bluuebunny/crossref_metadata_2025 huggingface dataset:
Exosome-Induced Vaginal Tissue Regeneration in a Porcine Mesh Exposure Model
Authors: Kisby Cassandra K. , Shadrin Ilya Y. , Rolland Tyler J. , Stalboerger Paul G. , Zhou Boran , Trabuco Emanuel C. , Behfar Atta , Occhino John A.
Published: January 2021

Objectives

The purpose of this study was to explore the utility of an injectable purified exosome product derived from human apheresis blood to (1) augment surgical closure of vaginal mesh exposures, and (2) serve as a stand-alone therapy for vaginal mesh exposure.

Methods

Sixteen polypropylene meshes (1×1–3×3 cm) were implanted in the vaginas of 7 Yorkshire-crossed pigs by urogynecologic surgeons (day 0). On day 7, group 1 underwent surgical intervention via vaginal tissue suture reclosure with (n=2 pigs, n=4 meshes) or without (n=2 pigs, n=4 meshes) exosome injection; group 2 underwent medical intervention with an exosome injection (n=3, n=8 meshes). One animal in group 2 was given oral 2′-deoxy-5-ethynyluridine to track cellular regeneration. Euthansia occurred at 5 weeks.

Results

Mesh exposures treated with surgical closure alone experienced reexposure of the mesh. Exosome treatment with or without surgical closure resulted in partial to full mesh exposure resolution up to 3×3 cm. Exosome-treated tissues had significantly thicker regenerated epithelial tissue (208 μm exosomes-only and 217 μm surgery+exosomes, versus 80 μm for surgery-only; P < 0.05); evaluation of 2′-deoxy-5-ethynyluridine confirmed de novo regeneration throughout the epithelium and underlying tissues. Capillary density was significantly higher in the surgery+exosomes group (P = 0.03). Surgery-only tissues had a higher inflammatory and fibrosis response as compared with exosome-treated tissues.

Conclusions

In this pilot study, exosome treatment augmented healing in the setting of vaginal mesh exposure, reducing the incidence of mesh reexposure after suture closure and decreasing the area of mesh exposure through de novo tissue regeneration after exosome injection only. Further study of varied local tissue conditions and mesh configurations is warranted.
Acute Complete Oculomotor Nerve Palsy in a Young Male Due to a Skull Base Myofibroma
Authors: Hoang Tung Thanh , Van Le Thuy , Tran Dat , Ho Thuong Duc , Thi Le Nhung Hong , Subramanian Prem S.
Published: January 2021

A 25-year-old male patient visited the ophthalmology clinic because of upper eye lid ptosis in the right eye, binocular double vision, and light sensitivity. He was diagnosed with a complete third nerve palsy caused by a skull base myofibroma, a rare clinical entity that has not been described before in oculomotor nerve palsy.
Occupational and environmental exposure to SARS-CoV-2 in and around infected mink farms
Authors: de Rooij Myrna M.T. , Hakze-Van der Honing Renate W. , Hulst Marcel M. , Harders Frank , Engelsma Marc , van de Hoef Wouter , Meliefste Kees , Nieuwenweg Sigrid , Munnink Bas B. Oude , Schothorst Isabella van , Sikkema Reina S. , van der Spek Arco N. , Spierenburg Marcel , Spithoven Jack , Bouwstra Ruth , Molenaar Robert-Jan , Koopmans Marion , Stegeman Arjan , van der Poel Wim H.M. , Smit Lidwien A.M.
Published: January 2021

Unprecedented SARS-CoV-2 infections in farmed minks raised immediate concerns regarding human health which initiated intensive environmental investigations. Air sampling was performed in infected mink farms, at farm premises and at residential sites. A range of other environmental samples were collected from minks’ housing units including bedding material. Inside the farms, high levels of SARS-CoV-2 RNA were found in airborne dust, on surfaces, and on various other environmental matrices. This warns for occupational exposure which was substantiated by considerable SARS-CoV-2 RNA concentrations in personal air samples. Dispersion of SARS-CoV-2 to outdoor air was found to be limited and SARS-CoV-2 RNA was not detected in air samples collected beyond farm premises, implying a negligible environmental exposure risk for nearby communities. Our occupational and environmental risk assessment is in line with whole genome sequences analyses showing mink-to-human transmission in farm workers, but no indications for direct zoonotic transmission events to nearby communities.
Emergence of multiple SARS-CoV-2 mutations in an immunocompromised host
Authors: Khatamzas Elham , Rehn Alexandra , Muenchhoff Maximilian , Hellmuth Johannes , Gaitzsch Erik , Weiglein Tobias , Georgi Enrico , Scherer Clemens , Stecher Stephanie , Weigert Oliver , Girl Philipp , Zange Sabine , Keppler Oliver T. , Stemmler Joachim , von Bergwelt-Baildon Michael , Wölfel Roman , Antwerpen Markus
Published: January 2021

Prolonged shedding of infectious SARS-CoV-2 has recently been reported in a number of immunosuppressed individuals with COVID-19. Here, we describe the detection of high levels of replication-competent SARS-CoV-2 in specimens taken from the respiratory tract of a B-cell depleted patient up to 154 days after initial COVID-19 diagnosis concomitant with the development of high mutation rate. In this patient, a total of 11 nonsynonymous mutations were detected in addition to the Y144 deletion in the spike protein of SARS-CoV-2.

Virus evolution studies revealed a dramatic diversification in viral population coinciding with treatment with convalescent plasma and clinical respiratory deterioration. Our findings highlight the urgent need for continuous real-time surveillance of genetic changes of SARS-CoV-2 adaptation alongside immunological investigations in patients with severely compromised humoral responses who may shed infectious virus over prolonged periods of time.
Social and Leisure Activity Contribute to the Attenuation of Decline in Behavioral Variant Frontotemporal Degeneration
Authors: Kinney Nikolas G. , Bove Jessica , Phillips Jeffrey S. , Cousins Katheryn A. , Olm Christopher A. , Wakeman Daniel G. , McMillan Corey T. , Massimo Lauren
Published: January 2021

Behavioral variant frontotemporal degeneration (bvFTD) is clinically characterized by progressive decline in social and executive domains. Previous work suggests that early lifestyle factors such as education and occupational attainment may relate to structural integrity and moderate the rate of cognitive decline in bvFTD, but the role of other cognitively stimulating activities is understudied. We sought to investigate the effect of such activities on cortical thickness (CT) in bvFTD. bvFTD patients (n=31) completed a baseline MRI scan, and informants for the patients completed the Lifetime of Experiences Questionnaire (LEQ), which measures specific activities considered to be undertaken primarily within one particular life phase, such as education (young-life), occupation (mid-life), and social/leisure activity (late-life). At baseline, linear models assessed the effect of LEQ scores from each life phase on regional CT. A subset (n=19) of patients completed longitudinal MRI, and to evaluate the association of LEQ with longitudinal rates of CT decline, we derived individualized slopes of decline using linear mixed effects models and these were related to LEQ scores from each life phase. At baseline, a higher late-life LEQ score was associated with less atrophy in bilateral superior anterior temporal regions. Longitudinally, we observed that higher late-life LEQ scores were associated with an attenuated rate of CT loss in insular cortex. Late-life LEQ score was positively associated with both relatively preserved CT early in bvFTD and a slower rate of cortical loss in regions important for social functioning. These findings suggest that social and leisure activities may contribute to a form of resilience against pathologic effects of disease.
Transmission dynamics and forecasts of the COVID-19 pandemic in Mexico, March 20-November 11, 2020
Authors: Tariq Amna , Banda Juan M. , Skums Pavel , Dahal Sushma , Castillo-Garsow Carlos , Espinoza Baltazar , Brizuela Noel G. , Saenz Roberto A. , Kirpich Alexander , Luo Ruiyan , Srivastava Anuj , Gutierrez Humberto , Chan Nestor Garcia , Bento Ana I. , Jimenez-Corona Maria-Eugenia , Chowell Gerardo
Published: January 2021

Mexico has experienced one of the highest COVID-19 death rates in the world. A delayed response towards implementation of social distancing interventions until late March 2020 and a phased reopening of the country in June 2020 has facilitated sustained disease transmission in the region. Here, we systematically generate and compare 30-day ahead forecasts using previously validated growth models based on mortality trends from the Institute for Health Metrics and Evaluation for Mexico and Mexico City in near real-time. Moreover, we estimate reproduction numbers for SARS-CoV-2 based on methods that rely on genomic data as well as case incidence data. Subsequently, functional data analysis techniques are utilized to analyze the shapes of COVID-19 growth rate curves at the state level to characterize the spatial-temporal transmission patterns. The early estimates of reproduction number for Mexico were estimated between R∼1.1-from genomic and case incidence data. Moreover, the mean estimate of R has fluctuated ∼1.0 from late July till end of September 2020. The spatial analysis characterizes the state-level dynamics of COVID-19 into four groups with distinct epidemic trajectories. We found that the sequential mortality forecasts from the GLM and Richards model predict downward trends in the number of deaths for all thirteen forecasts periods for Mexico and Mexico City. The sub-epidemic and IHME models predict more realistic stable trajectory of COVID-19 mortality trends for the last three forecast periods (09/21-10/21 - 09/28-10/27) for Mexico and Mexico City. Our findings support the view that phenomenological models are useful tools for short-term epidemic forecasting albeit forecasts need to be interpreted with caution given the dynamic implementation and lifting of social distancing measures.
Lessons learnt from the use of compartmental models over the COVID-19 induced lockdown in France
Authors: Gauchon Romain , Ponthus Nicolas , Pothier Catherine , Rigotti Christophe , Volpert Vitaly , Derrode Stéphane , Bertoglio Jean-Pierre , Bienvenüe Alexis , Goffard Pierre-Olivier , Eyraud-Loisel Anne , Pageaud Simon , Iwaz Jean , Loisel Stéphane , Roy Pascal
Published: January 2021

Background

Compartmental models help making public health decisions. They were used during the COVID-19 outbreak to estimate the reproduction numbers and predict the number of hospital beds required. This study examined the ability of closely related compartmental models to reflect equivalent epidemic dynamics.

Methods

The study considered three independently designed compartmental models that described the COVID-19 outbreak in France. Model compartments and parameters were expressed in a common framework and models were calibrated using the same hospitalization data from two official public databases. The calibration procedure was repeated over three different periods to compare model abilities to: i) fit over the whole lockdown; ii) predict the course of the epidemic during the lockdown; and, iii) provide profiles to predict hospitalization prevalence after lockdown. The study considered national and regional coverages.

Results

The three models were all flexible enough to match real hospitalization data during the lockdown, but the numbers of cases in the other compartments differed. The three models failed to predict reliably the number of hospitalizations after the fitting periods at national as at regional scales. At the national scale, an improved calibration led to epidemic course profiles that reflected hospitalization dynamics and reproduction numbers that were coherent with official and literature estimates.

Conclusion

This study shows that prevalence data are needed to further refine the calibration and make a selection between still divergent models. This underlines strongly the need for repeated prevalence studies on representative population samples.
Sub-lethal aquatic doses of pyriproxyfen may increase pyrethroid resistance in malaria mosquitoes
Authors: Opiyo Mercy A. , Ngowo Halfan S. , Mapua Salum A. , Mpingwa Monica , Matowo Nancy S. , Majambere Silas , Okumu Fredros O.
Published: January 2021

Background

Pyriproxyfen (PPF), an insect growth hormone mimic is widely used as a larvicide and in some second-generation bed nets, where it is combined with pyrethroids to improve impact. It has also been evaluated as a candidate for auto-dissemination by adult mosquitoes to controlAedesandAnophelesspecies. We examined whether PPF added to larval habitats of pyrethroid-resistant malaria vectors can modulate levels of resistance among emergent adult mosquitoes.

Methodology

Third-instar larvae of pyrethroid-resistantAnopheles arabiensis(both laboratory-reared and field-collected) were reared in different PPF concentrations, between 1×10-9milligrams active ingredient per litre of water (mgAI/L) and 1×10-4mgAI/L, or no PPF at all. Emergent adults escaping these sub-lethal exposures were tested using WHO-standard susceptibility assays on pyrethroids (0.75% permethrin and 0.05% deltamethrin), carbamates (0.1% bendiocarb) and organochlorides (4% DDT). Biochemical basis of pyrethroid resistance was investigated by pre-exposure to 4% PBO. Bio-efficacies of long-lasting insecticide-treated nets, Olyset®and PermaNet 2.0 were also examined against adult mosquitoes with or without previous aquatic exposure to PPF.

Results

Addition of sub-lethal doses of PPF to larval habitats of pyrethroid-resistantAn. arabiensis, consistently resulted in significantly reduced mortalities of emergent adults when exposed to pyrethroids, but not to bendiocarb or DDT. Mortality rates after exposure to Olyset®nets, but not PermaNet 2.0 were also reduced following aquatic exposures to PPF. Pre-exposure to PBO followed by permethrin or deltamethrin resulted in significant increases in mortality, compared to either insecticide alone.

Conclusions

Partially-resistant mosquitoes exposed to sub-lethal aquatic concentrations of PPF may become more resistant to pyrethroids than they already are without such pre-exposures. Studies should be conducted to examine whether field applications of PPF, either by larviciding or other means actually excercebates pyrethroid-resistance in areas where signs of such resistance already exist in wild the vector populations. The studies should also investigate mechanisms underlying such magnification of resistance, and how this may impact the potential of PPF-based interventions in areas with pyrethroid resistance.
GIS-Based Analysis Framework for identifying COVID-19 Incidence and Fatality Determinants at National Level Case study: Africa
Authors: Hassan Mahmoud A. , Ghazy Ramy Mohamed , Abdelwahab Rofida G. , Elbarky Toka A.
Published: January 2021

Background

COVID-19 pandemic is an extraordinary threat with significant implications in all aspects of human life, therefore, it represents the most immediate challenges for all countries all over the world.

Objectives

This study is intended to develop a GIS-based analysis model to explore, quantify and model the relationships between COVID-19 morbidity and mortality and their potential predictor variables.

Method

For this purpose, a model was developed to estimate COVID-19 incidence and fatality rates in Africa up to 16thof August 2020 at the national level. The model involved Ordinary Least Squares (OLS) and Geographically Weighted Regression (GWR) analysis through ArcGIS was applied.

Result

Spatial Autocorrelation Analysis revealed that there was positive spatial autocorrelation in COVID-19 incidence (Moran index 0.16.Pvalue <0.1), and fatality (Moran index 0.0.35,Pvalue<0.01) rates within different African countries. At continental level, OLS revealed that COVID-19 incidence rate was found to be positively associated with overcrowding, health expenditure, HIV infections and air pollution and negatively associated with BCG vaccine (β=2.97,1.45, 0.01, 3.29, −47.65 respectively,P< 0.05) At the same time, COVID-19 fatality was found to be positively related to asthma prevalence and tobacco use. Yet, certain level of inconsistency was noted in the case of COVID-19 fatality, which was negatively related to elder population, poverty, and cardiovascular mortality (P<0.05). This model showed convenient level of validity in modeling the relationship between COVID-19 incidence as well as fatality and their key predictors using GWR. In this respect, the model explained about 58% and 55% of the variance in COVID-19 incidence and fatality rates, respectively, as a function of considered predictors.

Conclusion

Application of the suggested model can assist in guiding intervention strategies, particularly in case of local and community level whenever the data on COVID-19 cases and predictors variables are available.
Benefits of natural habitat particularly woodland on children’s cognition and mental health
Authors: Maes Mikaël J. A. , Pirani Monica , Booth Elizabeth R. , Shen Chen , Milligan Ben , Jones Kate E. , Toledano Mireille B.
Published: January 2021

Life in urban areas is associated with adverse human health effects, including risks of developing cognitive problems and mental health issues. Many epidemiological studies have established associations between urban nature, cognitive development and mental health, but why specifically we receive these health benefits remains unclear, especially in children. Here, we used longitudinal data in a cohort of 3,568 children aged 9 to 15 years at 31 schools across London to develop a model and examine the associations between natural habitat type, and children’s cognitive development and mental health. We show that, after adjusting for other environmental, demographic and socioeconomic variables, higher daily exposure rates to natural habitat and particularly woodland were associated with enhanced cognitive development and mental health from late childhood to early adolescence. Our results suggest that optimising ecosystem services linked to cognitive development and mental health benefits should prioritise the type of natural habitat for sustainable urban planning decisions.
Diverse Humoral Immune Responses in Younger and Older Adult COVID-19 Patients
Authors: Sasson Jennifer M. , Campo Joseph J. , Carpenter Rebecca M. , Young Mary K. , Randall Arlo Z. , Trappl-Kimmons Krista , Oberai Amit , Hung Christopher , Edgar Joshua , Teng Andy A. , Pablo Jozelyn V. , Liang Xiaowu , Yee Angela , Petri William A. , Camerini David
Published: January 2021

We sought to discover links between antibody responses to SARS-CoV-2 and patient clinical variables, cytokine profiles and antibodies to endemic coronaviruses. Serum from patients of varying ages and clinical severity were collected and used to probe a novel multi-coronavirus protein microarray containing SARS-CoV-2 proteins and overlapping protein fragments of varying length as well as SARS-CoV, MERS-CoV, HCoV-OC43 and HCoV-NL63 proteins. IgG, IgA and IgM antibody responses to specific epitopes within the spike (S), nucleocapsid (N) and membrane proteins (M) were higher in older adult patients. Moreover, the older age group displayed more consistent correlations of antibody reactivity with systemic cytokine and chemokine responses when compared to the younger adult group. A subset of patients, however, had little or no response to SARS-CoV-2 antigens and disproportionately severe clinical outcomes. Further characterization of these serosilent individuals with cytokine analysis revealed significant differences in IL-10, IL-15, IP-10, EGF and sCD40L levels when compared to seroreactive patients in the cohort.
State-of-the-art structural variant calling: What went conceptually wrong and how to fix it?
Authors: Schmidt Markus , Kutzner Arne
Published: January 2021

Structural variant (SV) calling belongs to the standard tools of modern bioinformatics for identifying and describing alterations in genomes. Initially, this work presents several complex genomic rearrangements that reveal conceptual ambiguities inherent to the SV representations of state-of-the-art SV callers. We contextualize these ambiguities theoretically as well as practically and propose a graph-based approach for resolving them. Our graph model unifies both genomic strands by using the concept of skew-symmetry; it supports graph genomes in general and pan genomes in specific. Instances of our model are inferred directly from seeds instead of the commonly used alignments that conflict with various types of SV as reported here. For yeast genomes, we practically compute adjacency matrices of our graph model and demonstrate that they provide highly accurate descriptions of one genome in terms of another. An open-source prototype implementation of our approach is available under the MIT license at https://github.com/ITBE-Lab/MA.
Low generalizability of polygenic scores in African populations due to genetic and environmental diversity
Authors: Majara Lerato , Kalungi Allan , Koen Nastassja , Zar Heather , Stein Dan J. , Kinyanda Eugene , Atkinson Elizabeth G. , Martin Alicia R.
Published: January 2021

African populations are vastly underrepresented in genetic studies but have the most genetic variation and face wide-ranging environmental exposures globally. Because systematic evaluations of genetic prediction had not yet been conducted in ancestries that span African diversity, we calculated polygenic risk scores (PRS) in simulations across Africa and in empirical data from South Africa, Uganda, and the UK to better understand the generalizability of genetic studies. PRS accuracy improves with ancestry-matched discovery cohorts more than from ancestry-mismatched studies. Within ancestrally and ethnically diverse South Africans, we find that PRS accuracy is low for all traits but varies across groups. Differences in African ancestries contribute more to variability in PRS accuracy than other large cohort differences considered between individuals in the UK versus Uganda. We computed PRS in African ancestry populations using existing European-only versus ancestrally diverse genetic studies; the increased diversity produced the largest accuracy gains for hemoglobin concentration and white blood cell count, reflecting large-effect ancestry-enriched variants in genes known to influence sickle cell anemia and the allergic response, respectively. Differences in PRS accuracy across African ancestries originating from diverse regions are as large as across out-of-Africa continental ancestries, requiring commensurate nuance.
Using a biologically mimicking climbing robot to explore the performance landscape of climbing in lizards
Authors: Schultz Johanna T. , Beck Hendrik K. , Haagensen Tina , Proost Tasmin , Clemente Christofer J.
Published: January 2021

The life and death of an organism often depends on its ability to perform well at some ecologically relevant task. Yet despite this significance we have little idea how well species are optimised for competing locomotor tasks. Most scientists generally accept that the ability for natural systems to become optimised for a specific task is limited by structural, historic or functional constraints. Climbing lizards provide a good example of constraint where climbing ability requires the optimization of conflicting tasks such as speed, stability, or efficiency. Here we reconstruct multiple performance landscapes of climbing locomotion using a 10-DOF robot based upon the lizard bauplan, including an actuated spine, shoulders, and feet, the latter which interlock with the surface via claws. This design allows us to independently vary speed, foot angles, and range of motion, while simultaneously collecting data on climbed distance, stability and efficiency. We first demonstrate a trade-off between speed and stability with high speeds resulting in decreased stability and low speeds an increased cost of transport. By varying foot orientation of fore and hindfeet independently, we found geckos converge on a narrow optimum for both speed and stability, but avoid a secondary wider optimum highlighting a possible constraint. Modifying the spine and limb range of movement revealed a gradient in performance. Evolutionary modifications in movement among extant species appear to follow this gradient towards areas which promote speed and efficiency. This approach can give us a better understanding about locomotor optimization, and provide inspiration for industrial and search-and-rescue robots.

Significance Statement

Climbing requires the optimization of conflicting tasks such as speed, stability, or efficiency, but understanding the relative importance of these competing performance traits is difficult.

We used a highly modular bio-inspired climbing robot to reconstruct performance landscapes for climbing lizards. We then compared the performance of extant species onto these and show strong congruence with lizard phenotypes and robotic optima.

Using this method we can show why certain phenotypes are not present among extant species, illustrating why these would be potentially mal-adaptive.

These principles may be useful to compare with relative rates of evolution along differing evolutionary histories. It also highlights the importance of biological inspiration towards the optimization of industrial climbing robots, which like lizards, must negotiate complex environments.
COVID-19: Rapid Antigen detection for SARS-CoV-2 by lateral flow assay: a national systematic evaluation for mass-testing
Authors: Peto Tim ,   UK COVID-19 Lateral Flow Oversight Team
Published: January 2021

Lateral flow device (LFD) viral antigen immunoassays have been developed around the world as diagnostic tests for SARS-CoV-2 infection. They have been proposed to deliver an infrastructure-light, cost-economical solution giving results within half an hour. Here we report on standardised laboratory evaluations of LFDs, and for those that met the published criteria, field testing in the Falcon-C19 research study and UK pilots (UK COVID-19 testing centres, hospital, schools, armed forces). 4/64 LFDs so far have desirable performance characteristics (Orient Gene, Deepblue, Abbott and Innova SARS-CoV-2 Antigen Rapid Qualitative Test). All these LFDs have a viral antigen detection of >90% at 100,000 RNA copies/ml. 8951 Innova LFD tests were performed with a kit failure rate of 5.6% (502/8951, 95% CI: 5.1-6.1), false positive rate of 0.32% (22/6954, 95% CI: 0.20-0.48). Viral antigen detection/sensitivity across the sampling cohort when performed by laboratory scientists (156/198, 95% CI 72.4-84.3) was 78.8%. Our results suggest LFDs have promising performance characteristics for mass population testing and can be used to identify infectious positive individuals. The Innova LFD shows good viral antigen detection/sensitivity with excellent specificity, although kit failure rates and the impact of training are potential issues. These results support the expanded evaluation of LFDs, and assessment of greater access to testing on COVID-19 transmission.

Funding

Department of Health and Social Care. University of Oxford. Public Health England Porton Down, Manchester University NHS Foundation Trust, National Institute of Health Research.
Evaluation of Urine SARS-COV-2 RT-PCR as a predictor of Acute Kidney Injury and disease severity in critical COVID-19 patients
Authors: de Souza Sérgio Pinto , Silveira Marcelo Augusto Duarte , de Freitas Souza Bruno Solano , Nonaka Carolina Kymie Vasques , de Melo Erica , Cabral Julia , Coelho Fernanda , da Hora Passos Rogério
Published: January 2021

The novel coronavirus disease (COVID-19) is an emerging infectious disease caused by SARS-CoV-2, which began as an outbreak in Wuhan, China and spread rapidly throughout the globe. Although the majority of infections are mild, severe and critical COVID-19 patients face deterioration of respiratory function, and may also present extrapulmonary manifestations, mostly affecting the kidney, digestive tract, heart and nervous system. Here, we prospectively evaluated the presence of SARS-CoV-2 genetic material by RT-PCR in urine samples obtained from critical care COVID-19 patients. In 51 patients included, we found higher serum creatinine levels, a longer hospital stay and a more frequent dialysis need in urine-positive patients. These findings could suggest that, in predisposed patients, a direct viral cytopathic effect may contribute to a more severe disease phenotype.
Application of Optical Genome Mapping For Comprehensive Assessment of Chromosomal Structural Variants for Clinical Evaluation of Myelodysplastic Syndromes
Authors: Yang Hui , Garcia-Manero Guillermo , Rush Diana , Montalban-Bravo Guillermo , Mallampati Saradhi , Medeiros L. Jeffrey , Levy Brynn , Luthra Rajyalakshmi , Kanagal-Shamanna Rashmi
Published: January 2021

Structural chromosomal variants [copy number variants (CNVs): losses/ gains and structural variants (SVs): inversions, balanced and unbalanced fusions/translocations] are important for diagnosis and risk-stratification of myelodysplastic syndromes (MDS). Optical genome mapping (OGM) is a novel single-platform cytogenomic technique that enables high-throughput, accurate and genome-wide detection of all types of clinically important chromosomal variants (CNVs and SVs) at a high resolution, hence superior to current standard-of-care cytogenetic techniques that include conventional karyotyping, FISH and chromosomal microarrays. In this proof-of-principle study, we evaluated the performance of OGM in a series of 12 previously well-characterized MDS cases using clinical BM samples. OGM successfully facilitated detection and detailed characterization of twenty-six of the 28 clonal chromosomal variants (concordance rate: 93% with conventional karyotyping; 100% with chromosomal microarray). These included copy number gains/losses, inversions, inter and intra-chromosomal translocations, dicentric and complex derivative chromosomes; the degree of complexity in latter aberrations was not apparent using standard technologies. The 2 missed aberrations were from a single patient within a composite karyotype, below the limit of detection. Further, OGM uncovered 6 additional clinically relevant sub-microscopic aberrations in 4 (33%) patients that were cryptic by standard-of-care technologies, all of which were subsequently confirmed by alternate platforms. OGM permitted precise gene-level mapping of clinically informative genes such as TP53, TET2 and KMT2A, voiding the need for multiple confirmatory assays. OGM is a potent single-platform assay for high-throughput and accurate identification of clinically important chromosomal variants.
Do antibody positive healthcare workers have lower SARS-CoV-2 infection rates than antibody negative healthcare workers? Large multi-centre prospective cohort study (the SIREN study), England: June to November 2020
Authors: Hall V , Foulkes S , Charlett A , Atti A , Monk EJM , Simmons R , Wellington E , Cole MJ , Saei A , Oguti B , Munro K , Wallace S , Kirwan PD , Shrotri M , Vusirikala A , Rokadiya S , Kall M , Zambon M , Ramsay M , Brooks T ,   SIREN Study Group, Brown CS , Chand MA , Hopkins S
Published: January 2021

Background

There is an urgent need to better understand whether individuals who have recovered from COVID-19 are protected from future SARS-CoV-2 infection.

Methods

A large multi-centre prospective cohort was recruited from publicly funded hospital staff in the UK. Participants attended regular SARS-CoV-2 PCR and antibody testing (every 2-4 weeks) and completed fortnightly questionnaires on symptoms and exposures. At enrolment, participants were assigned to either the positive cohort (antibody positive or prior PCR/antibody test positive) or negative cohort (antibody negative, not previously known to be PCR/antibody positive). Potential reinfections were clinically reviewed and classified according to case definitions (confirmed, probable, possible (subdivided by symptom-status)) depending on hierarchy of evidence. Individuals in the primary infection were excluded from this analysis if infection was confirmed by antibody only. Reinfection rates in the positive cohort were compared against new PCR positives in the negative cohort using a mixed effective multivariable logistic regression analysis.

Findings

Between 18 June and 09 November 2020, 44 reinfections (2 probable, 42 possible) were detected in the baseline positive cohort of 6,614 participants, collectively contributing 1,339,078 days of follow-up. This compares with 318 new PCR positive infections and 94 antibody seroconversions in the negative cohort of 14,173 participants, contributing 1,868,646 days of follow-up. The incidence density per 100,000 person days between June and November 2020 was 3.3 reinfections in the positive cohort, compared with 22.4 new PCR confirmed infections in the negative cohort. The adjusted odds ratio was 0.17 for all reinfections (95% CI 0.13-0.24) compared to PCR confirmed primary infections. The median interval between primary infection and reinfection was over 160 days.

Interpretation

A prior history of SARS-CoV-2 infection was associated with an 83% lower risk of infection, with median protective effect observed five months following primary infection. This is the minimum likely effect as seroconversions were not included.

Funding

Department of Health and Social Care and Public Health England, with contributions from the Scottish, Welsh and Northern Irish governments.
Genome-wide functional screen of 3’UTR variants uncovers causal variants for human disease and evolution
Authors: Griesemer Dustin , Xue James R , Reilly Steven K , Ulirsch Jacob C , Kukreja Kalki , Davis Joe , Kanai Masahiro , Yang David K , Montgomery Stephen B , Novina Carl D , Tewhey Ryan , Sabeti Pardis C
Published: January 2021

3’ untranslated region (3’UTR) variants are strongly associated with human traits and diseases, yet few have been causally identified. We developed the Massively Parallel Reporter Assay for 3’UTRs (MPRAu) to sensitively assay 12,173 3’UTR variants. We applied MPRAu to six human cell lines, focusing on genetic variants associated with genome-wide association studies (GWAS) and human evolutionary adaptation. MPRAu expands our understanding of 3’UTR function, suggesting that low-complexity sequences predominately explain 3’UTR regulatory activity. We adapt MPRAu to uncover diverse molecular mechanisms at base-pair resolution, including an AU-rich element ofLEPRlinked to potential metabolic evolutionary adaptations in East Asians. We nominate hundreds of 3’UTR causal variants with genetically fine-mapped phenotype associations. Using endogenous allelic replacements, we characterize one variant that disrupts a miRNA site regulating the viral defense geneTRIM14, and one that altersPILRBabundance, nominating a causal variant underlying transcriptional changes in age-related macular degeneration.
Achromobactergenetic adaptation in cystic fibrosis
Authors: Gabrielaite Migle , Nielsen Finn C. , Johansen Helle K. , Marvig Rasmus L.
Published: January 2021

Achromobacteris an emerging pathogen in patients with cystic fibrosis (CF) andAchromobactercaused infections are associated with more severe disease outcomes and high intrinsic antibiotic resistance. While conventional CF pathogens are studied extensively, little is known about the genetic determinants leading to antibiotic resistance and the genetic adaptation inAchromobacterinfections.

Here, we analyzed 101Achromobactergenomes from 51 patients with CF isolated during the course of up to 20 years of infection to identify within-host adaptation, mutational signatures, and genetic variation associated with increased antibiotic resistance.

We found that the same regulatory and inorganic ion transport genes were frequently mutated in persisting clone types within and betweenAchromobacterspecies indicating convergent genetic adaptation. Genome-wide association study (GWAS) of six antibiotic resistance phenotypes revealed the enrichment of associated genes involved in inorganic ion transport genes, transcription gene enrichment in β-lactams, and energy production and translation gene enrichment in the trimethoprim/sulfonamide group.

Overall, we provide insights into the pathogenomics ofAchromobacterinfections in patients with CF airways. Since emerging pathogens are increasingly recognised as an important healthcare issue, our findings on evolution of antibiotic resistance and genetic adaptation can facilitate better understanding of disease progression and how mutational changes have implications for patients with CF.
Beeporter: a high-throughput tool for non-invasive analysis of honey bee virus infection
Authors: Evans Jay D. , Banmeke Olubukola , Palmer-Young Evan C. , Chen Yanping , Ryabov Eugene V.
Published: January 2021

Honey bees face numerous pests and pathogens but arguably none are as devastating as Deformed wing virus (DWV). Development of antiviral therapeutics and virus-resistant honey bee lines to control DWV in honey bees is slowed by the lack of a cost-effective high-throughput screening of DWV infection. Currently, analysis of virus infection and screening for antiviral treatments in bees and their colonies is tedious, requiring a well-equipped molecular biology laboratory and the use of hazardous chemicals. Here we utilize a cDNA clone of DWV tagged with green fluorescent protein (GFP) to develop the Beeporter assay, a method for detection and quantification of DWV infection in live honey bees. The assay involves infection of honey bee pupae by injecting a standardized DWV-GFP inoculum, followed by incubation for up to 44 hours. GFP fluorescence is recorded at intervals via commonly available long-wave UV light sources and a smartphone camera or a standard ultraviolet transilluminator gel imaging system. Nonlethal DWV monitoring allows high-throughput screening of antiviral candidates and a direct breeding tool for identifying honey bee parents with increased antivirus resistance. For even more rapid drug screening, we also describe a method for screening bees using 96-well trays and a spectrophotometer.
The Relationship between Chronological Age, Dental Age, and Salivary Alkaline Phosphatase in Indonesian Children Aged 8-14 Years: A Cross-Sectional Study
Authors: Nelwan Sindy Cornelia , Wahluyo Soegeng , Khairani Firli Cahaya , Nugraha Ricardo Adrian , Utomo Haryono , Tedjosasongko Udijanto
Published: January 2021

Background

Inability to predict dental age accurately has long been the Achilles heel of pediatric dentistry. Whilst dental age has an important aspect in clinical practice, saliva can be one of the most practically important diagnostic tools to estimate biological age.

Aims

This study was aimed to analyze a correlation between chronological age, dental age, and salivary alkaline phosphatase in Indonesian children aged 8-14 years.

Methods

This study was an observational study with cross-sectional design. Twenty healthy children (10 boys; age 10.504 ± 1.895 years) were selected by a consecutive sampling. Chronological age was assessed by recording date of birth. Dental age was assessed by orthopantamogram following Demirjian’s method. Salivary samples were collected by passive drool method and estimation of alkaline phosphatase was done by autoanalyzer.

Results

Normality test was assessed using Kolmogorov-Smirnov and Shapiro-Wilk test. Statistical analyses were assessed using Spearman’s rank-order correlation coefficients. Results are presented as mean ± standard deviation (SD). Mean chronological age was10.504 ± 1.895 years, mean Demirjian’s score was 91.74 ± 5.972, and mean salivary alkaline phosphatase was 291.563 ± 115.135 pg/ml. There is a very strong positive correlation between chronological age and dental age (r=+0.804; p<0.001). On the contrary, levels of salivary alkaline phosphatase was negatively correlated to dental age (r=-0.780; p<0.001) and chronological age (r=-0.508; p=0.022).

Conclusions

This study showed a strong correlation between dental age, chronological age, and salivary alkaline phosphatase; hence, estimation of dental age and salivary alkaline phosphatase in Indonesian children during early and late childhood has significant meaning to chronological age.
Evaluating the effects of re-opening plans on dynamics of COVID-19 in São Paulo, Brazil1
Authors: Rubio F.A. , Vilches T.N.
Published: January 2021

Coronavirus disease 2019 (COVID-19) was declared a pandemic by the World Health Organization in early March 2020. In Brazil, São Paulo is the most affected state, comprising about 20% of the country’s cases. With no vaccine available to date, distancing measures have been taken to reduce virus transmission. To reduce the pandemic’s effect on the economy, the government of São Paulo has proposed a plan consisting of five phases of the gradual re-opening of activities. In this context, we have developed a mathematical model to simulate the gradual re-opening plan on the transmission dynamics of COVID-19, in the city of São Paulo. The model shows that a precipitous reopening can cause a higher peak of the disease, which may compromise the local health system. Waiting for the reduction in the incidence of infected individuals for at least 15 days to phase transition is the most efficient strategy compared to the fixed-period scenario at each phase of the re-opening plan.
Regional Variation in COVID-19 Scarce Resource Allocation Protocols
Authors: Gandhi Rupali , Piscitello Gina M. , Parker William F. , Michelson Kelly
Published: January 2021

Background

Scarce resource allocation policies vary across the United States. Little is known about regional variation in hospital-level resource allocation protocols and variation in their application.

Objective

To evaluate how scarce resource allocation policies throughout the Chicagoland area vary and whether there are differences in policy application within and amongst hospitals.

Design

Two cross-sectional surveys.

Setting

Chicagoland hospitals.

Participants

Representatives from Chicagoland hospitals and triage officers at these hospitals.

Measurements

Survey responses and categorical variables are described by frequency of occurrence. Intra- and interhospital variation in ranking of hypothetical patients was assessed using Kappa coefficients.

Results

Eight Chicago area hospitals responded to the survey assessing scarce resource allocation protocols. For hospitals willing to describe their specific ventilator allocation protocol (n=7), the initial scoring system varied with most utilizing the sequential organ failure assessment (SOFA) score (86%) and medical comorbidities (57%). A majority gave priority to pre-defined groups in their initial scoring system (86%), all discussed withdrawal of mechanical ventilation for adult patients (100%), and a minority had exclusion criteria (43%). Forty-nine triage officers from nine hospitals responded to the second survey. Triage officer rankings of hypothetical patients had slight agreement amongst all hospitals (Kappa 0.158) and fair agreement within two hospitals with the most respondents (Kappa 0.21 and 0.25). Almost half of triage officer respondents reported using tiebreakers to rank patients (N=23/49, 47%).

Conclusion

Although most Chicago area hospitals surveyed created guidelines for resource allocation during the COVID-19 pandemic, these guidelines and application of these protocols by triage officers varied significantly.

Funding Source

None.
High-throughput phenotypic screen for genetic modifiers in patient-derivedOPA1mutant fibroblasts identifiesPGS1as a functional suppressor of mitochondrial fragmentation
Authors: Cretin Emma , Lopes Priscilla , Vimont Elodie , Tatsuta Takashi , Langer Thomas , Yu-Wai-Man Patrick , Reynier Pascal , Wai Timothy
Published: January 2021

Mutations affecting the mitochondrial fusion protein Optic Atrophy 1 (OPA1) cause autosomal dominant optic atrophy (DOA) – one of the most common form of mitochondrial disease. The majority of patients develop isolated optic atrophy, but about 20% ofOPA1mutation carriers manifest more severe neurological deficits as part of a “DOA+” phenotype. OPA1 deficiency causes mitochondrial fragmentation and also disrupts cristae organization, oxidative phosphorylation, mitochondrial DNA (mtDNA) maintenance, and cell viability. It has not yet been established whether phenotypic severity can be modulated by genetic modifiers of OPA1. To better understand the genetic regulation of mitochondrial dynamics, we established a high-throughput imaging pipeline using supervised machine learning (ML) to perform unbiased, quantitative mitochondrial morphology analysis that was coupled with a bespoke siRNA library targeting the entire known mitochondrial proteome (1531 genes), providing a detailed phenotypic screening of human fibroblasts. In control fibroblasts, we identified known and novel genes whose depletion promoted elongation or fragmentation of the mitochondrial network. In DOA+ patient fibroblasts, we identified 91 candidate genes whose depletion prevents mitochondrial fragmentation, including the mitochondrial fission genesDNM1L,MIEF1, andSLC25A46, but also genes not previously linked to mitochondrial dynamics such as Phosphatidyl Glycerophosphate Synthase (PGS1), which belongs to the cardiolipin (CL) synthesis pathway. PGS1 depletion reduces CL content in mitochondria and rebalances mitochondrial dynamics in OPA1-deficient fibroblasts by inhibiting mitochondrial fission, which improves defective respiration, but does not rescue mtDNA depletion, cristae dysmorphology or apoptotic sensitivity. Our data reveal that the multifaceted roles of OPA1 in mitochondria can be functionally uncoupled by modulating mitochondrial lipid metabolism, providing novel insights into the cellular relevance of mitochondrial fragmentation. This study illustrates the power of a first-in-kind objective automated imaging approach to uncover genetic modifiers of mitochondrial disease through high-throughput phenotypic screening of patient fibroblasts.
MLH1/3variants causing aneuploidy, pregnancy loss, and premature reproductive aging
Authors: Singh Priti , Fragoza Robert , Blengini Cecilia S. , Tran Tina N. , Pannafino Gianno , Al-Sweel Najla , Schimenti Kerry J. , Schindler Karen , Alani Eric A. , Yu Haiyuan , Schimenti John C.
Published: January 2021

Most spontaneous pregnancy losses are a result of embryonic aneuploidy stemming from mis-segregation of chromosomes during meiosis. Proper disjunction of homologous chromosomes is dependent upon precise control of crossing-over, a process requiring the mismatch repair (MMR) genesMLH1andMLH3. Both are required for fertility and completion of meiosis in mice. People inheriting variants in these genes are often at high risk for colorectal cancer and Lynch syndrome, yet the potential impacts of variants upon reproduction are unclear. To determine ifMLH1/3variants (namely single nucleotide polymorphisms, or SNPs) in human populations can cause reproductive abnormalities, we used a combination of computational predictions, yeast two-hybrid assays, and assays of MMR and recombination in yeast to select nineMLH1andMLH3variants for modeling in mice via genome editing. We identified 7 alleles that caused reproductive defects in mice including subfertility in females, male infertility, reduced sperm counts, and increased spermatocyte apoptosis. Remarkably, these alleles in females caused age-dependent decreases in litter size, and increased resorption of embryos during pregnancy. These outcomes were likely a consequence of reduced meiotic chiasmata, in turn causing an increase in misaligned chromosomes and univalents in meiotic metaphase I (MI). Our data indicate that segregating hypomorphic alleles of meiotic recombination genes in populations can predispose females to increased incidence of pregnancy loss from gamete aneuploidy.