTMS) protocols have been developed for many of these symptoms in the general population.

Objective:

To conduct a scoping review of the literature on rTMS for neuropsychological and neurocognitive symptoms following concussion.

Methods:

PubMed and Google Scholar search engines identified 9 articles, written in English, corresponding to the search terms TBI or concussion; and TMS or rTMS; and depression, PTSD, or cognition. Studies that were not therapeutic trials or case reports, did not have neuropsychiatric or neurocognitive primary outcome measures, or described samples where 80% or more of the cohort did not have a TBI were excluded.

Results:

There were no reports of seizures nor difference in the frequency or quality of other adverse events as compared with the broader rTMS literature, supporting the safety of rTMS in this population. Support for the efficacy of rTMS for the treatment of neuropsychiatric and neurocognitive symptoms, in this population, is limited.

Conclusions:

Large-scale, innovative, neuroscience-informed protocols are recommended to elucidate the potential utility of rTMS for the complex neuropsychiatric and neurocognitive symptoms associated with military concussions.
Variables Affecting Attitudes Toward Suicide Among the Adolescent Population
Authors: Kim Hyeyoung , Choi Seo-Hyun , Lee Sang-Eun , Lee Chai Won , Maeng Seri , Kim Won-Hyoung , Bae Jae Nam , Lee Jeong Seop
Published: November 2020

Past research has supported the positive association between prosuicide attitudes and suicidal behavior. The aim of the present study was to determine the factor structure of adolescents' attitudes toward suicide and to explore correlates associated with their attitudes. A questionnaire was distributed to 1292 adolescents at eight middle schools to assess their demographic information, clinical variables, and attitudes toward suicide. After factor analysis, we reached a four-factor solution of the attitudes toward suicide. Significantly more females, nonreligious adolescents, those with a lower socioeconomic status, those with higher levels of depressive symptoms, and those with a history of suicidal ideation/plans had more understanding attitudes toward suicide. Depressive adolescents were also more permissive and believed that suicides were unpreventable and that loneliness led to suicide. In conclusion, adolescents' attitudes toward suicide were significantly associated with not only various sociodemographic correlates but also the severity of depressive symptoms and their own experiences of suicidality.
Single-Session Dance/Movement Therapy for Thought and Behavioral Dysfunction Associated With Schizophrenia
Authors: Biondo Jacelyn , Gerber Nancy , Bradt Joke , Du Wei , Goodill Sherry
Published: November 2020

This purposes of this mixed methods feasibility study were to determine whether people with schizophrenia in an inpatient psychiatric facility were able to complete the research protocol, and to obtain preliminary treatment effects of a single-session dance/movement therapy (DMT) intervention versus verbal treatment as usual (TAU). Thirty-two participants were randomized to a 45-minute DMT or verbal TAU session. Data were collected quantitatively using the Brief Psychiatric Rating Scale (BPRS) and qualitatively through open-ended interviews. Results indicated that participants in the DMT group had statistically significant symptom reduction compared with those in the TAU group in overall BPRS scores (effect size [ES] = 0.67), psychological discomfort (ES = 0.64), negative symptoms (ES = 0.67), and positive symptoms (ES = 0.55). No statistical significance was shown for resistance. Qualitative findings substantiate the quantitative findings, however, show divergence regarding resistance. Participants in the DMT group expressed feeling in control, less angry, and motivated for treatment.
How Does the Measurement of Disability in Low Back Pain Map Unto the International Classification of Functioning, Disability and Health?
Authors: Nicol Richard , Yu Hainan , Selb Melissa , Prodinger Birgit , Hartvigsen Jan , Côté Pierre
Published: November 2020

The objective of this study was to catalog items from instruments used to measure functioning, disability, and contextual factors in patients with low back pain treated with manual medicine (manipulation and mobilization) according to the International Classification of Functioning, Disability and Health. This catalog will be used to inform the development of an International Classification of Functioning, Disability and Health–based assessment schedule for low back pain patients treated with manual medicine. In this scoping review, we systematically searched MEDLINE, Embase, PsycINFO, and CINAHL. We identified instruments (questionnaires, clinical tests, single questions) used to measure functioning, disability, and contextual factors, extracted the relevant items, and then linked these items to the International Classification of Functioning, Disability and Health. We included 95 articles and identified 1510 meaningful concepts. All but 70 items were linked to the International Classification of Functioning, Disability and Health. Of the concepts linked to the International Classification of Functioning, Disability and Health, body functions accounted for 34.7%, body structures accounted for 0%, activities and participation accounted for 41%, environmental factors accounted for 3.6%, and personal factors accounted for 16%. Most items used to measure functioning and disability in low back pain patient treated with manual medicine focus on body functions, as well as activities and participation. The lack of measures that address environmental factors warrants further investigation.
Effects of Adipose-Derived Stem Cells and Platelet-Rich Plasma for Prevention of Alopecia and Other Skin Complications of Radiotherapy
Authors: Evin Nuh , Tosun Zekeriya , Aktan Tahsin Murad , Duman Selcuk , Harmankaya Ismail , Yavas Güler
Published: November 2020

Background

Radiotherapy (RT) involves the use of ionizing radiation in treating malignancies and benign disorders. However, RT damages target and healthy surrounding tissues in a dose-dependent manner. This effectively reduces patient compliance and quality of life, thereby warranting the prevention of RT-induced adverse effects on skin. Adipose-derived stem cells (ASCs) are used to treat RT-induced damage and platelet-rich plasma (PRP) provides a scaffold that potentiates the effects of ASCs. Thus, the aim of this study was to determine the mechanism employed by ASCs and PRP in protecting against RT-induced adverse effects.

Methods

We have established an immunodeficient mouse transplantation model using which human hair follicular units were implanted. When the follicular units were macroscopically and microscopically mature and anagenic, we administered localized RT. Subsequently, the mice were randomly divided into 4 groups based on the subcutaneous injection of the following to the irradiated transplantation site: saline, PRP, ASCs, and a combination of ASCs and PRP. Next, we used macroscopic and microscopic analyses to determine the protective effects of the injected solutions on skin and hair follicles.

Results

Adipose-derived stem cells reduced RT-induced adverse effects, such as impaired wound healing, alopecia, skin atrophy, and fibrosis by suppressing inflammation, dystrophy, degeneration, connective tissue synthesis, and apoptosis and increasing cellular proliferation, differentiation, and signaling. Moreover, these effects were augmented by PRP.

Conclusions

Thus, co-administering ASCs with PRP in mice prevented RT-induced adverse effects and can be tested for use in clinical practice.
Trends in Lung Transplantation Practices Across the United States During the COVID-19 Pandemic
Authors: Chan Ernest G. , Chan Patrick G. , Harano Takashi , Ryan John P. , Morrell Matthew R. , Sanchez Pablo G.
Published: November 2020

Background.

The purpose of this study is to examine the effects of the coronavirus disease 2019 (COVID-19) pandemic on adult lung transplants and report practice changes in the United States.

Methods.

A retrospective analysis of a public dataset from the United Network for Organ Sharing was performed regarding adult lung transplantation (January 19, 2020–June 30, 2020). Data were stratified into 3 periods: pre-COVID-19 (January 19, 2020–March 14, 2020), first COVID-19 era (March 15, 2020–May 8, 2020), and second COVID-19 era (May 9, 2020–June 30, 2020). Weekly changes in waitlist inactivations (COVID-19 precautions or not), waitlist additions, transplant volume, and donor recovery were examined across eras and changes across era were correlated.

Results.

During the first COVID-19 era, 301 patients were added to the waitlist, representing a 40% decrease when compared to the prior 8-week period. This was followed by a significant increase in listing during the second COVID-19 era (t = 2.16, P = 0.032). Waitlist inactivations decreased in the second COVID-19 era from the first COVID-19 era (t = 3.60, P < 0.001). There was no difference in waitlist inactivations between the pre-COVID era and the second COVID-19 era (P = 0.10). Weekly volume was not associated with trends in COVID-19 cases across any era, but was negatively associated with waitlist inactivations due to COVID-19 precautions entering the first COVID-19 era (r = −0.73, P = 0.04) and second COVID-19 era (r = −0.89, P = 0.003).

Conclusions.

Due to the COVID-19 pandemic, the United States experienced a decrease in lung transplant volume. While overall volume has returned to normal, additional studies are needed to identify areas of improvement to better prepare for future pandemics.
Pseudoalteromonas caenipelagi sp. nov., isolated from a tidal flat
Authors: Park Sooyeon , Lee Seo Yeon , Kim Wonyong , Yoon Jung-Hoon
Published: November 2020

A Gram-stain-negative, aerobic, non-spore-forming, motile by single polar flagellum and ovoid or rod-shaped bacterial strain, designated JBTF-M23T, was isolated from tidal flat sediment collected from the Yellow Sea, Republic of Korea. Neighbour-joining phylogenetic tree of 16S rRNA gene sequences showed that strain JBTF-M23Tfell within the clade comprising the type strains ofPseudoalteromonasspecies, clustering with the type strains ofP. byunsanensisandP. amylolytica. Strain JBTF-M23Texhibited the highest 16S rRNA gene sequence similarity value (98.6 %) to the type strain ofP. rubraand sequence similarities of 98.3 and 97.7 % to the type strains ofP. byunsanensisandP. amylolytica,respectively. The DNA G+C content of strain JBTF-M23Tfrom genomic sequence data was 41.98 %. The ANI and dDDH values between strain JBTF-M23Tand the type strains ofP. rubra,P. byunsanensisandP. amylolyticawere 71.3–76.6 and 19.4–19.9 %, respectively. Strain JBTF-M23Tcontained Q-8 as the predominant ubiquinone and C16 : 1 ω7cand/or C16 : 1 ω6c, C16 : 0and C18 : 1 ω7cas the major fatty acids. The major polar lipids of strain JBTF-M23Twere phosphatidylethanolamine and one unidentified aminolipid. Distinguished phenotypic properties, along with the phylogenetic and genetic distinctiveness, revealed that strain JBTF-M23Tis separated from recognizedPseudoalteromonasspecies. On the basis of the data presented, strain JBTF-M23Tis considered to represent a novel species of the genusPseudoalteromonas, for which the namePseudoalteromonas caenipelagisp. nov. is proposed. The type strain is JBTF-M23T(=KACC 19900T=NBRC 113647T).
Croceivirga litoralis sp. nov., isolated from coastal surface water, and reclassification of Muricauda lutea as Croceivirga lutea comb. nov.
Authors: Zhang Jiajie , Xu Yongle , Chen Xiao , Liu Daixi , Song Hui , Liu Jihua , Du Zong-Jun
Published: November 2020

A novel Gram-stain-negative, aerobic, yellow-pigmented bacterium was isolated from seawater of Aoshan Bay, and designated as strain ASW18T. Strain ASW18T was a long-rod-shaped bacterium without flagellum and lacked gliding ability. Based on 16S rRNA gene phylogeny, strain ASW18T showed the closest relationship to

Croceivirga radicis

MCCC 1A06690T, with a sequence similarity of 97.0 %. Strain ASW18T was able to grow at 25–40 °C, at pH 5.5–9.5 and with 0.5–9 % (w/v) NaCl. The genomic DNA G+C content of strain ASW18T was 37.3 %. The predominant cellular fatty acids of strain ASW18T were iso-C15 : 0, iso-C17 : 0 3-OH and iso-C15 : 1 G. The major polar lipids were phosphatidylethanolamine, phosphatidyldimethylethanolamine, an aminolipid and three unidentified lipids. The respiratory quinone of strain ASW18T was menaquinone with six isoprene units (MK-6). Based on the present polyphasic analysis, strain ASW18T represents a novel species of the genus

Croceivirga

, for which the name Croceivirga litoralis sp. nov. is proposed; the type strain is ASW18T (=MCCC 1K04203T=KCTC 72852T). In addition, it is also proposed that

Muricauda lutea

should be reclassified as Croceivirga lutea comb. nov.; the type strain is CSW06T (=CGMCC 1.15761T=JCM 31455T=KCTC 52375T=MCCC 1K03195T).
A novel substitution in NS5A enhances the resistance of hepatitis C virus genotype 3 to daclatasvir
Authors: Fernandes Campos Guilherme Rodrigues , Ward Joseph , Chen Shucheng , Bittar Cintia , Vilela Rodrigues João Paulo , Martinelli Ana de Lourdes Candolo , Souza Fernanda Fernandes , Pereira Leonardo Régis Leira , Rahal Paula , Harris Mark
Published: November 2020

Hepatitis C virus (HCV) genotype 3 presents a high level of both baseline and acquired resistance to direct-acting antivirals (DAAs), particularly those targeting the NS5A protein. To understand this resistance we studied a cohort of Brazilian patients treated with the NS5A DAA, daclatasvir and the nucleoside analogue, sofosbuvir. We observed a novel substitution at NS5A amino acid residue 98 [serine to glycine (S98G)] in patients who relapsed post-treatment. The effect of this substitution on both replication fitness and resistance to DAAs was evaluated using two genotype 3 subgenomic replicons. S98G had a modest effect on replication, but in combination with the previously characterized resistance-associated substitution (RAS), Y93H, resulted in a significant increase in daclatasvir resistance. This result suggests that combinations of substitutions may drive a high level of DAA resistance and provide some clues to the mechanism of action of the NS5A-targeting DAAs.
Expansin-related proteins: biology, microbe–plant interactions and associated plant-defense responses
Authors: Narváez-Barragán Delia A. , Tovar-Herrera Omar E. , Segovia Lorenzo , Serrano Mario , Martinez-Anaya Claudia
Published: November 2020

Expansins, cerato-platanins and swollenins (which we will henceforth refer to as expansin-related proteins) are a group of microbial proteins involved in microbe-plant interactions. Although they share very low sequence similarity, some of their composing domains are near-identical at the structural level. Expansin-related proteins have their target in the plant cell wall, in which they act through a non-enzymatic, but still uncharacterized, mechanism. In most cases, mutagenesis of expansin-related genes affects plant colonization or plant pathogenesis of different bacterial and fungal species, and thus, in many cases they are considered virulence factors. Additionally, plant treatment with expansin-related proteins activate several plant defenses resulting in the priming and protection towards subsequent pathogen encounters. Plant-defence responses induced by these proteins are reminiscent of pattern-triggered immunity or hypersensitive response in some cases. Plant immunity to expansin-related proteins could be caused by the following: (i) protein detection by specific host-cell receptors, (ii) alterations to the cell-wall-barrier properties sensed by the host, (iii) displacement of cell-wall polysaccharides detected by the host. Expansin-related proteins may also target polysaccharides on the wall of the microbes that produced them under certain physiological instances. Here, we review biochemical, evolutionary and biological aspects of these relatively understudied proteins and different immune responses they induce in plant hosts.
Efficacy and Safety of PD-1/PD-L1 plus CTLA-4 antibodies +/− Other Therapies in Lung Cancer: A Systematic Review and Meta-Analysis
Authors: Shen Xiang , Xiao Hua , Huang Shangke , Liu Jiexing , Ran Zhuolan , Xiong Bin
Published: November 2020

Background

Immune checkpoint inhibitors have brought hope for patients with advanced lung cancer, among which PD-1/PD-L1 and CTLA-4 inhibitors have achieved considerable results. This meta-analysis aims to investigate the efficacy and safety of PD-1/PD-L1 combined with CTLA-4 antibodies in patients with advanced lung cancer.

Materials and Methods

Randomized controlled trials (RCTs) study of PD-1/PD-L1 combined with CTLA-4 inhibitors for advanced lung cancer was searched in the database for systematic review and meta-analysis.

Results

The meta-analysis finally included 4 trials (actually 3 trials), and the results showed that the overall response rate of PD-1/PD-L1 combined with CTLA-4 inhibitor was higher than that of the control group (ORR = 2.29 [95% CI 1.58 3.32], P <0.0001). PFS significantly improved compared with conventional treatment (HR = 0.69 [95% CI 0.56, 0.85], P = 0.0005), which was statistically significant. OS also improved but did not statistically significant (HR = 0.80 [95% CI 0.61, 1.05], P = 0.11). PD-1/PD-L1 combined with CTLA-4 inhibitors had a higher incidence of adverse reactions than conventional treatment (OR = 1.72 [95% CI 0.59, 5.09], P = 0.33), but the incidence of grade≥3 AEs was lower than the control group (OR = 0.96 [95% CI 0.64, 1.44], P = 0.85).

Conclusion

Double checkpoint inhibitor PD-1/PD-L1 combined with CTLA-4 antibody has synergistic anti-cancer activity and improved ORR and PFS in lung cancer. Adverse reactions are more common than conventional treatment, but are generally controllable. Therefore, PD-1/PD-L1 combined with CTLA-4 inhibitors provides a beacon for the treatment of advanced lung cancer, which has guiding significance for the treatment selection in the future.
SARSeq, a robust and highly multiplexed NGS assay for parallel detection of SARS-CoV2 and other respiratory infections
Authors: Yelagandula Ramesh , Bykov Aleksandr , Vogt Alexander , Heinen Robert , Özkan Ezgi , Strobl Marcus Martin , Baar Juliane Christina , Uzunova Kristina , Hajdusits Bence , Kordic Darja , Suljic Erna , Kurtovic-Kozaric Amina , Izetbegovic Sebija , Schaefer Justine , Hufnagl Peter , Zoufaly Alexander , Seitz Tamara ,   VCDI, Födinger Manuela , Allerberger Franz , Stark Alexander , Cochella Luisa , Elling Ulrich
Published: November 2020

During a pandemic, mitigation as well as protection of system-critical or vulnerable institutions requires massively parallel, yet cost-effective testing to monitor the spread of agents such as the current SARS-CoV2 virus. Here we present SARSeq, saliva analysis by RNA sequencing, as an approach to monitor presence of SARS-CoV2 and other respiratory viruses performed on tens of thousands of samples in parallel. SARSeq is based on next generation sequencing of multiple amplicons generated in parallel in a multiplexed RT-PCR reaction. It relies on a two-dimensional unique dual indexing strategy using four indices in total, for unambiguous and scalable assignment of reads to individual samples. We calibrated this method using dilutions of synthetic RNA and virions to show sensitivity down to a few molecules, and applied it to hundreds of patient samples validating robust performance across various sample types. Double blinded benchmarking to gold-standard quantitative RT-PCR performed in a clinical setting and a human diagnostics laboratory showed robust performance up to a Ct of 36. The false positive rate, likely due to cross contamination during sample pipetting, was estimated at 0.04-0.1%. In addition to SARS-CoV2, SARSeq detects Influenza A and B viruses as well as human rhinovirus and can be easily expanded to include detection of other pathogens. In sum, SARSeq is an ideal platform for differential diagnostic of respiratory diseases at a scale, as is required during a pandemic.
Residual SARS-CoV-2 viral antigens detected in gastrointestinal and hepatic tissues from two recovered COVID-19 patients
Authors: Cheung Chun Chau Lawrence , Goh Denise , Lim Xinru , Tien Tracy Zhijun , Lim Jeffrey Chun Tatt , Nerurkar Sanjna Nilesh , Shihleone Loong , Cheow Peng Chung , Chan Chung Yip , Koh Ye Xin , Tan Thuan Tong , Kalimuddin Shirin , David Tai Wai Meng , Ng Jia Lin , Hong Low Jenny Guek , Yeong Joe , Hon Lim Tony Kiat
Published: November 2020

Residual SARS-CoV-2 RNA has been detected in stool samples and gastrointestinal tissues during the convalescence phase of COVID-19 infection. This raises concern for persistence of SARS-CoV-2 virus particles and faecal-oral transmissibility in recovered COVID-19 patients. Using multiplex immunohistochemistry, we unexpectedly detected SARS-CoV-2 viral antigens in intestinal and liver tissues, in surgical samples obtained from two patients who recovered from COVID-19. We further validated the presence of virus by RT-PCR and flow cytometry to detect SARS-CoV-2-specific immunity in the tissues. These findings might have important implications in terms of disease management and public health policy regarding transmission of COVID-19 via faecal-oral and iatrogenic routes during the convalescence phase.
Detecting corticospinal tract impairment in tumor patients with fiber density and tensor-based metrics
Authors: Fekonja L. S. , Wang Z. , Aydogan D. B. , Roine T. , Engelhardt M. , Dreyer F. R. , Vajkoczy P. , Picht T.
Published: November 2020

Tumors infiltrating the motor system lead to significant disability, often caused by corticospinal tract injury. The delineation of the healthy-pathological white matter (WM) interface area, for which diffusion magnetic resonance imaging (dMRI) has shown promising potential, may improve treatment outcome. However, up to 90% of white matter (WM) voxels include multiple fiber populations, which cannot be correctly described with traditional metrics such as fractional anisotropy (FA) or apparent diffusion coefficient (ADC). Here, we used a novel fixel-based along-tract analysis consisting of constrained spherical deconvolution (CSD) based probabilistic tractography and fixel-based apparent fiber density (FD), capable of identifying fiber orientation specific microstructural metrics. We addressed this novel methodology’s capability to detect corticospinal tract impairment.

We measured and compared tractogram-related FD and traditional microstructural metrics bihemispherically in 65 patients with WHO grade III and IV gliomas infiltrating the motor system. The cortical tractogram seeds were based on motor maps derived by transcranial magnetic stimulation. We extracted 100 equally distributed cross-sections along each streamline of corticospinal tract (CST) for along-tract statistical analysis. Cross-sections were then analyzed to detect differences between healthy and pathological hemispheres.

All metrics showed significant differences between healthy and pathologic hemispheres over the entire tract and between peritumoral segments. Peritumoral values were lower for FA and FD, but higher for ADC within the entire cohort. FD was more specific to tumor-induced changes in CST than ADC or FA, whereas ADC and FA showed higher sensitivity.

The bihemispheric along-tract analysis provides an approach to detect subject-specific structural changes in healthy and pathological WM. In the current clinical dataset, the more complex FD metrics did not outperform FA and ADC in terms of describing corticospinal tract impairment.
Simple discrete-time self-exciting models can describe complex dynamic processes: a case study of COVID-19
Authors: Browning Raiha , Sulem Deborah , Mengersen Kerrie , Rivoirard Vincent , Rousseau Judith
Published: November 2020

Hawkes processes are a form of self-exciting process that has been used in numerous applications, including neuroscience, seismology, and terrorism. While these self-exciting processes have a simple formulation, they are able to model incredibly complex phenomena. Traditionally Hawkes processes are a continuous-time process, however we enable these models to be applied to a wider range of problems by considering a discrete-time variant of Hawkes processes. We illustrate this through the novel coronavirus disease (COVID-19) as a substantive case study. While alternative models, such as compartmental and growth curve models, have been widely applied to the COVID-19 epidemic, the use of discrete-time Hawkes processes allows us to gain alternative insights. This paper evaluates the capability of discrete-time Hawkes processes by retrospectively modelling daily counts of deaths as two distinct phases in the progression of the COVID-19 outbreak: the initial stage of exponential growth and the subsequent decline as preventative measures become effective. We consider various countries that have been adversely affected by the epidemic, namely, Brazil, China, France, Germany, India, Italy, Spain, Sweden, the United Kingdom and the United States. These countries are all unique concerning the spread of the virus and their corresponding response measures, in particular, the types and timings of preventative actions. However, we find that this simple model is useful in accurately capturing the dynamics of the process, despite hidden interactions that are not directly modelled due to their complexity, and differences both within and between countries. The utility of this model is not confined to the current COVID-19 epidemic, rather this model could be used to explain many other complex phenomena. It is of interest to have simple models that adequately describe these complex processes with unknown dynamics. As models become more complex, a simpler representation of the process can be desirable for the sake of parsimony.
Phase II Clinical trial for Evaluation of BCG as potential therapy for COVID-19
Authors: Padmanabhan Usha , Mukherjee Sanjay , Borse Rohidas , Joshi Sameer , Deshmukh Rajesh
Published: November 2020

Bacillus Calmette−Guérin (BCG) is widely used in national vaccination programs worldwide. It is accepted that BCG alleviates both pathogen and allergy induced respiratory diseases that could also include Covid-19. To investigate this possibility, we randomly assigned 60 Covid-19 patients, after admission to the hospital with pneumonia and requirement for oxygen therapy in a 1:1 ratio to receive either a single adult dose of intradermal BCG or normal saline with concomitant standard of care (SoC) medications. Primary endpoints were favorable prognosis of Covid-19 as deduced from resolution of pneumonia, viremia and secondary outcome were enumeration of ICU admissions, duration thereof and mortalities.

Results

Both primary and secondary endpoints were significantly improved in the BCG+SoC group. This could be seen from reduction in oxygen requirement due to Covid-19 associated pneumonia decreasing from day 3-4, improved radiological resolution from day 7-15. There were a total of 6 (10%) adverse events in the study of which 2 deaths and 4 ICU admissions were in SoC group (1 ICU admission culminated in death of the subject) and in contrast only 1 ICU admission in the BCG+SoC group. While there was an increase in Covid-19 specific IgG levels in the BCG+SoC group, there was no evidence of BCG induced cytokine storm in this group. Four patients showed localized inflammatory response at the injection site in the BCG+SoC group.

Conclusions

BCG+SoC administration resulted in a significantly higher percentage of patients with favorable outcomes than did SoC. A third of the patients were naïve for childhood BCG vaccination. This mimicked elderly patients in countries with no universal vaccination policy for BCG. No BCG related adversity was seen in this group. The study shows that BCG is a safe, cost-effective treatment that can be introduced as a standard of care in patients with moderate Covid-19 that can reduce requirement of oxygen supplemented beds and disease burden in low resource countries, with additional long-term benefits of reducing risk for tuberculosis.
A Time-dependent mathematical model for COVID-19 transmission dynamics and analysis of critical and hospitalized cases with bed requirements
Authors: Singh Avaneesh , Bajpai Manish Kumar , Gupta Shyam Lal
Published: November 2020

A time-dependent SEAIHCRD model is the extension of the SEIR model, which includes some new compartment that is asymptomatic infectious people, hospitalized people, critical people, and dead compartments. In this article, we analyzed six countries, namely the United States, Brazil, India, South Africa, Russia, and Mexico. A time-dependent SEAIHCRD model calculates the magnitude of peaks for exposed people, asymptomatic infectious people, symptomatic infectious people, hospitalized people, the number of people admitted to ICUs, and the number of COVID-19 deaths over time. It also computes the spread scenario and endpoints of disease. The proposed model also involves asymptomatic infectious individuals. To estimate the various parameters, we first collect the data and fit that using the Lavenberg-Marquardt model for death cases. Then we calculate infection rate, recovery rate, case fatality rate, and the basic reproduction number over time. We calculate two types of case fatality rates: one is the daily case fatality rate, and the other is the total case fatality rate. The proposed model includes the social distance parameter, various age classes, hospital beds for severe cases, and ICU beds or ventilators for critical cases. This model will be useful to determine various essential parameters such as daily hospitalization rate, daily death rates, including the requirement of normal and ICU beds during peak days of infection.
Diagnostic concordance between physiotherapist and emergency physicians for patients with a musculoskeletal disorder in the emergency department
Authors: Gagnon Rose , Perreault Kadija , Brun Gabrielle , Matifat Eveline , Desmeules François , Berthelot Simon , Hébert Luc J.
Published: November 2020

Question

What is the level of diagnostic concordance between physicians and physiotherapists for patients consulting in an emergency department (ED) with musculoskeletal disorders (MSKDs)?

Design

Secondary analysis of data obtained through a pragmatic randomized controlled trial, physiotherapist (PT) and emergency physicians (EPs) unblinded, per-protocol analysis.

Participants

78 participants aged 18 to 80 years presenting with a minor MSKD were recruited and data from the 40 participants randomized in the intervention group were used (mean age 36.6 yrs (SD: 17.3, IQR: 22.0; 46.8); women: 55%).

Outcome measures

Diagnostic concordance was established using the International Classification of Diseases 11 (ICD-11) and examined between EP and PT using raw agreement and Gwet’s first-order agreement coefficient (AC1).

Results

Forty participants were recruited and 36 were assessed by the PT and EP (36.8 ± 18.2 years old; 55.6% women). Overall raw agreement was 86.1% and an almost perfect diagnostic concordance was observed between PT and EP (Gwet’s AC1: 0.84, 95% CI: 0.69 – 0.98). The most common reason for disagreement was suspected bone fracture or contusion in comparison with ligament or meniscus disorder.

Conclusion

Results from this study indicate that overall diagnostic concordance between PT and EP in the ED for patients consulting with MSKDs is almost perfect. These results tend to support the safety of such models of care. However, more studies are needed to confirm these results as the EP wasn’t always independent and the classification used was imprecise.

Registration

#NCT04009369
A catalog of associations between rare coding variants and COVID-19 outcomes
Authors: Kosmicki J. A. , Horowitz J. E. , Banerjee N. , Lanche R. , Marcketta A. , Maxwell E. , Bai X. , Sun D. , Backman J. D. , Sharma D. , Kang H. M. , O’Dushlaine C. , Yadav A. , Mansfield A. J. , Li A. H. , Watanabe K. , Gurski L. , McCarthy S. E. , Locke A. E. , Khalid S. , O’Keeffe S. , Mbatchou J. , Chazara O. , Huang Y. , Kvikstad E. , O’Neill A. , Nioi P. , Parker M. M. , Petrovski S. , Runz H. , Szustakowski J. D. , Wang Q. , Wong E. , Cordova-Palomera A. , Smith E. N. , Szalma S. , Zheng X. , Esmaeeli S. , Davis J. W. , Lai Y-P. , Chen X. , Justice A. E. , Leader J. B. , Mirshahi T. , Carey D. J. , Verma A. , Sirugo G. , Ritchie M. D. , Rader D. J. , Povysil G. , Goldstein D. B. , Kiryluk K. , Pairo-Castineira E. , Rawlik K. , Pasko D. , Walker S. , Meynert A. , Kousathanas A. , Moutsianas L. , Tenesa A. , Caulfield M. , Scott R. , Wilson J. F. , Baillie J. K. , Butler-Laporte G. , Nakanishi T. , Lathrop M. , Richards J.B. ,   Regeneron Genetics Center,   UKB Exome Sequencing Consortium, Jones M. , Balasubramanian S. , Salerno W. , Shuldiner A. R. , Marchini J. , Overton J. D. , Habegger L. , Cantor M. N. , Reid J. G. , Baras A. , Abecasis G. R. , Ferreira M. A.
Published: November 2020

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) causes coronavirus disease-19 (COVID-19), a respiratory illness that can result in hospitalization or death. We investigated associations between rare genetic variants and seven COVID-19 outcomes in 543,213 individuals, including 8,248 with COVID-19. After accounting for multiple testing, we did not identify any clear associations with rare variants either exome-wide or when specifically focusing on (i) 14 interferon pathway genes in which rare deleterious variants have been reported in severe COVID-19 patients; (ii) 167 genes located in COVID-19 GWAS risk loci; or (iii) 32 additional genes of immunologic relevance and/or therapeutic potential. Our analyses indicate there are no significant associations with rare protein-coding variants with detectable effect sizes at our current sample sizes. Analyses will be updated as additional data become available, with results publicly browsable athttps://rgc-covid19.regeneron.com.
Occupational risk of COVID-19 in the 1stvs 2ndwave of infection
Authors: Magnusson Karin , Nygård Karin , Methi Fredrik , Vold Line , Telle Kjetil
Published: November 2020

Aim

To study whether employees in occupations that typically imply close contact with other people are tested more and at higher risk of confirmed SARS-CoV-2 infection (COVID-19) and related hospitalization, in the 1stand 2ndwave of infection in Norway.

Methods

In all 3 559 694 residents of Norway on January 1st2020 aged 20-70 (with mean [SD] age 44.1 [14.3] years and 51% men), we studied COVID-19 testing patterns sorted by occupation (using Standard Classification of Occupations [ISCO-08]). We also studied whether selected occupations had a higher risk of 1) confirmed COVID-19 and 2) hospitalization with COVID-19, compared to everyone else aged 20-70 years using logistic regression adjusted for age, sex, testing behavior, and own and maternal country of birth.

Results

Occupations with high frequency of testing (e.g. health personnel and teachers) had a low frequency of positive tests. Nurses, physicians, dentists, physiotherapists, bus/tram and taxi drivers had 1.1-4 times the odds of COVID-19 during the 1stwave, whereas bartenders, waiters, transport conductors and travel stewards had 1.1-3 times the odds of COVID-19 during the 2ndwave (when compared to everyone else). Teachers had moderately increased odds of COVID-19. Occupation may be of limited relevance for hospitalization with the disease.

Conclusion

Studying the entire Norwegian population using international standardized codes of occupations, our findings may be of relevance to national and regional authorities in handling the pandemic. Also, our findings provide a knowledge foundation for the more targeted future studies of lockdown, testing strategies and disease control measures.
Using RT-PCR Testing to Assess the Effectiveness of Outbreak Control Efforts in São Paulo State, the Pandemic’s Epicenter in Brazil, according to Socioeconomic Vulnerabilities
Authors: Sousa Tatiane C M , Moreira Natália P , Krieger Jose E. , Rosa Isabel S C , Zamudio Marcela M. , Veras Maria Amélia S M , Kemp Brigina , Barberia Lorena G.
Published: November 2020

Background

The testing of infected persons with SARS-CoV-2 is one of the cornerstones of an effective strategy deployed for pandemic control. The public health diagnostic effort is particularly important in regions with a critical transmission scenario and in vulnerable populations in these districts, such as São Paulo state, the Brazilian epicenter of the COVID-19 pandemic.

Methods

We developed an RT-PCR testing intensity effort index (RT-PCR TIEI) composed of seven indicators to assess the survelliance efforts in the São Paulo State. We used dynamic time-series cross-sectional models to analyze the association between the RT-PCR TIEI, the population living under high socioeconomic vulnerability levels, dependent on public health service (SUS), per capita income, and population density.

Results

On average, the RT-PCR TIEI score was 21.07. In the long-run, the RT-PCR TIEI is negatively associated with socioeconomic vulnerability (p-value=0.000, 95% CI −0.887, - 0.811), with a higher proportion of the population dependent on SUS (p-value= 0.000, 95% CI −0.871, −0.805), per capita income (p-value= 0.000, 95% CI −0.849,-0.792) and with population density (p-value=0.000, 95% CI −0.853; −0.801).

Conclusion

Testing efforts declined as the pandemic advanced, and the the lowest RT-PCR TIEI values were found in the most socioeconomic vulnerable RHDs. Local public laboratory presence was a predictor of a higher score. Thus, the low testing RT-PCR efforts and local laboratory inequalities affected surveillance capability, especially for socioeconomic vulnerable populations.