bluuebunny/crossref_metadata_2025 huggingface dataset:
Longitudinal Evaluation of the Structural and Functional Changes Associated with Glaucoma in Myopia
Authors: Biswas Sayantan , Biswas Partha
Published: June 2020

SIGNIFICANCE

This study ascertains that myopia is a risk factor for glaucoma progression among eyes with primary open angle glaucoma. Myopic eyes with primary open angle glaucoma may benefit from measurement and incorporation of axial length information into clinical decision making.

PURPOSE

The purpose of this study was to estimate the rate of change in retinal nerve fiber layer (RNFL) thickness and the rate of change in visual field of glaucoma patients with and without myopia.

METHODS

We conducted a prospective, observational cohort study where we analyzed 245 eyes of 135 glaucoma patients followed for a mean period of 6.08 years. All the subjects had RNFL imaging and standard automated perimetry performed for both eyes in the same visit every 4 months for at least 60 months.

RESULTS

The rate of change of average RNFL thickness and visual field index (VFI) was −0.29 μm/y (95% confidence interval, −1.80 to +1.23 μm/y) and −0.30%/y (95% confidence interval, −2.24 to +1.64%/y), respectively, after adjusting for age, axial length, IOP, baseline RNFL thickness, signal strength, and correlation between fellow eyes. Axial length, as a continuous variable, was not associated with the rates of change of average RNFL thickness and VFI. However, high myopic eyes with axial lengths of ≥26.0 and ≥26.5 mm had an average rate of change of RNFL thickness of 0.15 and 0.16 μm/y faster than eyes with axial lengths of less than 26 and 26.5 mm, respectively. Similarly, myopic eyes with an axial length of ≥26.5 mm were associated with a 0.21%/y faster rate of VFI reduction.

CONCLUSIONS

Both RNFL and visual field progression rates are faster in myopic glaucomatous eyes with an axial length of ≥26.5 mm than in eyes <26.5 mm. However, the small difference that supports high myopia as a risk factor for progression does not indicate the clinical importance or significance of axial length.
Human Induced Pluripotent Stem Cell Derived Sensory Neurons are Sensitive to the Neurotoxic Effects of Paclitaxel
Authors: Xiong Chenling , Chua Katherina C. , Stage Tore B. , Kim Jeffrey , Altman-Merino Anne , Chan Daniel , Saraf Krishna , Ferracini Amanda Canato , Fattahi Faranak , Kroetz Deanna L.
Published: June 2020

Chemotherapy-induced peripheral neuropathy (CIPN) is a dose-limiting adverse event associated with treatment with paclitaxel and other chemotherapeutic agents. The prevention and treatment of CIPN are limited by a lack of understanding of the molecular mechanisms underlying this toxicity. In the current study, a human induced pluripotent stem cell–derived sensory neuron (iPSC-SN) model was developed for the study of chemotherapy-induced neurotoxicity. The iPSC-SNs express proteins characteristic of nociceptor, mechanoreceptor and proprioceptor sensory neurons and show Ca2+influx in response to capsaicin, α,β-meATP and glutamate. iPSC-SNs are relatively resistant to the cytotoxic effects of paclitaxel, with IC50values of 38.1 μM (95% CI: 22.9 – 70.9 μM) for 48 hr exposure and 9.3 μM (95% CI: 5.7 – 16.5 μM) for 72 hr treatment. Paclitaxel causes dose- and time-dependent changes in neurite network complexity detected by βIII-tubulin staining and high content imaging. The IC50for paclitaxel reduction of neurite area was 1.4μM (95% CI: 0.3 - 16.9μM) for 48 hr exposure and 0.6μM (95% CI: 0.09 - 9.9μM) for 72 hr exposure. Decreased mitochondrial membrane potential, slower movement of mitochondria down the neurites and changes in glutamate-induced neuronal excitability were also observed with paclitaxel exposure. The iPSC-SNs were also sensitive to docetaxel, vincristine and bortezomib. Collectively, these data support the use of iPSC-SNs for detailed mechanistic investigations of genes and pathways implicated in chemotherapy-induced neurotoxicity and the identification of novel therapeutic approaches for its prevention and treatment.
Wistar rats and C57BL/6J mice differ in their motivation to seek social interaction versus food in the Social versus Food Preference Test
Authors: Reppucci C.J. , Brown L.A. , Chambers A.Q. , Veenema A.H.
Published: June 2020

Here we characterized the Social versus Food Preference Test, a behavioral paradigm designed to investigate the competition between the choice to seek social interaction versus the choice to seek food. We assessed how this competition was modulated by internal cues (social isolation, food deprivation), external cues (time-of-testing, stimulus salience), sex (males, females), age (adolescents, adults), and rodent model (Wistar rats, C57BL/6J mice). We found that changes in stimulus preference in response to the internal and external cue manipulations were similar across cohorts. Specifically, social over food preference scores were reduced by food deprivation and social familiarly in Wistar rats and C57BL/6J mice of both sexes. Interestingly, the degree of food deprivation-induced changes in stimulus investigation patterns were greater in adolescents compared to adults in Wistar rats and C57BL/6J mice. Strikingly, baseline stimulus preference and investigation times varied greatly between rodent models: across manipulations, Wistar rats were generally more social-preferring and C57BL/6J mice were generally more food-preferring. Adolescent Wistar rats spent more time investigating the social and food stimuli than adult Wistar rats, while adolescent and adult C57BL/6J mice investigated the stimuli a similar amount. Neither social isolation nor time-of-testing altered behavior in the Social versus Food Preference Test. Together, our results indicate that the Social versus Food Preference Test is a flexible behavioral paradigm suitable for future interrogations of the peripheral and central systems that can coordinate the expression of stimulus preference related to multiple motivated behaviors.

HIGHLIGHTS

Rats prefer social over food when sated, and this is attenuated by food deprivation.

Mice have no preference when sated, and prefer food over social when food-deprived.

Rats prefer a familiar social stimulus or a novel social stimulus over food.

Mice prefer food over a familiar social stimulus.

Adolescent rats investigate social and food stimuli longer than adult rats.

GRAPHICAL ABSTRACT
Variance in cortical depth across the brain surface
Authors: Davis Nick J.
Published: June 2020

The distance between the surface of the scalp and the surface of the grey matter of the brain is a key factor in determining the effective dose of non-invasive brain stimulation for an individual person. The highly folded nature of the cortical surface means that the depth of a particular brain area is likely to vary between individuals. The question addressed here is: what is the variability of this measure of cortical depth? 94 anatomical MRI images were taken from the OASIS database. For each image, the minimum distance from each point in the grey matter to the scalp surface was determined. Transforming these estimates into standard space meant that the coefficient of variation could be determined across the sample. The results indicated that depth variability is high across the cortical surface, even when taking sulcal depth into account. This was true even for the primary visual and motor areas, which are often used in setting TMS dosage. The correlation of the depth of these areas and the depth of other brain areas was low. The results suggest that dose-setting of TMS based on visual or evoked potentials may offer poor reliability, and that individual brain images should be used when targeting non-primary brain areas.
A generative modeling approach for interpreting population-level variability in brain structure
Authors: Liu Ran , Subakan Cem , Balwani Aishwarya H. , Whitesell Jennifer , Harris Julie , Koyejo Sanmi , Dyer Eva
Published: June 2020

Understanding how neural structure varies across individuals is critical for characterizing the effects of disease, learning, and aging on the brain. However, disentangling the different factors that give rise to individual variability is still an outstanding challenge. In this paper, we introduce a deep generative modeling approach to find different modes of variation across many individuals. To do this, we start by training a variational autoencoder on a collection of auto-fluorescence images from a little over 1,700 mouse brains at 25 micron resolution. To then tap into the learned factors and validate the model’s expressiveness, we developed a novel bi-directional technique to interpret the latent space–by making structured perturbations to both, the high-dimensional inputs of the network, as well as the low-dimensional latent variables in its bottleneck. Our results demonstrate that through coupling generative modeling frameworks with structured perturbations, it is possible to probe the latent space to provide insights into the representations of brain structure formed in deep neural networks.
Trade-offs in Robustness to Perturbations of Bacterial Population Controllers
Authors: McBride Cameron , Del Vecchio Domitilla
Published: June 2020

Synthetic biology applications have the potential to have lasting impact; however, there is considerable difficulty in scaling up engineered genetic circuits. One of the current hurdles is resource sharing, where different circuit components become implicitly coupled through the host cell’s pool of resources, which may destroy circuit function. One potential solution around this problem is to distribute genetic circuit components across multiple cell strains and control the cell population size using a population controller. In these situations, perturbations in the availability of cellular resources, such as due to resource sharing, will affect the performance of the population controller. In this work, we model a genetic population controller implemented by a genetic circuit while considering perturbations in the availability of cellular resources. We analyze how these intracellular perturbations and extracellular disturbances to cell growth affect cell population size. We find that it is not possible to tune the population controller’s gain such that the population density is robust to both extracellular disturbances and perturbations to the pool of available resources.
Age-induced methylmalonic acid accumulation promotes tumor progression and aggressiveness
Authors: Gomes Ana P. , Ilter Didem , Low Vivien , Endress Jennifer E. , Fernández-García Juan , Rosenzweig Adam , Schild Tanya , Broekaert Dorien , Ahmed Adnan , Planque Melanie , Elia Ilaria , Han Julie , Kinzig Charles , Mullarky Edouard , Mutvei Anders P. , Asara John , de Cabo Rafael , Cantley Lewis C. , Dephoure Noah , Fendt Sarah-Maria , Blenis John
Published: June 2020

From age 65 onwards, the risk of cancer incidence and associated mortality is substantially higher1-3. Nonetheless, our understanding of the complex relationship between age and cancer is still in its infancy4. For decades, the link has largely been attributed to increased exposure time to mutagens in older individuals. However, this view does not account for the well-established role of diet, exercise and small molecules that target the pace of metabolic aging5-8. Here, we show that metabolic alterations that occur with age can render a systemic environment favorable to progression and aggressiveness of tumors. Specifically, we show that methylmalonic acid (MMA), a by-product of propionate metabolism, is significantly up-regulated in the serum of older people, and functions as a mediator of tumor progression. We traced this to the induction of SOX4 and a consequent transcriptional reprogramming that can endow cancer cells with aggressive properties. Thus, accumulation of MMA represents a novel link between aging and cancer progression, implicating MMA as a novel therapeutic target for advanced carcinomas.
Heparanase promotes Syndecan-1 expression to mediate fibrillar collagen and mammographic density in human breast tissue culturedex vivo
Authors: Huang Xuan , Reye Gina , Momot Konstantin I. , Blick Tony , Lloyd Thomas , Tilley Wayne D. , Hickey Theresa E. , Snell Cameron E. , Okolicsanyi Rachel K. , Haupt Larisa M. , Ferro Vito , Thompson Erik W. , Hugo Honor J
Published: June 2020

Mammographic density (MD) is a strong and independent factor for breast cancer (BC) risk and is increasingly associated with BC progression. We have previously shown in mice that high MD, which is characterised by the preponderance of a fibrous stroma, facilitates BC xenograft growth and metastasis. This stroma is rich in extracellular matrix (ECM) factors, including heparan sulfate proteoglycans (HSPGs), such as the BC-associated syndecan-1 (SDC1). These proteoglycans tether growth factors, which are released by heparanase (HPSE). MD is positively associated with estrogen exposure and, in cell models, estrogen has been implicated in the upregulation of HPSE, the activity of which promotes SDC expression. Herein we describe a novel measurement approach (single-sided NMR) using a patient-derived explant (PDE) model of normal human (female) mammary tissue culturedex vivoto investigate the role(s) of HPSE and SDC1 on MD. Relative HSPG gene and protein analyses determined in patient-paired high versus low MD tissues identified SDC1 and SDC4 as potential mediators of MD. Using the PDE model we demonstrate that HPSE promotes SDC1 rather than SDC4 expression and cleavage, leading to increased MD. In this model system, synstatin (SSTN), an SDC1 inhibitory peptide designed to decouple SDC1-ITGαvβ3 parallel collagen alignment, reduced the abundance of fibrillar collagen as assessed by picrosirius red viewed under polarised light, and reduced MD. Our results reveal a potential role for HPSE in maintaining MD via its direct regulation of SDC1, which in turn physically tethers collagen into aligned fibres characteristic of MD. We propose that inhibitors of HPSE and/or SDC1 may afford an opportunity to reduce MD in high BC risk individuals and reduce MD-associated BC progression in conjunction with established BC therapies.
Bioaugmented sand filter columns provide stable removal of pesticide residue from membrane retentate
Authors: Ellegaard-Jensen Lea , Schostag Morten Dencker , Fini Mahdi Nikbakht , Badawi Nora , Gobbi Alex , Aamand Jens , Hansen Lars Hestbjerg
Published: June 2020

Drinking water resources, such as groundwater, are threatened by pollution. The pesticide metabolite 2,6-dichlorobenzamide (BAM) is one of the compounds frequently found in groundwater. Studies have attempted to add specific BAM-degrading bacteria to sand-filters at drinking water treatment facilities. This biotechnology has shown great potential in removing BAM from contaminated water. However, the degradation potential was formerly lost after approximately 2-3 weeks due to a decrease of the degrader population over time.

The aim of the present study was to overcome the constraints leading to loss of degraders from inoculated filters. Our approach was threefold: 1) Development of a novel inoculation strategy, 2) lowering the flowrate to reduce washout of cells, and 3) increasing the concentration of nutrients hereunder the pollutant in a smaller inlet water stream. The two latter were achieved via modifications of the inlet water by applying membrane treatment which, besides producing an ultra-pure water fraction, produced a residual water stream with nutrients including BAM concentrated in an approximately 10-fold reduced volume. This was done to alleviate starvation of degrader bacteria in the otherwise oligotrophic sand-filters and to enable a decreased flowrate.

By this approach, we achieved 100% BAM removal over a period of 40 days in sand-filter columns inoculated with the BAM-degraderAminobactersp. MSH1. Molecular targeting of the degrader strain showed that the population of degrader bacteria persisted at high numbers throughout the sand-filter columns and over the entire timespan of the experiment. 16S rRNA gene amplicon sequencing confirmed that MSH1 dominated the bacterial communities.

IMPORTANCE

Many countries rely partly or solely on groundwater as the source of drinking water. Here groundwater contamination by pesticide residues poses a serious threat to the production of high quality drinking water. Since scarcity of clean groundwater may occur in progressively larger areas both locally and globally, the need for efficient purification technologies is growing. This study shows that a novel system combining membrane treatment and bioaugmented sand-filters can efficiently remove pesticide residues in laboratory columns when applying specific inoculation and flow conditions. Once upscaled, this system can be used directly for pump-and-treat of contaminated groundwater wells or at drinking water treatment plants.
Characterization of genomic regulation profiles in human mitral valve whole tissue to annotate genetic risk loci for mitral valve prolapse
Authors: Kyryachenko Sergiy , Georges Adrien , Yu Mengyao , Barrandou Takiy , Bruneval Patrick , Rubio Tony , Gronwald Judith , Baraki Hassina , Kutschka Ingo , Norris Russell A , Voigt Niels , Bouatia-Naji Nabila
Published: June 2020

Rationale

Mitral valve prolapse (MVP) is a common valve disease that leads to mitral insufficiency, heart failure and sudden death. The identification of risk loci provided insight into its genetic architecture, although the causal variants and target genes need to be fully characterized.

Objective

To establish the chromatin accessibility profiles and gene regulation specificities of human mitral valve and identify functional variants and target genes at MVP loci.

Methods and Results

We mapped the open chromatin accessible regions in nuclei from 11 human mitral valves by an assay for transposase-accessible chromatin with high-throughput sequencing (ATAC-Seq). Compared to the heart tissue and cardiac fibroblasts, we found that mitral valve-specific ATAC-Seq peaks were enriched near genes involved in extracellular matrix organization, chondrocyte differentiation, and connective tissue development. The most enriched motif in mitral valve-specific open chromatin peaks was for the nuclear factor of activated T cells (NFATC) family of transcription factors, involved in valve endocardial and interstitial cells formation. We also found that MVP-associated variants (p < 10−5) observed in the current MVP GWAS were significantly enriched (p< 0.05) in mitral valve open chromatin peaks. Integration of the ATAC-Seq data with GWAS loci, extensive functional annotation, and gene reporter assay revealed plausible causal variants at two risk loci: rs6723013 at the IGFBP5/TNS1 locus and rs2641440 at the SMG6/SRR locus. Circular chromosome conformation capture followed by high-throughput sequencing provided evidence for several target genes, including SRR, HIC1, and DPH1 at the SMG6/SRR locus and further supported TNS1 as the most likely target gene on Chr2.

Conclusions

Here we describe unprecedented genome-wide open chromatin profiles from human mitral valves that indicates specific gene regulation profiles, compared to the heart. We also report in vitro functional evidence for potential causal variants and target genes at MVP risk loci involving established and new biological mechanisms relevant to mitral valve disease.
Improving Risk Assessment of Miscarriage during Pregnancy with Knowledge Graph Embeddings
Authors: Tissot Hegler C. , Pedebos Lucas A.
Published: June 2020

Miscarriages are the most common type of pregnancy loss, mostly occurring in the first 12 weeks of pregnancy due to known factors of different natures. Pregnancy risk assessment aims to quantify evidence in order to reduce such maternal morbidities during pregnancy, and personalized decision support systems are the cornerstone of high-quality, patient-centered care in order to improve diagnosis, treatment selection, and risk assessment. However, the increasing number of patient-level observations and data sparsity requires more effective forms of representing clinical knowledge in order to encode known information that enables performing inference and reasoning. Whereas knowledge embedding representation has been widely explored in the open domain data, there are few efforts for its application in the clinical domain. In this study, we discuss differences among multiple embedding strategies, and we demonstrate how these methods can assist on clinical risk assessment of miscarriage both before and specially in the earlier pregnancy stages. Our experiments show that simple knowledge embedding approaches that utilize domain-specific metadata perform better than complex embedding strategies, although both are able to improve results comparatively to a population probabilistic baseline in both AUPRC, F1-score, a proposed normalized version of these evaluation metrics that better reflects accuracy for unbalanced datasets.
Understanding the impact of the COVID-19 pandemic on well-being and virtual care for people living with dementia and care partners living in the community
Authors: Roach P , Zwiers A , Cox E , Fischer K , Charlton A , Josephson CB , Patten SB , Seitz D , Ismail Z , Smith EE
Published: June 2020

The COVID-19 pandemic has necessitated public health measures that have impacted the provision of care for people living with dementia and their families. Additionally, the isolation that results from social distancing may be harming well-being for families, as formal and informal supports become less accessible. For those with living with dementia and experiencing agitation, social distancing may be even harder to maintain, or social distancing could potentially aggravate dementia-related neuropsychiatric symptoms. To understand the lived experience of social and physical distancing during the COVID-19 pandemic in Canada we remotely interviewed 21 participants who normally attend a dementia specialty clinic in Calgary, Alberta, during a period where essential businesses were closed and healthcare had abruptly transitioned to telemedicine. The impacts of the public health measures in response to the pandemic emerged in three main categories of experience: 1) personal; 2) health services; and 3) health status (of both person living with dementia and care partner). This in-depth understanding of the needs and experiences of the pandemic for people living with dementia suggests that innovative means are urgently needed to facilitate provision of remote medicine and also social interaction and integration.
Binocular integration of perceptually suppressed visual information in amblyopia
Authors: Chow Amy , Silva Andrew E. , Tsang Katelyn , Ng Gabriel , Ho Cindy , Thompson Benjamin
Published: June 2020

Abnormal visual experience during an early critical period of visual cortex development can lead to a neurodevelopmental disorder of vision called amblyopia. A key feature of amblyopia is interocular suppression, whereby information from the amblyopic eye is blocked from conscious awareness when both eyes are open. Suppression of the amblyopic eye is thought to occur at an early stage of visual processing and to be absolute. Using a binocular rivalry paradigm, we demonstrate that suppressed visual information from the amblyopic eye remains available for binocular integration and can influence overall perception of stimuli. This finding reveals that suppressed visual information continues to be represented within the brain even when it is blocked from conscious awareness by chronic pathological suppression. These results have direct implications for the clinical management of amblyopia.
FEAT: A Flexible, Efficient and Accurate Test for COVID-19
Authors: Fang Linjiajie , Jing Bing-Yi , Ling Shen , Yang Qing
Published: June 2020

Early detection of COVID-19 is critical in mitigating the spread of the virus. Commonly used tests include nucleic acid detection, antibodies detection via blood testing and CT imaging. Some tests are accurate but time-consuming, while others are cheaper but less accurate. Exactly which test to use is constrained by various considerations, such as availability, cost, accuracy and efficiency. In this paper, we propose a Flexible, Efficient and Accurate Test (FEAT). FEAT is based on group testing with simple but careful design by incorporating ideas such as close contact cliques and repeated tests. FEAT could dramatically improve the efficiency and/or accuracy for any existing test. For example, for accurate but slow test such as RT-PCR, FEAT can improve efficiency by multiple times without compromising accuracy. On the other hand, for fast but inaccurate tests, FEAT can sharply lower the false negative rates (FNR) and greatly increase efficiency. Theoretical justifications are provided. We point out some scenarios where the FEAT can be effectively employed.
Impaired glucose metabolism in patients with diabetes, prediabetes and obesity is associated with severe Covid-19
Authors: Smith Stephen M. , Boppana Avinash , Traupman Julie A. , Unson Enrique , Maddock Daniel A. , Chao Kathy , Dobesh David P. , Connor Ruth I.
Published: June 2020

Background

Identification of risk factors of severe Covid-19 is critical for improving therapies and understanding SARS-CoV-2 pathogenesis.

Methods

We analyzed 184 patients hospitalized for Covid-19 in Livingston, New Jersey for clinical characteristics associated with severe disease.

Results

The majority of Covid-19 patients had diabetes mellitus (DM) (62.0%), Pre-DM (23.9%) with elevated FBG, or a BMI > 30 with normal HbA1C (4.3%). SARS-CoV-2 infection was associated with new and persistent hyperglycemia in 29 patients, including several with normal HbA1C levels. Forty-four patients required intubation, which occurred significantly more often in patients with DM as compared to non-diabetics.

Conclusions

Severe Covid-19 occurs in the presence of impaired glucose metabolism in patients with SARS-CoV-2 infection. The association of dysregulated glucose metabolism and severe Covid-19 suggests a previously unrecognized manifestation of primary SARS-CoV-2 infection. Exploration of pathways by which SARS-CoV-2 impacts glucose metabolism is critical for understanding disease pathogenesis and developing therapies.
Cohort-based approach to understanding the roles of generation and serial intervals in shaping epidemiological dynamics
Authors: Park Sang Woo , Sun Kaiyuan , Champredon David , Li Michael , Bolker Benjamin M. , Earn David J. D. , Weitz Joshua S. , Grenfell Bryan T. , Dushoff Jonathan
Published: June 2020

Generation intervals and serial intervals are critical quantities for characterizing outbreak dynamics. Generation intervals characterize the time between infection and transmission, while serial intervals characterize the time between the onset of symptoms in a chain of transmission. They are often used interchangeably, leading to misunderstanding of how these intervals link the epidemic growth raterand the reproduction numberℛ. Generation intervals provide a mechanistic link betweenrandℛbut are harder to measure via contact tracing. While serial intervals are easier to measure from contact tracing, recent studies suggest that the two intervals give different estimates ofℛfromr. We present a general framework for characterizing epidemiological delays based on cohorts (i.e., a group of individuals that share the same event time, such as symptom onset) and show thatforward-lookingserial intervals, which correctly linkℛwithr, are not the same as “intrinsic” serial intervals, but instead change withr. We provide a heuristic method for addressing potential biases that can arise from not accounting for changes in serial intervals across cohorts and apply the method to estimatingℛfor the COVID-19 outbreak in China using serial-interval data — our analysis shows that using incorrectly defined serial intervals can severely bias estimates. This study demonstrates the importance of early epidemiological investigation through contact tracing and provides a rationale for reassessing generation intervals, serial intervals, andℛestimates, for COVID-19.

Significance Statement

The generation- and serial-interval distributions are key, but different, quantities in outbreak analyses. Recent theoretical studies suggest that two distributions give different estimates of the reproduction numberℛfrom the exponential growth rater; however, both intervals, by definition, describe disease transmission at the individual level. Here, we show that the serial-interval distribution, defined from the correct reference time and cohort, gives the same estimate ofℛas the generation-interval distribution. We then apply our framework to serial-interval data from the COVID-19 outbreak in China. While our study supports the use of serial-interval distributions in estimatingℛ, it also reveals necessary changes to the current understanding and applications of serial-interval distribution.
Profiles of Social Distance Compliance: Psychological and Situational Predictors of Risky Behavior during COVID-19
Authors: Haupt Michael Robert , Weiss Staci Meredith , Chiu Michelle , Cuomo Raphael , Chein Jason M. , Mackey Tim
Published: June 2020

The purpose of this study was to explore the factors underlying variability in compliance with CDC guidelines in response to the novel coronavirus, or COVID-19. To do this, we examined the frequency of once ordinary, but newly risky behavior (as deemed by CDC guidelines) in a sample of 482 MTurkers. We ran analyses probing the situational and dispositional variables that predicted variance in risky behavior using data-driven and hypothesis-generated approaches. We found situational and dispositional variables contributed unique variance to risky behavior, controlling for variability accounted for by demographic factors. More frequent report of risky activity was associated with higher extraversion, need for cognitive closure, behavior activation, and perceived resource scarcity; in contrast, more frequent report of risky activity was associated with less empathy and living space access, as well as younger age. To break down these findings, we used a cluster analysis to profile individuals, using only situational and dispositional variables belonging to seven clusters. Combined with testing differences in risk taking by cluster identity, we suggest this profile approach might allow consideration of multi-faceted attributes that influence adherence with public health guidance in the context of health emergencies like the COVID-19 pandemic.
A tertiary center experience of multiple myeloma patients with COVID-19: lessons learned and the path forward
Authors: Wang Bo , Van Oekelen Oliver , Mouhieddine Tarek H. , Del Valle Diane Marie , Richter Joshua , Cho Hearn Jay , Richard Shambavi , Chari Ajai , Gnjatic Sacha , Merad Miriam , Jagannath Sundar , Parekh Samir , Madduri Deepu
Published: June 2020

Background

The COVID-19 pandemic, caused by SARS-CoV-2 virus, has resulted in over 100,000 deaths in the United States. Our institution has treated over 2,000 COVID-19 patients during the pandemic in New York City. The pandemic directly impacted cancer patients and the organization of cancer care. Mount Sinai Hospital has a large and diverse multiple myeloma (MM) population. Herein, we report the characteristics of COVID-19 infection and serological response in MM patients in a large tertiary care institution in New York.

Methods

We performed a retrospective study on a cohort of 58 patients with a plasma-cell disorder (54 MM, 4 smoldering MM) who developed COVID-19 between March 1, 2020 and April 30, 2020. We report epidemiological, clinical and laboratory characteristics including persistence of viral detection by polymerase chain reaction (PCR) and anti-SARS-CoV-2 antibody testing, treatments initiated, and outcomes.

Results

Of the 58 patients diagnosed with COVID-19, 36 were hospitalized and 22 were managed at home. The median age was 67 years; 52% of patients were male and 63% were non-white. Hypertension (64%), hyperlipidemia (62%), obesity (37%), diabetes mellitus (28%), chronic kidney disease (24%) and lung disease (21%) were the most common comorbidities. In the total cohort, 14 patients (24%) died. Older age (>70 years), male sex, cardiovascular risk, and patients not in complete remission (CR) or stringent CR were significantly (p<0.05) associated with hospitalization. Among hospitalized patients, laboratory findings demonstrated elevation of traditional inflammatory markers (CRP, ferritin, D-dimer) and a significant (p<0.05) association between elevated inflammatory markers, severe hypogammaglobulinemia, non-white race, and mortality. Ninety-six percent (22/23) of patients developed antibodies to SARS-CoV-2 at a median of 32 days after initial diagnosis. Median time to PCR negativity was 43 (range 19-68) days from initial positive PCR.

Conclusions

Drug exposure and MM disease status at the time of contracting COVID-19 had no bearing on mortality. Mounting a severe inflammatory response to SARS-CoV-2 and severe hypogammaglobulinemia were associated with higher mortality. The majority of patients mounted an antibody response to SARS-CoV-2. These findings pave a path to identification of vulnerable MM patients who need early intervention to improve outcome in future outbreaks of COVID-19.
CoVID-19 in Singapore: Impact of Contact Tracing and Self-awareness on Healthcare Demand
Authors: Huang Qiuyang , Wang Lin , Yang Yongjian , Huang Liping , Du Zhanwei , Xiao Gaoxi
Published: June 2020

Background

A great concern around the globe now is to mitigate the COVID-19 pandemic via contact tracing. Analyzing the control strategies during the first five months of 2020 in Singapore is important to estimate the effectiveness of contacting tracing measures.

Methods

We developed a mathematical model to simulate the COVID-19 epidemic in Singapore, with local cases stratified into 5 categories according to the conditions of contact tracing and self-awareness. Key parameters of each category were estimated from local surveillance data. We also simulated a set of possible scenarios to predict the effects of contact tracing and self-awareness for the following month.

Findings

During January 23 - March 16, 2020, the success probabilities of contact tracing and self-awareness were estimated to be 31% (95% CI 28%-33%) and 54% (95% CI 51%-57%), respectively. During March 17 - April 7, 2020, several social distancing measures (e.g., limiting mass gathering) were introduced in Singapore, which, however, were estimated with minor contribution to reduce the non-tracing reproduction number per local case (Rι,2). If contact tracing and self-awareness cannot be further improved, we predict that the COVID-19 epidemic will continue to spread in Singapore ifRι,2≥ 1.5.

Conclusion

Contact tracing and self-awareness can mitigate the COVID-19 transmission, and can be one of the key strategies to ensure a sustainable reopening after lifting the lockdown.

We evaluate the efficiency of contact tracing and self-awareness in Singapore’s early-stage control of COVID-19. Then use a branching model to simulate and evaluate the possible prospective outcomes of Singapore’s COVID-19 control in different scenarios.
Protocol for partnering with peers intervention to improve medication adherence among African Americans with Type 2 Diabetes
Authors: Shiyanbola Olayinka O , Maurer Martha , C Ward Earlise , Sharp Lisa , Lee Jonas , Tarfa Adati
Published: June 2020

African Americans (AAs) with diabetes are more likely to develop diabetes-related complications and have the highest diabetes-related mortality rates, than all other racial/ethnic groups. These health disparities are primarily due to poor medication adherence (defined as not taking medications as prescribed). AAs have substantially lower adherence to diabetes medications than whites, which contributes to higher rates of diabetes-related complications, such as amputations and strokes. There is a critical need to develop diabetes self-management interventions that improve medication adherence, clinical outcomes and in turn reduce morbidity and mortality among AAs with diabetes. Focusing on psychosocial factors such as health beliefs, self-efficacy and patient-provider communication is instrumental to improving AAs medication adherence. To address this need, we developed, the Peers Supporting Health Literacy, Self-Efficacy, Self-Advocacy, and Adherence (Peers LEAD) intervention, which provides AAs with culturally adapted diabetes and medication beliefs information, one-on-one peer support from AAs with diabetes, and communication and self-efficacy skill development to enhance medication adherence. This pilot research is a pre-post single group intervention study design which will be conducted in two phases using a community engaged approach. The objective is to test the Peers LEAD intervention in Phase 1, and then examine specific intervention elements for refinement in Phase 2. We will employ both quantitative and qualitative methods to assess the feasibility, acceptability, and outcomes of Peers LEAD. Building on established community partnerships, we plan to recruit and enroll 30 Peer Buddies and 20 Peer Ambassadors to participate in the intervention. By utilizing patient feedback to refine Peers LEAD and piloting it to examine its feasibility, we will generate evidence regarding its real world use and provide support for a randomized controlled trial of its impact on AAs diabetes medication adherence and clinical outcomes.
AIM2 Inflammasome Mediates Hallmark Neuropathological Alterations and Cognitive Impairment in a Mouse Model of Vascular Dementia
Authors: Poh Luting , Fann David Y. , Wong Peiyan , Lim Hong Meng , Foo Sok Lin , Kang Sung-Wook , Rajeev Vismitha , Selvaraji Sharmelee , Iyer Vinaya Rajagopal , Parathy Nageiswari , Khan Mohammad Badruzzaman , Hess David C. , Jo Dong-Gyu , Drummond Grant R. , Sobey Christopher G. , Lai Mitchell K.P. , Chen Christopher Li-Hsian , Lim Lina H. K. , Arumugam Thiruma V.
Published: June 2020

Chronic cerebral hypoperfusion is associated with vascular dementia (VaD). Cerebral hypoperfusion may initiate complex molecular and cellular inflammatory pathways that contribute to long-term cognitive impairment and memory loss. Here we used a bilateral common carotid artery stenosis (BCAS) mouse model of VaD to investigate its effect on the innate immune response – particularly the inflammasome signaling pathway. Comprehensive analyses revealed that chronic cerebral hypoperfusion induces a complex temporal expression and activation of inflammasome components and their downstream products (IL-1β and IL-18) in different brain regions, and promotes activation of apoptotic and pyroptotic cell death pathways. Polarized glial cell activation, white matter lesion formation and hippocampal neuronal loss also occurred in a spatiotemporal manner. Moreover, in AIM2 knockout mice we observed attenuated inflammasome-mediated production of proinflammatory cytokines, apoptosis and pyroptosis, as well as resistance to chronic microglial activation, myelin breakdown, hippocampal neuronal loss, and behavioural and cognitive deficits following BCAS. Hence, we have demonstrated that activation of the AIM2 inflammasome substantially contributes to the pathophysiology of chronic cerebral hypoperfusion-induced brain injury and may therefore represent a promising therapeutic target for attenuating cognitive impairment in VaD.
Phenotype Spectrum reflects Synergies among the Cell Architecture over Stages of the Cell Cycle
Authors: Lan Tian , Yu Meng , Chen Weisheng , Yin Jun , Chang Hsiang-Tsun , Tang Shan , Zhao Ye , Svoronos Spyros , Wong Samuel W. K. , Tseng Yiider
Published: June 2020

The heterogeneity of cell phenotypes remains a barrier in progressing cell research and a challenge in conquering cancer-related drug resistance. Cell morphology, the most direct property of cell phenotype, evolves along the progression of the cell cycle; meanwhile, cell motility, the dynamic property of cell phenotype, also alters over the cell cycle. However, a quantifiable research understanding the strict relationship between the cell cycle and cell migration is missing. Herein, we separately elucidate the correspondence of single NIH 3T3 fibroblast migratory behaviors with the G1, S, and G2 phases of the cell cycle, an underlying property of proliferation. The results show that synergies among the highly spatiotemporal arrangements of signals in Rho GTPases and cyclin-dependent kinase inhibitors, p21Cip1, and p27Kip1coordinates proliferation and migration. Taken together, we explain the synergies among these processes through providing an interactive molecular mechanism between the cell cycle and cell migration and demonstrate that both cell morphology and the dynamic subcellular behavior are homogenous within each stage of the cell cycle phases, posing potential implications in countering drug resistance.
Orphan nuclear receptor COUP-TFII drives the myofibroblast metabolic shift leading to fibrosis
Authors: Li Li , Galichon Pierre , Xiao Xiaoyan , Figueroa-Ramirez Ana C , Tamayo Diana , Lee Jake June-Koo , Kalocsay Marian , Gonzalez-Sanchez David , Chancay Maria S , McCracken Kyle , Lemos Dario , Lee Nathan , Ichimura Takaharu , Mori Yutaro , Valerius M. Todd , Sun Xiaoming , Edelman Elazer R , Bonventre Joseph V
Published: June 2020

Recent studies demonstrated that metabolic disturbance, such as augmented glycolysis, contributes to fibrosis. The molecular regulation of this metabolic perturbation in fibrosis, however, has been elusive. COUP-TFII (also known as NR2F2) is an important regulator of glucose and lipid metabolism. Its contribution to organ fibrosis is undefined. Here, we found increased COUP-TFII expression in myofibroblasts in kidneys of patients with chronic kidney disease, fibrotic lungs of patients with idiopathic pulmonary fibrosis, fibrotic human kidney organoids, and fibrotic mouse kidneys after injury. Genetic ablation of COUP-TFII in mice resulted in attenuation of injury-induced kidney fibrosis. A non-biased proteomic study revealed the suppression of fatty acid oxidation and the enhancement of glycolysis pathways in COUP-TFII overexpressing fibroblasts. Overexpression of COUP-TFII in fibroblasts was sufficient to enhance glycolysis and increase alpha smooth muscle actin (αSMA) and collagen1 levels. Knockout of COUP-TFII decreased glycolysis and collagen1 levels in fibroblasts. Chip-qPCR assays revealed the binding of COUP-TFII on the promoter of PGC1α, a critical regulator of mitochondrial genesis and oxidative metabolism. Overexpression of COUP-TFII reduced the cellular level of PGC1α. In conclusion, COUP-TFII mediates fibrosis by serving as a key regulator of the shift in cellular metabolism of interstitial pericytes/fibroblasts from oxidative respiration to aerobic glycolysis. The fibrogenic response may share a common pathway in different organ injury and failure. Targeting COUP-TFII serves as a novel treatment approach for mitigating fibrosis in chronic kidney disease and potential other organ fibrosis.
Several FDA-approved drugs effectively inhibit SARS-CoV-2 infectionin vitro
Authors: Xiong Hua-Long , Cao Jia-Li , Shen Chen-Guang , Ma Jian , Qiao Xiao-Yang , Shi Tian-Shu , Yang Yang , Ge Sheng-Xiang , Zhang Jun , Zhang Tian-Ying , Yuan Quan , Xia Ning-Shao
Published: June 2020

To identify drugs that are potentially used for the treatment of COVID-19, the potency of 1403 FDA-approved drugs were evaluated using a robust pseudovirus assay and the candidates were further confirmed by authentic SARS-CoV-2 assay. Four compounds, Clomiphene (citrate), Vortioxetine, Vortioxetine (hydrobromide) and Asenapine (hydrochloride), showed potent inhibitory effects in both pseudovirus and authentic virus assay. The combination of Clomiphene (citrate), Vortioxetine and Asenapine (hydrochloride) is much more potent than used alone, with IC50 of 0.34 μM.
A Genome-wide Library of MADM Mice for Single-Cell Genetic Mosaic Analysis
Authors: Contreras Ximena , Davaatseren Amarbayasgalan , Amberg Nicole , Hansen Andi H. , Sonntag Johanna , Andersen Lill , Bernthaler Tina , Heger Anna , Johnson Randy , Schwarz Lindsay A. , Luo Liqun , Rülicke Thomas , Hippenmeyer Simon
Published: June 2020

Mosaic Analysis with Double Markers (MADM) offers a unique approach to visualize and concomitantly manipulate genetically-defined cells in mice with single-cell resolution. MADM applications include the analysis of lineage; single-cell morphology and physiology; genomic imprinting phenotypes; and dissection of cell-autonomous gene functionsin vivoin health and disease. Yet, MADM could only be applied to <25% of all mouse genes on select chromosomes thus far. To overcome this limitation, we generated transgenic mice with knocked-in MADM cassettes near the centromeres of all 19 autosomes and validated their use across organs. With this resource, >96% of the entire mouse genome can now be subjected to single-cell genetic mosaic analysis. Beyond proof-of-principle, we applied our MADM library to systematically trace sister chromatid segregation in distinct mitotic cell lineages. We found striking chromosome-specific biases in segregation patterns, reflecting a putative mechanism for the asymmetric segregation of genetic determinants in somatic stem cell division.
Properties of Glial Cell at the Neuromuscular Junction are Incompatible with synaptic repair in the SOD1G37RALS mouse model
Authors: Éric Martineau , Arbour Danielle , Vallée Joanne , Richard Robitaille
Published: June 2020

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease affecting motoneurons in a motor-unit (MU) dependent manner. Glial dysfunction contributes to numerous aspects of the disease. At the neuromuscular junction (NMJ), early alterations in perisynaptic Schwann cell (PSC), glial cells at this synapse, may impact their ability to regulate NMJ stability and repair. Indeed, muscarinic receptors (mAChR) regulate the repair phenotype of PSCs and are overactivated at disease-resistant NMJs (Soleusmuscle) in SOD1G37Rmice. However, it remains unknown whether this is the case at disease-vulnerable NMJs and whether it translates into an impairment of PSC-dependent repair mechanisms. We usedSoleusandSternomastoidmuscles from SOD1G37Rmice and performed Ca2+-imaging to monitor PSC activity and used immunohistochemistry to analyze their repair and phagocytic properties. We show that PSC mAChR-dependent activity was transiently increased at disease-vulnerable NMJs (Sternomastoidmuscle). Furthermore, PSCs from both muscles extended disorganized processes from denervated NMJs and failed to initiate or guide nerve terminal sprouts at disease-vulnerable NMJs, a phenomenon essential for compensatory reinnervation. This was accompanied by a failure of numerous PSCs to upregulate Galectin-3 (MAC-2), a marker of glial axonal debris phagocytosis, upon NMJ denervation in SOD1 mice. Finally, differences in these PSC-dependent NMJ repair mechanisms were MU-type dependent, thus reflecting MU vulnerability in ALS. Together, these results reveal that neuron-glia communication is ubiquitously altered at the NMJ in ALS. This appears to prevent PSCs from adopting a repair phenotype, resulting in a maladapted response to denervation at the NMJ in ALS.

SIGNIFICANCE STATEMENT

Understanding how the complex interplay between neurons and glial cells ultimately lead to the degeneration of motor neurons and loss of motor function is a fundamental question to comprehend amyotrophic lateral sclerosis. An early and persistent alteration of glial cell activity takes place at the neuromuscular junction (NMJ), the output of motor neurons, but its impact on NMJ repair remains unknown. Here, we reveal that glial cells at disease-vulnerable NMJs often fail to guide compensatory nerve terminal sprouts and to adopt a phagocytic phenotype on denervated NMJs in SOD1G37Rmice. These results show that glial cells at the NMJ elaborate an inappropriate response to NMJ degeneration in a manner that reflects motor-unit vulnerability and potentially impairs compensatory reinnervation.