bluuebunny/crossref_metadata_2025 huggingface dataset:
Recent Developments in Mutation Enrichment and Detection Technologies
Authors: Darbeheshti Farzaneh , Yu Fangyan , Ahmed Farzana , Adalsteinsson Viktor A , Makrigiorgos G Mike
Published: June 2022

Background

Presence of excess unaltered, wild-type DNA (wtDNA) providing information of little clinical value may often mask low-level mutations containing important diagnostic or therapeutic clues. This is a recurring hurdle in biotechnology and medicine, including cancer, prenatal diagnosis, infectious diseases, and organ transplantation. Mutation enrichment techniques that allow reduction of unwanted DNA to enable the detection of low-level mutations have emerged since the early 1990s. They are continuously being refined and updated with new technologies. The burgeoning interest in liquid biopsies for residual cancer monitoring, detection of resistance to therapy, and early cancer detection has driven an expanded interest in new and improved methodologies for practical and effective mutation enrichment and detection of low-level mutations of clinical relevance.

Content

Newly developed mutation enrichment technologies are described and grouped according to the main principle of operation, PCR-blocking technologies, enzymatic methods, and physicochemical approaches. Special emphasis is given to technologies enabling pre-PCR blockage of wtDNA to bypass PCR errors [nuclease-assisted minor-allele enrichment assay with overlapping probes (NaME-PrO) and UV-mediated cross-linking minor allele enrichment (UVME)] or providing high multiplexity followed by next-generation sequencing [Minor allele enriched sequencing through recognition oligonucleotides (MAESTRO)].

This review summarizes technological developments in rare mutation enrichment over the last 12 years, complementing pre-2010 reviews on this topic. The expanding field of liquid biopsy calls for improved limits of detection (LOD) and highly parallel applications, along with the traditional requirements for accuracy, speed, and cost-effectiveness. The current technologies are reviewed with regards to these new requirements.
Major adverse cardiovascular events after diagnosis of myocardial injury and types 1 and 2 myocardial infarction
Authors: Knott Jonathan D , Ola Olatunde , De Michieli Laura , Akula Ashok , Mehta Ramila A , Dworak Marshall , Crockford Erika , Lobo Ronstan , Rastas Nicholas , Karturi Swetha , Wohlrab Scott , Hodge David O , Grube Eric , Tak Tahir , Cagin Charles , Gulati Rajiv , Jaffe Allan S , Sandoval Yader
Published: June 2022

Aims

Limited US outcome data exist among patients with myocardial injury and types 1 and 2 myocardial infarction (MI) evaluated with high-sensitivity cardiac troponin (hs-cTn).

Methods and results

This is an observational US cohort study of emergency department (ED) patients undergoing hs-cTnT measurement. Cases with ≥1 hs-cTnT increase >99th percentile were adjudicated following the Fourth Universal Definition of MI. Post-discharge major adverse cardiovascular events (MACE) included death, MI, heart failure (HF) hospitalization, stroke or transient ischaemic attack, and new-onset atrial fibrillation or flutter during 2 years follow-up. Among 2002 patients, 857 (43%) had ≥1 hs-cTnT >99th percentile. Among these, 702 (81.9%) had myocardial injury, 64 (7.5%) had type 1 MI, and 91 (10.6%) had type 2 MI. Compared with patients without myocardial injury, type 2 MI [8.4 vs. 50%; adjusted hazard ratio (HR) 2.31, 95% confidence interval (CI) 1.49–3.58] and myocardial injury (8.4 vs. 47%; adjusted HR 3.13, 95% CI 2.39–4.09) had a higher risk of MACE, in large part because of death and HF hospitalizations. Compared with patients with type 1 MI, type 2 MI (23 vs. 50%; adjusted HR 2.24; 95% CI 1.23–4.10) and myocardial injury (23 vs. 47%; adjusted HR 2.02; 95% CI 1.20–3.40) also have a higher risk of MACE.

Conclusion

Among unselected US ED patients undergoing hs-cTnT measurement, most increases are due to myocardial injury, and type 2 MI is more frequent than type 1 MI. Patients with myocardial injury and type 2 MI have morbid outcomes, in large part due to death and HF.
ChemChaste: Simulating spatially inhomogeneous biochemical reaction–diffusion systems for modeling cell–environment feedbacks
Authors: Johnson Connah G M , Fletcher Alexander G , Soyer Orkun S
Published: June 2022

Background

Spatial organization plays an important role in the function of many biological systems, from cell fate specification in animal development to multistep metabolic conversions in microbial communities. The study of such systems benefits from the use of spatially explicit computational models that combine a discrete description of cells with a continuum description of one or more chemicals diffusing within a surrounding bulk medium. These models allow the in silico testing and refinement of mechanistic hypotheses. However, most existing models of this type do not account for concurrent bulk and intracellular biochemical reactions and their possible coupling.

Conclusions

Here, we describe ChemChaste, an extension for the open-source C++ computational biology library Chaste. ChemChaste enables the spatial simulation of both multicellular and bulk biochemistry by expanding on Chaste’s existing capabilities. In particular, ChemChaste enables (i) simulation of an arbitrary number of spatially diffusing chemicals, (ii) spatially heterogeneous chemical diffusion coefficients, and (iii) inclusion of both bulk and intracellular biochemical reactions and their coupling. ChemChaste also introduces a file-based interface that allows users to define the parameters relating to these functional features without the need to interact directly with Chaste’s core C++ code. We describe ChemChaste and demonstrate its functionality using a selection of chemical and biochemical exemplars, with a focus on demonstrating increased ability in modeling bulk chemical reactions and their coupling with intracellular reactions.

Availability and implementation

ChemChaste version 1.0 is a free, open-source C++ library, available via GitHub at https://github.com/OSS-Lab/ChemChaste under the BSD license, on the Zenodo archive at zendodo doi, as well as on BioTools (biotools:chemchaste) and SciCrunch (RRID:SCR022208) databases.
Agricultural plant cataloging and establishment of a data framework from UAV-based crop images by computer vision
Authors: Günder Maurice , Ispizua Yamati Facundo R , Kierdorf Jana , Roscher Ribana , Mahlein Anne-Katrin , Bauckhage Christian
Published: June 2022

Background

Unmanned aerial vehicle (UAV)–based image retrieval in modern agriculture enables gathering large amounts of spatially referenced crop image data. In large-scale experiments, however, UAV images suffer from containing a multitudinous amount of crops in a complex canopy architecture. Especially for the observation of temporal effects, this complicates the recognition of individual plants over several images and the extraction of relevant information tremendously.

Results

In this work, we present a hands-on workflow for the automatized temporal and spatial identification and individualization of crop images from UAVs abbreviated as “cataloging” based on comprehensible computer vision methods. We evaluate the workflow on 2 real-world datasets. One dataset is recorded for observation of Cercospora leaf spot—a fungal disease—in sugar beet over an entire growing cycle. The other one deals with harvest prediction of cauliflower plants. The plant catalog is utilized for the extraction of single plant images seen over multiple time points. This gathers a large-scale spatiotemporal image dataset that in turn can be applied to train further machine learning models including various data layers.

Conclusion

The presented approach improves analysis and interpretation of UAV data in agriculture significantly. By validation with some reference data, our method shows an accuracy that is similar to more complex deep learning–based recognition techniques. Our workflow is able to automatize plant cataloging and training image extraction, especially for large datasets.
Interactions between demersal fish body condition and density during the regime shift of the Gulf of Lions
Authors: Bensebaini C M , Certain G , Billet N , Jadaud A , Gourguet S , Hattab T , Fromentin J M
Published: June 2022

Environmentally driven changes in small pelagic fish condition and size have been observed in the Gulf of Lions (GOL) since 2008, leading to a significant fishery crisis. However, the effect of changes in environment and/or in the small pelagic community on the demersal community remain unknown. For the first time, this study examines the body condition (bc) and population density of 22 demersal species since 1994, using dynamic factor analysis (DFA). Most (but not all) of demersal species have shown a common shift between 2006 and 2009, which is synchronous with that observed in small pelagic species and the environmental conditions in the GOL. It had been concluded that the environmentally driven changes detected in the pelagic fish community also affected the demersal fish community, but with less drastic and lasting consequences. As the DFA revealed that the bc displayed important variations for several species, notably hake (Merlucius merluccius), the interaction between the bc and population density was investigated using the Multivariate Autoregressive (MAR) model on hake population at three life stages (recruits, juveniles, and adults). Results showed that adult bc, while negatively affected by density, had a positive effect on recruitment. So hake bc could have affected population dynamics by promoting higher recruitment at low densities. Further work is needed to ascertain whether such effects exist in other demersal species.
Offshore wind farms affect the spatial distribution pattern of plaice Pleuronectes platessa at both the turbine and wind farm scale
Authors: Buyse Jolien , Hostens Kris , Degraer Steven , De Backer Annelies
Published: June 2022

We investigated how the distribution of plaice Pleuronectes platessa, a typical soft-sediment fish species, has been affected by the introduction of hard substrate [turbines and scour protection layer (SPL)] at both turbine and wind farm scale in two Belgian offshore wind farms (OWFs). Diving transects (40 m) at 11 monopiles revealed four times higher plaice abundances on the sandy patches of the SPL (average radius 16.5 m) compared to the surrounding sand. We suggest that the configuration of the SPL, i.e. an open rock field, offering increased food and shelter opportunities, with sandy patches in between, facilitating the natural burrowing behaviour of plaice, forms the basis for the increased plaice abundances at the turbine scale. At the wind farm scale, beam trawl catches in between the turbines and in reference zones revealed significantly increased plaice abundances in one OWF, which suggests that wind farms can act as refuge areas for plaice, at least under specific conditions. Differences in environmental conditions, turbine foundation type, and surrounding fishing pressure may explain the equivocal findings between both OWFs, whereas low statistical power could have hampered the detection of general refuge effects. Next to the integration of different spatial scales (turbine/wind farm) within one study, longer-term monitoring and including extra life history parameters (e.g. length and sex ratio) might enhance the detectability of potential refuge effects.
A Comparison of Lyme Serological Testing Platforms with a Panel of Clinically Characterized Samples from Various Stages of Lyme Disease
Authors: Pratt George W , Platt Mihae , Velez Ana , Rao Lokinendi V
Published: June 2022

Background

In 2019, the CDC updated serology testing guidelines for Lyme disease diagnosis to include alternative modified two-tiered testing that replaces the western blots of standard testing with an additional ELISA. Antibody-capture serological assays have also been used as an aid for Lyme diagnosis. A panel of clinically characterized samples from the CDC was tested to compare modified two-tiered testing to the standard two-tiered algorithm and an antibody capture immunoassay.

Methods

A CDC panel of 92 samples comprised a range of samples including early Lyme, Lyme neuroborreliosis, Lyme arthritis, infections by other pathogens, and healthy controls. The panel was tested on a standard two-tiered platform by the CDC, the ZEUS Borrelia Test System for modified two-tiered testing, and a lab-developed antibody-capture serological assay. Sensitivity and specificity results from each assay were compared to determine significance.

Results

The antibody-capture assay demonstrated increased sensitivity but decreased specificity compared to the modified and standard two-tiered platforms. There was no statistical difference found between the modified and standard two-tiered platforms.

Conclusions

Improved sensitivity of antibody-capture when testing early Lyme disease samples is offset by decreased specificity, especially with syphilis-positive samples. Modified two-tiered testing is similar to standard two-tiered methods while also being more scalable and simpler to interpret.
Loss of PROTEIN TARGETING TO STARCH 2 has variable effects on starch synthesis across organs and species
Authors: Watson-Lazowski Alexander , Raven Emma , Feike Doreen , Hill Lionel , Barclay J Elaine , Smith Alison M , Seung David
Published: June 2022

Recent work has identified several proteins involved in starch granule initiation, the first step of starch synthesis. However, the degree of conservation in the granule initiation process remains poorly understood, especially among grass species differing in patterns of carbohydrate turnover in leaves, and granule morphology in the endosperm. We therefore compared mutant phenotypes of Hordeum vulgare (barley), Triticum turgidum (durum wheat), and Brachypodium distachyon defective in PROTEIN TARGETING TO STARCH 2 (PTST2), a key granule initiation protein. We report striking differences across species and organs. Loss of PTST2 from leaves resulted in fewer, larger starch granules per chloroplast and normal starch content in wheat, fewer granules per chloroplast and lower starch content in barley, and almost complete loss of starch in Brachypodium. The loss of starch in Brachypodium leaves was accompanied by high levels of ADP-glucose and detrimental effects on growth and physiology. Additionally, we found that loss of PTST2 increased granule initiation in Brachypodium amyloplasts, resulting in abnormal compound granule formation throughout the seed. These findings suggest that the importance of PTST2 varies greatly with the genetic and developmental background and inform the extent to which the gene can be targeted to improve starch in crops.
Inconsistent Reporting of Adverse Life Events Is Predicted by Current Internalizing Distress Among Military Service Members
Authors: Martin-Wagar Caitlin A , Marquardt Craig A , Liu Yuchen , Arbisi Paul A , Erbes Christopher R , Polusny Melissa A
Published: June 2022

Introduction

Accurate measurement of adverse life events is critical for understanding the effects of stressors on health outcomes. However, much of this research uses cross-sectional designs and self-report years after the events take place. The reliability of this retrospective reporting and the individual difference factors associated with inconsistent recall over time are not frequently addressed, especially among military service members.

Materials and Methods

A longitudinal cohort of National Guard service members (n = 801) completed the Deployment Risk and Resilience Inventory-2 Prior Stressors scale and several measures of general well-being, including anxious depressive symptomatology, personal functioning, perceived social support, and overall health at two time points (before and after completion of basic combat training; median 11-month interval).

Results

Consistency in reporting the life event items ranged from 69.5% to 99.7%, with an overall Cohen’s kappa coefficient of 0.215 for the scale, indicating minimal agreement. Lower well-being scores at Time 1 independently predicted yes-to-no changes in responding, whereas lower well-being scores at Time 2 independently predicted no-to-yes changes in responding. Follow-up mediations were conducted using study measures available only at Time 2. For all study measures, Time 2 well-being independently predicted changes from no-to-yes responding by way of indirect effects through self-reported non-specific internalizing distress and arousal.

Conclusions

These findings highlight the confounding effects of fluctuations in current emotional distress on past stressor recall. There is a need for additional caution regarding the use of retrospective self-report of adverse life events in research and clinical practice and greater consideration of current psychological distress at the time of measurement completion.
Unintended Consequences of Plant Domestication
Authors: Singh Jugpreet , van der Knaap Esther
Published: June 2022

Human selection on wild populations mostly favored a common set of plant traits during domestication. This process of direct selection also altered other independent traits that were not directly perceived or desired during crop domestication and improvement. A deeper knowledge of the inadvertent and undesirable phenotypic effects and their underlying genetic causes can help design strategies to mitigate their effects and improve genetic gain in crop plants. We review different factors explaining the negative consequences of plant domestication at the phenotypic and genomic levels. We further describe the genetic causes of undesirable effects that originate from the selection of favorable alleles during plant domestication. In addition, we propose strategies that could be useful in attenuating such effects for crop improvement. With novel -omics and genome-editing tools, it is relatively approachable to understand and manipulate the genetic and biochemical mechanisms responsible for the undesirable phenotypes in domesticated plants.
TwoStepCisMR: A novel method and R package for attenuating bias in cis-MR
Authors: Woolf Benjamin , Gill Dipender
Published: June 2022

Mendelian randomisation (MR) is an increasingly popular method for strengthening causal inference in epidemiological studies. cis-MR in particular uses genetic variants in the gene region for a genetic proxy of a drug target to provide quasi-experimental evidence for drug efficacy. A major problem for this framework is when the causal variant is correlated to another variant which effects the outcome of interest (confounding through linkage disequilibrium). Methods for correcting bias such as multivariable MR struggle in a cis setting because of the high correlation among genetic variants. Here, we therefore present an alternative method for attenuating bias which does not suffer from this problem. We have additionally developed a simple R package to facilitate the implementation of the method.
Sensitivity of rapid antigen tests for COVID-19 during the Omicron variant outbreak
Authors: Murakami Michio , Sato Hitoshi , Irie Tomoko , Kamo Masashi , Naito Wataru , Yasutaka Tetsuo , Imoto Seiya
Published: June 2022

Background

Rapid antigen tests have been used to prevent the spread of the coronavirus disease 2019 (COVID-19); however, there have been concerns about their decreased sensitivity to the Omicron variant.

Aims

In this study, we compared the sensitivity and specificity of the rapid antigen and the polymerase chain reaction (PCR) tests among the players and staff members of the Japan Professional Football League and clubs. Furthermore, we evaluated the relationship between the sensitivity and the duration from the onset of the symptoms to testing, the manufacturer of the rapid antigen test kits, and the PCR test analyte.

Design and methods

This was a retrospective observational study. We used 656 results from both the rapid antigen and PCR tests for COVID-19 using the analytes collected on the same day from January 12 to March 2, 2022, during the Omicron variant outbreak in Japan.

Results

The sensitivity of the rapid antigen test compared with the PCR test was 0.63 (95% confidence interval: 0.54–0.72) and the specificity was 0.998 (95% confidence interval: 0.995–1.000). There were no significant associations between the sensitivity and the duration from the onset of the symptoms to testing (including asymptomatic cases in the category), vaccination status, manufacturer of the rapid antigen test kit or PCR analyte (P > 0.05) with small effect sizes (Cramer’s V or φ: ≤ 0.22).

Conclusions

Even during the Omicron outbreak, the sensitivity of the rapid antigen tests did not depend on the duration from the onset of the symptoms to testing.
An exploratory assessment of the impact of a novel risk assessment test on breast cancer clinic waiting times and workflow: a discrete event simulation model
Authors: Smith Alison F. , Frempong Samuel N. , Sharma Nisha , Neal Richard D. , Hick Louise , Shinkins Bethany
Published: June 2022

Background

Breast cancer clinics across the UK have long been struggling to cope with high demand. Novel risk prediction tools – such as the PinPoint test – could help to reduce unnecessary clinic referrals. Using early data on the expected accuracy of the test, we explore the potential impact of PinPoint on: (a) the percentage of patients meeting the two-week referral target, and (b) the number of clinic ‘overspill’ appointments generated.

Methods

A simulation model was built to reflect the annual flow of patients through a single UK clinic. Due to current uncertainty around the exact impact of PinPoint testing on standard care, two primary scenarios were assessed. Scenario 1 assumed complete GP adherence to testing, with only non-referred cancerous cases returning for delayed referral. Scenario 2 assumed GPs would overrule 20% of low-risk results, and that 10% of non-referred non-cancerous cases would also return for delayed referral. A range of sensitivity analyses were conducted to explore the impact of key uncertainties on the model results. Service reconfiguration scenarios, removing individual weekly clinics from the clinic schedule, were also explored.

Results

Under standard care, 66.3% (95% CI: 66.0 to 66.5) of patients met the referral target, with 1,685 (1,648 to 1,722) overspill appointments. Under both PinPoint scenarios, >98% of patients met the referral target, with overspill appointments reduced to between 727 (707 to 746) [Scenario 1] and 886 (861 to 911) [Scenario 2]. The reduced clinic demand was sufficient to allow removal of one weekly low-capacity clinic [N=10], and the results were robust to sensitivity analyses.

Conclusions

The findings from this early analysis indicate that risk prediction tools could have the potential to alleviate pressure on cancer clinics, and are expected to have increased utility in the wake of heightened pressures resulting from the COVID-19 pandemic. Further research is required to validate these findings with real world evidence; evaluate the broader clinical and economic impact of the test; and to determine outcomes and risks for patients deemed to be low-risk on the PinPoint test and therefore not initially referred.
Reprogramming of three-dimensional microenvironments for in vitro hair follicle induction
Authors: Kageyama Tatsuto , Shimizu Akihiro , Anakama Riki , Nakajima Rikuma , Suzuki Kohei , Okubo Yusuke , Fukuda Junji
Published: June 2022

During embryonic development, reciprocal interactions between epidermal and mesenchymal layers trigger hair follicle morphogenesis. This study revealed that microenvironmental reprogramming via control over these interactions enabled hair follicle induction in vitro. A key approach is to modulate spatial distributions of epithelial and mesenchymal cells in their spontaneous organization. The de novo hair follicles with typical morphological features emerged in aggregates of the two cell types, termed hair follicloids, and hair shafts sprouted with near 100% efficiency in vitro. The hair shaft length reached ∼3 mm in culture. Typical trichogenic signaling pathways were upregulated in hair follicloids. Owing to replication of hair follicle morphogenesis in vitro, production and transportation of melanosomes were also monitored in the hair bulb region. This in vitro hair follicle model might be valuable for better understanding hair follicle induction, for evaluating hair growth as well as the inhibition of hair growth by drugs, and modeling gray hairs in a well-defined environment.

Teaser

In tissue morphogenesis, different types of cells harmonize in a pre-programmed manner using messenger systems such as epithelial-mesenchymal interactions. Organoids are a promising tool to elucidate such mechanisms on a molecular level. This work describes a strategy for reprograming three-dimensional microenvironments to trigger the initiation of in vitro regeneration of hair follicle organoids. Hair follicle organoids generated fully matured hair follicles, enabling the monitoring of hair follicle morphogenesis in vitro and determination of signaling pathways involved in early hair follicle morphogenesis. The principles uncovered herein may be relevant to other organ systems and will contribute to our understanding of developmental phenomena in physiological and pathological processes, eventually opening up new research avenues for the development of new treatment strategies.
Modeled grid cells aligned by a flexible attractor
Authors: Benas Sabrina , Fernandez Ximena , Kropff Emilio
Published: June 2022

Entorhinal grid cells implement a spatial code with hexagonal periodicity, signaling the position of the animal within an environment. Grid maps of cells belonging to the same module share spacing and orientation, only differing in relative two-dimensional spatial phase, which could result from being part of a two-dimensional attractor guided by path integration. However, this architecture has the drawbacks of being complex to construct and rigid, path integration allowing for no deviations from the hexagonal pattern such as the ones observed under a variety of experimental manipulations. Here we show that a simpler one-dimensional attractor is enough to align grid cells equally well. Using topological data analysis, we show that the resulting population activity is a sample of a torus, while the ensemble of maps preserves features of the network architecture. The flexibility of this low dimensional attractor allows it to negotiate the geometry of the representation manifold with the feedforward inputs, rather than imposing it. More generally, our results represent a proof of principle against the intuition that the architecture and the representation manifold of an attractor are topological objects of the same dimensionality, with implications to the study of attractor networks across the brain.
A simple, cost-effective and extraction-free molecular diagnostic test for sickle cell disease in noninvasive buccal swab specimen for a limited-resource setting
Authors: Thakur Priya , Gupta Pragya , Bhargava Nupur , Soni Rajat , Verma Narendra , Goswami Sangam Giri , Kharya Gaurav , Saravanakumar Vinodh , G Padma , Jain Suman , Dass Jasmita , Aggarwal Mukul , Ramalingam Sivaprakash
Published: June 2022

Sickle cell disease (SCD) is the most prevalent life threatening blood monogenic disorder. Currently, there is no cure available, apart from bone marrow transplantation. Early and efficient diagnosis of SCD is key to disease management which would make considerable strides in alleviating morbidity and reducing mortality. However, the cost and complexity of diagnostic procedures like Sanger sequencing impede the early detection of SCD in a resource-limited setting. To address this, the current study demonstrates a simple and efficient proof-of-concept assay for detection of patients and carriers from extraction free non-invasive buccal swab samples by isothermal DNA Amplification coupled Restrictase-mediated cleavage (iDAR). This study is a first of its kind reporting the use of buccal swab specimens for iDA in molecular diagnosis of a genetic disease all the while being cost effective and time saving with the total assay time of around 150 minutes at a cost of USD 5. Further, iDAR demonstrates 91.5% sensitivity and 100% specificity for detecting all three alleles; SS, AS and AA having 100% concordance with Sanger sequencing. The applicability of iDAR assay is further demonstrated with its adaptation to a one-pot reaction format, which simplifies the assay system. Overall, iDAR is a simple, cost-effective, precise and non-invasive assay for SCD screening with the potential for use in a limited resource setting.
Characteristics and costs of electric scooter injuries in Helsinki: a retrospective cohort study
Authors: Vasara Henri , Toppari Linda , Harjola Veli-Pekka , Virtanen Kaisa , Castrén Maaret , Kobylin Arja
Published: June 2022

Background and purpose

The incidence of electric scooter (e-scooter) injuries has increased drastically in numerous countries after widespread availability of shared e-scooters. Most publications on e-scooter injuries focus on a specific category of injuries. The economic impact on society from a broader perspective has not been studied.

Patients and methods

We performed a retrospective cohort study including all e-scooter-related injuries presented in the three adult emergency departments in Helsinki in 2021. We collected the patient data from the university hospital information system. Injury severity was evaluated based on the abbreviated injury score. Cost of the hospital treatment was analyzed based on our hospital district’s service price listing. In addition, we recorded the total amount of sick leave days and estimated their economic impact.

Results

In total, 446 e-scooter injuries were identified and taken into the analysis (434 affecting riders and 12 non-riders). The median age of the patients was 26 (IQR 22-33) and 59 % were male. 257 (58 %) of the of the injuries were minor, whereas 155 (35 %) were moderate, 30 (7 %) serious, 3 (0.7 %) severe, and one (0.2 %) critical. Furthermore, 220 (49 %) of the patients sustained head injuries. A major spike in accident incidence was seen during weekend (Friday to Sunday) nights, which was accompanied by a proportional increase in patients with alcohol intoxication. Including both the costs of the hospital care and absence from work, the approximated total cost of e-scooter injuries was 1.7 million euros, with a median cost of a single accident being 1148 euros (IQR 399 – 4263 €).

Interpretation

Comprehensive preventive measures must be conducted to decrease the incidence of e-scooter injuries. The usage of helmets should be strongly encouraged in order to prevent severe head injuries. The night-time bans during weekends and speed-limits on e-scooters appear to be justifiable.
Population knowledge, attitudes and practice towards Yellow Fever among nomadic populations: A cross-sectional study in Yellow Fever outbreak Communities in Ghana
Authors: Inusah Abdul-Wahab , Collins Gbeti , Dzomeku Peter , Head Michael , Ziblim Shamsu-Deen
Published: June 2022

Despite the government and Global health initiatives toward yellow fever epidemic control in Ghana, the country continues to witness sporadic outbreaks of yellow fever mostly among the unvaccinated population and suspected migrates(nomadic) who enter the country through the porous borders. Little is known about nomadic knowledge, attitudes and practice regarding this communicable disease in Ghana.

We conducted a community-based cross-sectional survey in 22 yellow fever outbreak communities to assess nomadic household heads’ knowledge, attitudes and practices regarding yellow fever after the November, 2021 outbreak. Our study results were analyzed using descriptive statistics, and univariate and multivariate logistics regression with dichotomous outcomes.

About 90% of the nomadic had poor knowledge of the signs and symptoms of yellow with only 16% knowing the vector that transmits yellow fever. The most common source of information on yellow fever was the health campaign.

Over 80% of household heads surveyed had positive attitudes regarding yellow fever with about 84% worried about the disease outbreak in their community. In a multivariate analysis, Age group, gender ideology, occupation, source of health information, duration of in the community and Nationality were associated with positive attitudes towards yellow fever.

Close to 74% have a positive practice, with 97.3% adopting a strategy to control mosquitoes in their household. Nationality, duration of stay in the community, and age group were associated with Positive practices.

Our findings show that yellow fever epidemic control can be improved in hard-to-reach communities through locally-tailored education and health promotion campaigns to improve knowledge and preventive practices against this infectious disease.
XLID Syndrome Gene Med12 Promotes Ig Isotype Switching through Chromatin Modification and Enhancer RNA regulation
Authors: Haque Farazul , Honjo Tasuku , Begum Nasim A.
Published: June 2022

The transcriptional co-activator Med12 regulates gene expression through the function of its kinase module and by interacting with the larger Mediator complex and associated RNA Polymerase II (RNAPII). Here, we show a kinase module-independent function of Med12 in antibody class switching recombination (CSR). Med12 is essential for IgH 3’ regulatory region (3’RR) or super-enhancer activation and functions with p300 and Jmjd6/Carm1 coactivator complexes. Med12 deficiency leads to a dramatic decrease in H3K27 acetylation and enhancer RNA (eRNA) transcription at 3’RR, with concomitant impairment of AID-induced DNA double strand breaks, long-range S-S synapse formation, and 3’RR-Eμ interaction. CRISPR/dCas9-mediated enhancer activation re-establishes the epigenomic and transcriptional hallmarks of the 3’RR super-enhancer, fully restoring Med12 depletion defects. Notably, we find that 3’RR derived eRNAs are critical for promoting proper S region epigenetic regulation, S-S synapse formation and recruitment of Med12 and AID to the IgH locus. We find specific X-Linked intellectual disability syndrome associated Med12 mutations are defective in both 3’RR eRNA transcription and CSR, suggesting B and neuronal cells may have cell-specific super-enhancer dysfunctions. We conclude Med12 is essential for IgH3’RR activation and eRNA transcription and plays a central role in AID-induced antibody gene diversification and genomic instability in B cells.
Neither kin selection nor familiarity explain affiliative biases towards maternal siblings in wild mountain gorillas
Authors: Grebe Nicholas M. , Hirwa Jean Paul , Stoinski Tara S. , Vigilant Linda , Rosenbaum Stacy
Published: June 2022

Evolutionary theories predict that sibling relationships will reflect a complex balance of cooperative and competitive dynamics. In most mammals, dispersal and death patterns mean that sibling relationships occur in a relatively narrow window during development, and/or only with same-sex individuals. Besides humans, one notable exception are mountain gorillas, in which non-sex biased dispersal, relatively stable group composition, and the long reproductive tenures of alpha males mean that animals routinely reside with both same and opposite-sex, and full and half siblings, throughout their lives. Using nearly 40,000 hours of observation data collected over 14 years on 699 sibling and 1258 non-sibling pairs of wild mountain gorillas, we demonstrate that individuals have strong affiliative preferences for full and maternal siblings over paternal siblings or unrelated animals, consistent with an inability to discriminate paternal kin. Intriguingly, however, aggression data imply the opposite. Aggression rates were statistically indistinguishable among all types of dyads except one: in mixed-sex dyads, non-siblings engaged in substantially more aggression than siblings of any type. This pattern suggests mountain gorillas may be capable of distinguishing paternal kin, but nonetheless choose not to affiliate with them over non-kin. A preference for maternal kin occurs despite gorillas not possessing low male reproductive skew, the key characteristic believed to underlie such biases. These results call into question reasons for strong maternal kin biases when paternal kin are identifiable, familiar, and similarly likely to be long-term social partners, and suggest behavioral mismatches at play during a transitional period in mountain gorilla society.
Exploring the lifetime effect of children on wellbeing using two-sample Mendelian randomisation
Authors: Woolf Benjamin , Sallis Hannah , Munafò Marcus R.
Published: June 2022

Objectives

To provide Mendelian randomisation evidence of the effect of having children on parental wellbeing.

Design

Two sample Mendelian randomisation.

Setting

Non-clinical European ancestry participants.

Participants

We used the UK Biobank (460,654 male and female European ancestry participants) as a source of genotype-exposure associations, and the Social Science Genetics Consortia (SSGAC) (298,420 male and female European ancestry participants) and Within-Family Consortia (effective sample of 22,656 male and female European ancestry participants) as sources of genotype-outcome associations.

Interventions

The lifetime effect of an increase in the genetic liability to having children.

Primary and secondary outcome measures

The primary analysis was an inverse variance weighed analyses of subjective wellbeing measured in the 2016 SSGAC GWAS. Secondary outcomes included pleiotropy robust estimators applied in the SSGAC and an analysis using the Within-Family consortia GWAS.

Results

The primary IVW estimate found evidence of a 0.153 standard deviation increase for every child a parent has (95% CI: -0.210 to 0.516). Secondary outcomes were generally slightly deflated (e.g. -0.049 [95% CI: -0.533 to 0.435] for the WFC and 0.090 [95% CI: -0.167 to 0.347] for weighted median) implying the presence of some residual confounding and pleiotropy.

Conclusions

Contrary to the existing literature, our results are not compatible with a measurable negative effect of number of children on the average wellbeing of a parent over their life course. However, we were unable to explore non-linearities, interactions, or time varying effects.

Strengths and limitations of this study

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Mendelian randomisation (MR) is a natural experiment which is theoretically robust to confounding and reverse causation.

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We were able to use two negative control analyses to explore the robustness of our study to two potential sources of residual confounding (populations structure and passive gene-environment correlation).

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We additionally use pleiotropy robust estimates (like MR-PRESSO, MR-Egger, weighted median, and weighed mode) to explore if our result was affected by direct effects of the genetic variants on the outcome, not mediated by the exposure.

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Because we use summary data, we were unable to explore interactions, non-linear and time-varying, or time sensitive, effects.

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Our study is a proof of concept for using MR to explore the causal effect of the heritable environment.
The effect of altruism on COVID-19 vaccination rates*
Authors: Hierro Luis Á. , Patiño David , Atienza Pedro , Garzón Antonio J. , Cantarero David
Published: June 2022

Context

After the emergence of the first vaccines against the COVID-19, public health authorities have promoted mass vaccination in order to achieve herd immunity and reduce the effects of the disease. Vaccination rates have differed between countries, depending on supply (availability of resources) and demand (altruism and resistance to vaccination) factors.

Methods

This work considers the hypothesis that individuals’ health altruism has been an important factor to explain the different levels of vaccination between countries, using the number of transplants as a proxy for altruism. Taking European Union’s countries to remove, as far as possible, supply factors that might affect vaccination, we carry out cross-sectional regressions for the most favorable date of the vaccination process (maximum vaccination speed) and for each month during the vaccination campaign.

Results

Our findings confirm that altruism has affected vaccination rates against the COVID-19. We find a direct relationship between transplants rates (proxy variable) and vaccination rates during periods in which the decision to be vaccinated depended on the individual’s choice, without supply restrictions. The results show that other demand factors have worked against vaccination: political polarization and belonging to the group of countries of the former Eastern bloc.

Conclusions

Altruism is a useful tool to define future vaccination strategies, since it favors the individuals’ awareness for vaccination.
The complete cell atlas of an aging multicellular organism
Authors: Roux Antoine E. , Yuan Han , Podshivalova Katie , Hendrickson David , Kerr Rex , Kenyon Cynthia , Kelley David R.
Published: June 2022

Here we describe a single-cell atlas of aging for the nematode Caenorhabditis elegans. This unique resource describes the expression across adulthood of over 20,000 genes among 211 groups of cells that correspond to virtually every cell type in this organism. Our findings suggest that C. elegans aging is not random and stochastic in nature, but rather characterized by coordinated changes in functionally related metabolic and stress-response genes in a highly cell-type specific fashion. Aging signatures of different cell types are largely different from one another, downregulation of energy metabolism being the only nearly universal change. Some biological pathways, such as genes associated with translation, DNA repair and the ER unfolded protein response, exhibited strong (in some cases opposite) changes in subsets of cell types, but many more were limited to a single cell type. Similarly, the rates at which cells aged, measured as genome-wide expression changes, differed between cell types; some of these differences were tested and validated in vivo by measuring age-dependent changes in mitochondrial morphology. In some, but not all, cell types, aging was characterized by an increase in cell-to-cell variance. Finally, we identified a set of transcription factors whose activities changed coordinately across many cell types with age. This set was strongly enriched for stress-resistance TFs known to influence the rate of aging. We tested other members of this set, and discovered that some, such as GEI-3, likely also regulate the rate of aging. Our dataset can be accessed and queried at c.elegans.aging.atlas.research.calicolabs.com/.
UK Biobank release and systematic evaluation of optimised polygenic risk scores for 53 diseases and quantitative traits
Authors: Thompson Deborah J. , Wells Daniel , Selzam Saskia , Peneva Iliana , Moore Rachel , Sharp Kevin , Tarran William A. , Beard Edward J. , Riveros-Mckay Fernando , Giner-Delgado Carla , Palmer Duncan , Seth Priyanka , Harrison James , Futema Marta ,   Genomics England Research Consortium, McVean Gil , Plagnol Vincent , Donnelly Peter , Weale Michael E.
Published: June 2022

We present and assess the UK Biobank (UKB) Polygenic Risk Score (PRS) Release, a set of PRSs for 28 diseases and 25 quantitative traits being made available on the individuals in UKB. We also release a benchmarking software tool to enable like-for-like performance evaluation for different PRSs for the same disease or trait. Extensive benchmarking shows the PRSs in the UKB Release to outperform a broad set of 81 published PRSs. For many of the diseases and traits we also validate the PRS algorithms in other cohorts. The availability of PRSs for 53 traits on the same set of individuals also allows a systematic assessment of their properties, and the increased power of these PRSs increases the evidence for their potential clinical benefit.
Dysfunctional cortical gradient topography in treatment resistant major depression
Authors: Pasquini Lorenzo , Fryer Susanna L. , Eisendrath Stuart J. , Segal Zindel V. , Lee Alex J. , Brown Jesse A. , Saggar Manish , Mathalon Daniel H.
Published: June 2022

Background

Treatment-Resistant Depression (TRD) refers to patients with major depressive disorder who do not remit after two or more antidepressant trials. TRD is common and highly debilitating, but its neurobiological basis remains poorly understood. Recent neuroimaging studies have revealed cortical connectivity gradients that dissociate primary sensorimotor areas from higher-order associative cortices. This fundamental topography determines cortical information flow and is affected by psychiatric disorders. We examined how TRD impacts this hierarchical cortical organization.

Methods

We analyzed resting-state fMRI data from a mindfulness-based intervention study in 56 TRD patients and 28 healthy controls. Using novel gradient extraction tools, measures of cortical gradient dispersion within and between functional brain networks were derived, compared across groups, and associated with graph theoretical measures of network topology. Within TRD, baseline cortical gradient dispersion measures were correlated with baseline clinical measures (anxiety, depression, mindfulness), as well as with changes in these measures following treatment with either mindfulness-based therapy or a health enhancement program.

Results

Cortical gradient dispersion was reduced within major intrinsic brain networks in TRD. Reduced cortical gradient dispersion correlated with increased network modularity assessed through graph theory-based measures of network topology. Lower dispersion among Default Mode Network regions, a transmodal system linked to depression symptomatology, related to current levels of trait anxiety, depression, and mindfulness, but not to changes in these domains following treatment.

Conclusions

Our findings reveal widespread alterations in cortical gradient architecture in TRD, implicating a significant role for the Default Mode Network in mediating depression, anxiety, and lower mindfulness in patients.
Rapid detection of myeloid neoplasm fusions using Single Molecule Long-Read Sequencing
Authors: Sala-Torra Olga , Reddy Shishir , Hung Ling-Hong , Beppu Lan , Wu David , Radich Jerald , Yeung Ka Yee , Yeung Cecilia CS
Published: June 2022

Recurrent gene fusions are common drivers of disease pathophysiology in leukemias. Identification of these structural variants helps stratify disease by risk and assists with therapy choice. Current fusion detection methods require long turnaround time (7-10 days) or advance knowledge of the genes involved in the fusions. To address the need for rapid identification of clinically actionable fusion genes in heme malignancies without a-priori knowledge of the genes, we describe a long-read sequencing DNA assay designed with CRISPR guides to select and enrich for recurrent leukemia fusion genes. By applying rapid sequencing technology based on nanopores, we sequenced long pieces of genomic DNA and successfully detected fusion genes in cell lines and primary specimens (e.g., BCR-ABL1, PML-RARA, CBFB-MYH11, KMT2A-AF4) using cloud-based bioinformatics workflows with novel custom fusion finder software. We detected fusion genes in 100% of cell lines with the expected breakpoints and confirmed the presence or absence of a recurrent fusion gene in 12 of 14 patient cases. With our optimized assay and cloud-based bioinformatics workflow, these assays and analyses could be performed in under 8 hours.

Key points

We describe a CRISPR-Cas9 enrichment Nanopore sequencing assay with streamlined bioinformatics that outperforms other fusion detectors.

We successfully detected both fusion genes and specific breakpoints in CML, APL, and AML in under 8 hours in 80% of patients.

Visual Abstract (Figure 1)

We successfully detected fusion genes in hematological malignancies with a fast and efficient long-read sequencing workflow in under 8 hours. The method makes the genomic characterization of BCR-ABL1 DNA breakpoint in patients quick and simple, which potentiates design of patient specific primers for personalized monitoring MRD assays.

Our assay is based on a CRISPR-Cas9 non-amplification enrichment library preparation strategy and uses Nanopore sequencing single stranded genomic DNA coupled with streamlined bioinformatic workflow containing a novel fusion detector software which outperforms current fusion detection software.