bluuebunny/crossref_metadata_2025 huggingface dataset:
Classifying liganded states in heterogeneous single-particle cryo-EM datasets
Authors: Arnold William R , Asarnow Daniel , Cheng Yifan
Published: October 2021

A powerful aspect of single-particle cryogenic electron microscopy is its ability to determine high-resolution structures from samples containing heterogeneous mixtures of the same macromolecule in different conformational or compositional states. Beyond determining structures at higher resolutions, one outstanding question is if macromolecules with only subtle conformation differences, such as the same protein bound with different ligands in the same binding pocket, can be separated reliably, and if information concerning binding kinetics can be derived from the particle distributions of different conformations obtained in classification. In this study, we address these questions by assessing the classification of synthetic heterogeneous datasets of Transient Receptor Potential Vanilloid 1 generated by combining different homogeneous experimental datasets. Our results indicate that classification can isolate highly homogeneous subsets of particle for calculating high-resolution structures containing individual ligands, but with limitations.
Observing correlations between dark matter accretion and galaxy growth: II. testing the impact of galaxy mass, star formation indicator, and neighbour colours
Authors: O’Donnell Christine , Behroozi Peter , More Surhud
Published: October 2021

A crucial question in galaxy formation is what role new accretion has in star formation. Theoretical models have predicted a wide range of correlation strengths between halo accretion and galaxy star formation. Previously, we presented a technique to observationally constrain this correlation strength for isolated Milky Way mass galaxies at z ∼ 0.12, based on the correlation between halo accretion and the density profile of neighbouring galaxies. By applying this technique to both observational data from the Sloan Digital Sky Survey and simulation data from the UniverseMachine, where we can test different correlation strengths, we ruled out positive correlations between dark matter accretion and recent star formation activity. In this work, we expand our analysis by (1) applying our technique separately to red and blue neighbouring galaxies, which trace different infall populations, (2) correlating dark matter accretion rates with Dn 4000 measurements as a longer-term quiescence indicator than instantaneous star-formation rates, and (3) analysing higher-mass isolated central galaxies with 1011.0 < M*/M⊙ < 1011.5 out to z ∼ 0.18. In all cases, our results are consistent with non-positive correlation strengths with ≳ 85 per cent confidence, which is most consistent with models where processes such as gas recycling dominate star formation in massive z = 0 galaxies.
Dynamics of Colombo’s top: tidal dissipation and resonance capture, with applications to oblique super-Earths, ultra-short-period planets and inspiraling hot Jupiters
Authors: Su Yubo , Lai Dong
Published: October 2021

We present a comprehensive theoretical study on the spin evolution of a planet under the combined effects of tidal dissipation and gravitational perturbation from an external companion. Such a ‘spin + companion’ system (called Colombo’s top) appears in many [exo]planetary contexts. The competition between the tidal torque (which drives spin-orbit alignment and synchronization) and the gravitational torque from the companion (which drives orbital precession of the planet) gives rise to two possible spin equilibria (‘tidal Cassini Equilibria’, tCE) that are stable and attracting: the ‘simple’ tCE1, which typically has a low spin obliquity, and the ‘resonant’ tCE2, which can have a significant obliquity. The latter arises from a spin-orbit resonance and can be broken when the tidal alignment torque is stronger than the precessional torque from the companion. We characterize the long-term evolution of the planetary spin (both magnitude and obliquity) for an arbitrary initial spin orientation, and develop a new theoretical method to analytically obtain the probability of resonance capture driven by tidal dissipation. Applying our general theoretical results to exoplanetary systems, we find that a super-Earth (SE) with an exterior companion can have a substantial probability of being trapped in the high-obliquity tCE2, assuming that SEs have a wide range of primordial obliquities. We also evaluate the recently proposed ‘obliquity tide’ scenarios for the formation of ultra-short-period Earth-mass planets and for the orbital decay of hot Jupiter WASP-12b. We find in both cases that the probability of resonant capture into tCE2 is generally low and that such a high-obliquity state can be easily broken by the required orbital decay.
Model-independent redshift estimation of BL Lac objects through very-high-energy observations
Authors: Malik Zahoor , Sahayanathan Sunder , Shah Zahir , Iqbal Naseer , Manzoor Aaqib , Bhatt Nilay
Published: October 2021

The very-high-energy (VHE) gamma-ray spectral indices of blazars show a strong correlation with the source redshift. The absence of any such correlation in low-energy gamma-rays and X-rays indicates the presence of extragalactic background light (EBL)-induced absorption of VHE gamma-rays. By employing a linear regression analysis, this observational feature of blazars is used to constrain the redshifts of BL Lac objects that were unknown/uncertain earlier. In addition, we compare the observed VHE spectral index–redshift correlation with those predicted from commonly adopted EBL models. Our study highlights the deviation of EBL-model-based predictions from observations, especially at high redshifts.
How Uzawa differs from Lucas
Authors: Sasakura By Kazuyuki
Published: November 2021

The Uzawa–Lucas model is a benchmark model in endogenous growth theory. But Lucas is so influential that the Uzawa–Lucas model is virtually the Lucas model. This article distinguishes between the Uzawa model and the Lucas model, and examines the Uzawa model in detail for the first time. It is certainly true that the two models have much in common. However, there are also important differences. Economically, in the Uzawa model, people choose between working in the production sector and working in the education sector, whereas in the Lucas model people choose between working in the production sector and not working in order to go to school. Mathematically, the potentially maximum growth rate must be smaller than the rate of time preference (less population growth) in the former, whereas the opposite must hold in the latter. This means that the two models are not applicable to the same economy.
A cluster of atypical resistance genes in soybean confers broad-spectrum antiviral activity
Authors: Yan Ting , Zhou Zikai , Wang Ru , Bao Duran , Li Shanshan , Li Aoga , Yu Ruonan , Wuriyanghan Hada
Published: October 2021

Soybean mosaic virus (SMV) is a severe soybean (Glycine max) pathogen. Here we characterize a soybean SMV resistance cluster (SRC) that comprises five resistance (R) genes. SRC1 encodes a Toll/interleukin-1 receptor and nucleotide-binding site (TIR-NBS [TN]) protein, SRC4 and SRC6 encode TIR proteins with a short EF-hand domain, while SRC7 and SRC8 encode TNX proteins with a noncanonical basic secretory protein (BSP) domain at their C-termini. We mainly studied SRC7, which contains a noncanonical BSP domain and gave full resistance to SMV. SRC7 possessed broad-spectrum antiviral activity toward several plant viruses including SMV, plum pox virus, potato virus Y, and tobacco mosaic virus. The TIR domain alone was both necessary and sufficient for SRC7 immune signaling, while the NBS domain enhanced its activity. Nuclear oligomerization via the interactions of both TIR and NBS domains was essential for SRC7 function. SRC7 expression was transcriptionally inducible by SMV infection and salicylic acid (SA) treatment, and SA was required for SRC7 triggered virus resistance. SRC7 expression was posttranscriptionally regulated by miR1510a and miR2109, and the SRC7-miR1510a/miR2109 regulatory network appeared to contribute to SMV–soybean interactions in both resistant and susceptible soybean cultivars. In summary, we report a soybean R gene cluster centered by SRC7 that is regulated at both transcriptional and posttranscriptional levels, possesses a yet uncharacterized BSP domain, and has broad-spectrum antiviral activities. The SRC cluster is special as it harbors several functional R genes encoding atypical TIR-NBS-LRR (TNL) type R proteins, highlighting its importance in SMV–soybean interaction and plant immunity.
Evaluation of mitochondrial dysfunction due to oxidative stress in therapeutic, toxic and lethal concentrations of tramadol
Authors: Mohammadnejad Leila , Soltaninejad Kambiz , Seyedabadi Mohammad , Ghasem Pouri Seyed Khosro , Shokrzadeh Mohammad , Mohammadi Hamidreza
Published: October 2021

Tramadol (TR) is a centrally acting analgesic drug that is used to relieve pain. The therapeutic (0.1–0.8 mg/l), toxic (1–2 mg/l) and lethal (>2 mg/l) ranges were reported for TR. The present study was designed to evaluate which doses of TR can induce liver mitochondrial toxicity. Mitochondria were isolated from the five rats’ liver and were incubated with therapeutic to lethal concentrations (1.7–600 μM) of TR. Biomarkers of oxidative stress including: reactive oxygen species (ROS), lipid peroxidation (LPO), protein carbonyl content, glutathione (GSH) content, mitochondrial function, mitochondrial membrane potential (MMP) and mitochondrial swelling were assessed. Our results showed that ROS and LPO at 100 μM and protein carbonylation at 600 μM concentrations of TR were significantly increased. GSH was decreased specifically at 600 μM concentration. Mitochondrial function, MMP and mitochondrial swelling decreased in isolated rat liver mitochondria after exposure to 100 and 300 μM, respectively. This study suggested that TR at therapeutic and toxic levels by single exposure could not induce mitochondrial toxicity. But, in lethal concentration (≥100 μM), TR induced oxidative damage and mitochondria dysfunction. This study suggested that ROS overproduction by increasing of TR concentration induced mitochondrial dysfunction and caused mitochondrial damage via Complex II and membrane permeability transition pores disorders, MMP collapse and mitochondria swelling.
Levonorgestrel-Releasing Intrauterine System for Endometrial Hyperplasia
Authors: Mittermeier Theresa , Farrant Charlotte , Wise Michelle R.
Published: November 2021

(Abstracted from Cochrane Database Syst Rev 2020;9(9):CD012658)

Endometrial hyperplasia (EH) is a histological diagnosis of excessive production of cells in the endometrium that represents a precursor in the development of endometrial cancer (EC), the sixth most common cancer in women globally. Obesity is the leading risk factor for both EH and EC in premenopausal women with abnormal uterine bleeding (AUB).
Analysis of Patient-reported Outcomes Measures Used in Lumbar Fusion Surgery Research for Degenerative Spondylolisthesis
Authors: Ravishankar Pavitra , Winkleman Robert , Rabah Nicholas , Steinmetz Michael , Mroz Thomas
Published: November 2021

Study Design:

Meta-analyses.

Objective:

This study aims to document the most common Patient-reported Outcome Measures (PROMs) used to assess lumbar fusion surgery outcomes and provide an estimate of the average improvement following surgical treatment.

Summary of Background Data:

As health care institutions place more emphasis on quality of care, accurately quantifying patient perceptions has become a valued tool in measuring outcomes. To this end, greater importance has been placed on the use of PROMs. This is a systemic review and meta-analysis of randomly controlled trials published between 2014 and 2019 assessing surgical treatment of degenerative spondylolisthesis.

Methods:

A fixed effect size model was used to calculate mean difference and a 95% confidence interval (95% CI). Linear regression was used to calculate average expected improvement, adjusted for preoperative scores.

Results:

A total of 4 articles (7 study groups) were found for a total of 444 patients. The 3 most common PROMs were Oswestry Disability Index (ODI) (n=7, 100%), Short-Form-12 or Short-Form-36 (SF-12/36) (n=4, 57.1%), and visual analog scale-back pain (n=3, 42.8%). Pooled average improvement was 24.12 (95% CI: 22.49–25.76) for ODI, 21.90 (95% CI: 19.71–24.08) for SF-12/36 mental component score, 22.74 (95% CI: 20.77–24.71) for SF-12/36 physical component score, and 30.87 (95% CI: 43.79–47.97) for visual analog scale-back pain. After adjusting for preoperative scores, patients with the mean preoperative ODI (40.47) would be expected to improve by 22.83 points postoperatively.

Conclusions:

This study provides a range of expected improvement for common PROMs used to evaluate degenerative spondylolisthesis with the goal of equipping clinicians with a benchmark value to use when counseling patients regarding surgery. In doing so, it hopes to provide a comparison point by which to judge individual patient improvement.

Level of Evidence:

Level II.
Trends in rectal cancer incidence, relative survival, and mortality in Denmark during 1978–2018
Authors: Urbute Aivara , Sand Freja L. , Belmonte Federica , Iversen Lene H. , Munk Christian , Kjaer Susanne K.
Published: November 2021

Objective

Rectal cancer is common in developed countries, though incidence varies globally. We assessed time trends in incidence, relative survival and mortality in Denmark.

Methods

Rectal cancer cases (N = 50 461) diagnosed in 1978–2018 were identified in the Danish Cancer Registry. We calculated age-standardized incidence rates, overall and according to sex and age. Average annual percentage changes (AAPC) were estimated using Poisson regression. We estimated 5-year relative survival and evaluated the effect of age, calendar year of diagnosis, sex and stage of disease on mortality using the Cox proportional hazards model.

Results

The incidence of rectal cancer tended to decrease in all age groups and both sexes during 1978–1997, but increased since 1998, more in men (AAPC = 2.05%; 95% CI,1.80; 2.31) than in women (AAPC = 0.99%; 95% CI,0.68; 1.30). It increased in men until 79 years and in women up to 59 years. Mortality decreased over time when adjusting for age, stage and sex. Overall, men had the highest 5-year mortality after adjusting for age, calendar period and stage. Five-year relative survival improved (1978–2018) for all stages. Initially, the overall 5-year relative survival tended to be better for women, but in recent years, it has been similar in both sexes.

Conclusion

Incidence of rectal cancer increased in the last two decades, most markedly in women 59 years and younger. Mortality decreased when adjusting for age and stage. Relative survival improved over time more for men than for women, so in recent years, it has been virtually identical in men and women.
Disparities in Kangaroo Care for Premature Infants in the Neonatal Intensive Care Unit
Authors: Brignoni-Pérez Edith , Scala Melissa , Feldman Heidi M. , Marchman Virginia A. , Travis Katherine E.
Published: November 2021

Objective:

The aim of this study was to investigate whether preterm infants whose families have lower socioeconomic status (SES) or communicate with clinical staff in a language other than English experience differences in the rate, frequency, and duration of kangaroo care (KC) in the neonatal intensive care unit (NICU) compared with preterm infants of higher SES or primarily English-speaking families.

Methods:

Participants were infants born <32 weeks' gestational age (GA), N = 116. We defined SES by the infants' health insurance (private/higher vs public/lower) and language by the language mothers used to communicate with clinical staff (English vs Other language). SES or language groups were compared on (1) rate of KC infants experienced during hospitalization per visitation days, (2) frequency of KC per visitation days, and (3) duration of KC events per day.

Results:

Infants in the lower SES and Other language groups experienced KC in reduced amounts, lower frequencies, and shorter durations than infants in either the higher SES or English language groups. SES and language group differences remained significant after controlling for family visitation and GA at birth. After controlling for SES, language group differences in KC duration remained significant.

Conclusion:

Our findings revealed disparities in the rate, frequency, and duration of KC experienced in the NICU as a function of both SES and language. Such disparities reduced infants' access to this developmental care practice shown to stabilize clinical status and promote neurodevelopment. We recommend that hospital nurseries implement policies that minimize these disparities.
Characteristics of Lower Extremity Infection Rates Following Mohs Micrographic Surgery
Authors: Niklinska Eva B. , Hicks Alexander , Wheless Lee , Hanlon Allison
Published: November 2021

BACKGROUND

Surgical site infection (SSI) is the most common complication for Mohs micrographic surgery (MMS). Lower extremity surgical sites are at an increased risk for developing SSI.

OBJECTIVE

This study aimed to evaluate lower extremity SSI rates post-MMS based on closure type and antibiotic usage.

MATERIALS AND METHODS

A retrospective review was performed of all lower extremity MMS cases from 2011 to 2016 at Vanderbilt University Medical Center. Patient history, surgical details, and follow-up appointments were reviewed.

RESULTS

Six hundred twenty MMS lower extremity surgeries were eligible. Review identified an overall lower extremity SSI rate of 7.4%. Infection rates were significantly increased in wound closed by flaps/grafts (p < .001). Although wound size and preoperative antibiotic prophylaxis were initially associated with increased infection rate (p = .03, p = .015), the associations were fully attenuated when adjusting for closure type.

CONCLUSION

More complicated repair techniques (flap/graft) for larger wound sizes contribute to increased SSI risk among lower extremity MMS cases. Providers can use this information to guide antibiotic prophylaxis.
MORPHOLOGIC AND ANATOMICAL FEATURES OF TYPE 1 MACULAR NEOVASCULARIZATION TRUNKS IN AGE-RELATED MACULAR DEGENERATION USING OPTICAL COHERENCE TOMOGRAPHY ANGIOGRAPHY
Authors: Choi Kwang-Eon , Kim Seong-Woo , Yun Cheolmin , Oh Jaeryung
Published: November 2021

Purpose:

To evaluate the morphologic features of macular neovascularization (MNV) trunks at different layers using optical coherence tomography angiography.

Methods:

Type 1 MNV trunks in age-related macular degeneration were retrospectively evaluated at the subretinal pigment epithelium and sub-Bruch membrane (subBM) layers. The detectability and location of the trunks were compared. MNV trunks at the subBM layer on optical coherence tomography angiography B-scans were evaluated using a flow overlay. The correlations of the MNV trunk with optical coherence tomography angiography and optical coherence tomography parameters were evaluated.

Results:

Among the 63 included eyes, 27 showed core vessels at the subretinal pigment epithelium layer and 52 showed MNV trunks at the subBM layer, which were connected with the MNV at the subretinal pigment epithelium layer. The locations of the MNV trunks in each layer were different. MNV trunk types at the subBM layer were related to disease duration, distance from the large choroidal vessels, and MNV vessel density. The large choroidal vessel diameter was correlated with the MNV trunk diameter at the subBM layer.

Conclusion:

Macular neovascularization trunks at the subBM layer were detected more frequently than distal MNV trunks at the subretinal pigment epithelium layer. Macular neovascularization trunk features at the subBM layer may be related to disease duration and a large choroidal vessel.
Recent developments in anterior capsulotomy for cataract surgery
Authors: Abbas Anser A. , Bu Jennifer J. , Chung Jinkwon , Afshari Natalie A.
Published: November 2021

Purpose of review

Successful anterior capsulotomy is an important step in cataract surgery. This article reviews the various anterior capsulotomy techniques available to surgeons to optimize the step, including those that have become available since the introduction of femtosecond-laser-assisted cataract surgery (FLACS). Studies comparing the relative advantages of each technique will be emphasized.

Recent findings

Manual continuous curvilinear capsulorhexis (CCC) and FLACS remain the two most widely studied techniques for achieving anterior capsulotomy. Each technique has been shown to be effective for a wide range of patients and cataract surgery complications. Meta-analyses have shown that FLACS provides similar results to manual CCC for long-term cataract surgery outcomes. Several alternative methods for anterior capsulotomy have been described, which aim to provide some of the advantages of laser capsulotomy at a lower cost; among these, precision pulse capsulotomy (PPC) and selective laser capsulotomy (SLC) have been investigated the most in the literature so far.

Cataract surgeons have an increasing number of techniques for anterior capsulotomy available. Manual CCC and FLACS remain the most widely used, and most well studied. The latest techniques, PPC and SLC, have shown promise in the few studies performed since they were introduced.
Efficient use of ultrasound in cataract surgery
Authors: Bu Jennifer J. , Chung Jinkwon , Afshari Natalie A.
Published: November 2021

Purpose of review

Modern phacoemulsification machines apply ultrasound through a variety of settings and parameters to remove a cataract. Using these new technologies efficiently is critical for both reducing surgical times and improving postoperative outcomes. The present article reviews recent findings in phacodynamics to explore the optimum use of ultrasound in cataract surgery.

Recent findings

In studies seeking to determine the optimum parameters in both fluidics and power, increased power and aspiration does not necessarily equate to more efficiency. New developments, such as torsional ultrasound, micropulse, and burst mode have shown increased efficiency in randomized control trials and in-vitro compared with conventional ultrasound. Regarding vacuums, the venturi pump has demonstrated greater efficiency compared with the peristaltic pump. We also explore other parameters, such as chamber pressure and tip selection. Meta-analyses on femtosecond-laser assisted cataract surgery (FLACS) have shown similar long-term visual outcomes compared to conventional cataract surgery.

Though conventional cataract surgery remains highly effective, surgeons have increasing options for customizing their ultrasound settings and phacoemulsification techniques.
Efficacy of omega-3-rich Camelina sativa on the metabolic and clinical markers in nonalcoholic fatty liver disease: a randomized, controlled trial
Authors: Musazadeh Vali , Dehghan Parvin , Khoshbaten Manouchehr
Published: November 2021

Objective

Recently, omega-3 fatty acids and antioxidants co-supplementation was considered as alternative treatment in the management of nonalcoholic fatty liver disease (NAFLD). This trial evaluated effects of Camelina sativa oil (CSO) as a rich source of omega-3 fatty acids and antioxidants on anthropometric indices, lipid profile, liver enzymes, and adiponectin in NAFLD patients.

Participants and methods

This triple-blind, placebo-controlled, randomized clinical trial was conducted on 46 NAFLD patients who were randomly assigned to either a CSO supplement or placebo for 12 weeks. Both groups received a loss weight diet. Levels of liver enzymes, adiponectin, lipid profile, atherogenic index, and anthropometric indices were assessed for all patients at baseline and post-intervention.

Results

CSO caused significant differences in weight, BMI, waist circumference, waist-to-hip ratio, triglyceride, total cholesterol (TC), low-density lipoprotein cholesterol (LDL-c), TC/HDL-c, LDL-c/HDL-c, atherogenic index, alanine aminotransferase, and adiponectin concentrations in the CSO group compared with the placebo group (P < 0.046 for all). No significant differences were found in hip circumference, neck circumference, HDL-c, and other liver enzymes in the CSO group compared with the placebo group (P = 0.790, P = 0.091, P = 0.149, P < 0.159 for liver enzymes, respectively).

Discussion and conclusion

This study showed that CSO supplementation for 12 weeks causes significant changes in all of anthropometric indices (except hip circumference and neck circumference), ALT, lipid profile (except HDL-c), atherogenic index, and adiponectin in NAFLD patients.
Progression of Peritoneal Mesothelioma In Situ to Invasive Mesothelioma Arising in the Setting of Endometriosis With Germline BAP1 Mutation: A Case Report
Authors: Fels Elliott Daffolyn R. , Travieso Jennifer L. , As-Sanie Sawsan , Hrycaj Steven M. , Lieberman Richard W. , Myers Jeffrey L. , Huang Tao
Published: November 2021

Mesothelioma in situ has been proposed as a precursor to malignant mesothelioma arising in the pleura or peritoneum. We report a case of malignant peritoneal mesothelioma which progressed from mesothelioma in situ over a 10-mo period in a 24-yr-old woman with stage IV endometriosis. Initial surgery showed deeply infiltrative endometriosis with progestin effect. Postoperatively the patient had intractable pelvic pain and vaginal discharge. Imaging studies were negative. Repeat laparoscopy 10 mo later revealed vesicular lesions on the omentum and pinpoint white lesions studding the small bowel, appendix, and pelvic peritoneum. A diagnosis of epithelioid mesothelioma was established on biopsy of the omentum and confirmed by immunohistochemistry showing complete loss of BRCA1-associated protein-1 (BAP1) nuclear staining. Retrospectively, BAP1 loss was identified in the cytologically bland, single-layer surface mesothelium of the prior resection specimen, consistent with mesothelioma in situ. The patient underwent genetic testing and was found to have a pathogenic germline mutation in BAP1.
Structural Stigma and Sexual Health Disparities Among Gay, Bisexual, and Other Men Who Have Sex With Men in Australia
Authors: Saxby Karinna , Chan Curtis , Bavinton Benjamin R.
Published: November 2021

Background:

Discrimination and stigmatization at the institutional and sociocultural level (conceptualized as “structural stigma”) has been associated with adverse health outcomes among sexual and gender minorities. However, few studies explore whether structural stigma is associated with sexual health outcomes. Addressing this gap, here, we explore this relationship among Australian gay, bisexual, and other men who have sex with men (GBM)—a population disproportionately affected by HIV.

Setting and Methods:

Using responses from the 2017 Australian Marriage Law Postal Survey, we operationalized structural stigma related to sexual minority status as the regional percentage of votes against legalizing same-sex marriage. These responses were then linked to national HIV behavioral surveillance data from Australian GBM (43,811 responses between 2015 and 2019). Controlling for a rich set of individual and regional level confounders, regression analyses were used to estimate the extent to which structural stigma was associated with testing for, and diagnoses of, HIV and sexually transmitted infections (STIs), and awareness and use of HIV prevention and treatment interventions (pre-exposure and postexposure prophylaxis, combination therapy, and HIV-related clinical care).

Results:

Australian GBM living in regions with higher levels of structural stigma were less likely to undergo HIV/STI testing, receive HIV/STI diagnoses, and be taking, or aware of, biomedical prevention strategies. Among GBM living with HIV, structural stigma was associated with a reduced likelihood of being on combination therapy and fewer HIV-related clinical visits.

Conclusions:

Altogether, these results suggest that structural stigma may undermine HIV prevention strategies as well as adequate management of HIV infection among GBM.
A Systems-Based Morbidity and Mortality Conference Was Associated With a Transient Reduction in ECG Completion Times
Authors: Levy Andrew E. , Whittington Melanie D. , Anstett Tyler J. , Simon Steven T. , Wentworth Allen , Carter James E. , Ho P. Michael
Published: November 2021

Background and Objectives:

During its monthly morbidity and mortality conference (MMC), the University of Colorado Division of Cardiology reviewed a “near-miss” patient safety event involving the delayed completion of a Stat-priority (ie, statim, meaning high priority) electrocardiogram (ECG). Because critical and interprofessional stakeholders participated in the conference, we hypothesized that the MMC would be associated with reduced ECG completion times.

Methods:

Data were collected for in-hospital ECGs performed at the University of Colorado Hospital between January 1, 2017, and June 30, 2018. An interrupted time series analysis was used to estimate the immediate and ongoing impact of the MMC (held on February 28, 2018) on ECG completion times, stratified by order priority (Stat, Now, or Routine). The percentage of delayed Stat-priority ECGs was analyzed as a secondary outcome.

Results:

Before the MMC, ECG completion times were stable for all order priorities (P > .2), but the proportion of delayed Stat-priority ECGs increased from 5% in January 2017 to 20% in February 2018 (P < .01). The MMC was associated with an immediate reduction in average daily ECG completion times for Routine (−18.4 minutes, P = .03) and Now (−8 minutes, P = .024) priority ECGs. No reduction was seen for Stat ECGs (P = .97), though the percentage of delayed Stat ECGs stopped increasing (P = .63). In the post-MMC period, completion times for Routine-priority ECGs increased and approached pre-MMC levels.

Conclusions:

The MMC was associated with an immediate, but temporary, improvement in ECG completion times. Although the observed clinical benefit of the MMC is novel, these data support the need for more durable reforms to sustain initial improvements.
Adipose-Derived Stem Cells Therapy for Radiation-Induced Skin Injury
Authors: Huayllani Maria T. , Ruiz-Garcia Henry , Boczar Daniel , Avila Francisco R. , Lu Xiaona , Rinker Brian D. , Moran Steven L. , Sarabia-Estrada Rachel , Quiñones-Hinojosa Alfredo , Forte Antonio J.
Published: November 2021

Background

Radiation-induced skin injuries have been treated with different medical therapies and have shown diverse outcomes. We aim to evaluate the effect of adipose-derived stem cells (ADSCs) therapy on radiation-induced skin injury.

Methods

We performed a review by querying PubMed, Ovid MEDLINE, and EMBASE databases from inception to April 2020 following Preferred Reporting Items for Systematic reviews and Meta-Analyses guidelines. The MeSH terms “adipose-derived stem cells,” “wound healing,” “radiation,” and synonyms in combinations determined our search strategy. Experimental peer-reviewed articles describing the protocol and comparing the results with controls were included. Non-English studies were excluded.

Results

Our search recorded a total of 137 articles. Only 8 studies met our inclusion criteria and were included in this review. Five studies evaluated the use of ADSC alone, whereas the others evaluated the efficacy of ADSC seeded in scaffolds. Adipose-derived stem cell–based therapies, either alone or seeded in scaffolds, were shown to improve wound healing in most studies when compared with controls.

Conclusions

There is evidence supporting the positive benefits from ADSC-based therapies in radiation-induced skin injury. However, further studies are needed to standardize the method of ADSC extraction, radiation-induced skin injury experimental model, and increase the time of follow-up to evaluate the results accurately.
Multiplex PCR Assays for Identifying All Major SARS-CoV-2 Variants
Authors: Dikdan Ryan J. , Marras Salvatore AE , Field Amanda P. , Brownlee Alicia , Cironi Alexander , Hill D. Ashley , Tyagi Sanjay
Published: October 2021

Variants of Concern (VOC) of SARS-CoV-2, including Alpha, Beta, Gamma, Delta, and Omicron threaten to prolong the pandemic leading to more global morbidity and mortality. Genome sequencing is the mainstay of tracking the development and evolution of the virus, but is costly, slow, and not easily accessible. A multiplex qRT-PCR assay for SARS-CoV-2 was developed, which identifies all VOC as well as other mutations of interest in the viral genome, eight mutations total, using single nucleotide discriminating molecular beacons in a two-tube assay. The presented variant molecular beacon assay showed a limit of detection of five copies of the viral RNA, with 100% specificity. Twenty-six SARS-CoV-2 positive patient samples were blinded and tested using this assay. When testing patient samples, the assay was in full agreement with results from deep sequencing with a sensitivity and specificity of 100% (26/26). We have used our design methodology to rapidly design an assay which detects the new Omicron variant. This Omicron assay was used to accurately identify this variant in 17 of 33 additional patient samples. These qRT-PCR assays identify all currently circulating VOC of SARS-CoV-2 as well as other important mutations in its Spike protein coding sequence. These assays can be easily implemented on broadly available five-color thermal cyclers and will help track the spread of these variants.
Clinical sequencing of soft tissue and bone sarcomas delineates diverse genomic landscapes and potential therapeutic targets
Authors: Nacev Benjamin A. , Sanchez-Vega Francisco , Smith Shaleigh A. , Antonescu Cristina R. , Rosenbaum Evan , Shi Hongyu , Tang Cerise , Socci Nicholas D. , Rana Satshil , Gularte-Mérida Rodrigo , Zehir Ahmet , Gounder Mrinal M. , Bowler Timothy G. , Luthra Anisha , Jadeja Bhumika , Okada Azusa , Strong Jonathan A. , Stoller Jake , Chan Jason E. , Chi Ping , D’Angelo Sandra P. , Dickson Mark A. , Kelly Ciara M. , Keohan Mary Louise , Movva Sujana , Thornton Katherine , Meyers Paul A. , Wexler Leonard H. , Slotkin Emily K. , Glade Bender Julia L. , Shukla Neerav N. , Hensley Martee L. , Healey John H. , La Quaglia Michael P. , Alektiar Kaled M. , Crago Aimee M. , Yoon Sam S. , Untch Brian R. , Chiang Sarah , Agaram Narasimhan P. , Hameed Meera R. , Berger Michael F. , Solit David B. , Schultz Nikolaus , Ladanyi Marc , Singer Samuel , Tap William D.
Published: October 2021

The genetic, biologic, and clinical heterogeneity of sarcomas poses a challenge for the identification of therapeutic targets, clinical research, and advancing patient care. Because there are > 100 sarcoma subtypes, in-depth genetic studies have focused on one or a few subtypes. Herein, we report a comparative genetic analyses analysis of 2,138 sarcomas representing 45 pathological entities. This cohort was prospectively analyzed using targeted sequencing to characterize subtype-specific somatic alterations in targetable pathways, rates of whole genome doubling, mutational signatures, and subtype-agnostic genomic clusters. The most common alterations were in cell cycle control andTP53, receptor tyrosine kinases/PI3K/RAS, and epigenetic regulators. Subtype-specific associations includedTERTamplification in intimal sarcoma and SWI/SNF alterations in uterine adenosarcoma. Tumor mutational burden, while low compared to other cancers, varied between and within subtypes. This resource will improve sarcoma models, motivate studies of subtype-specific alterations, and inform investigations of genetic factors and their correlations with treatment response.
The integrity of the antimicrobial supply chain in Bangladesh: assessing the regulatory environment and contextual challenges
Authors: Orubu Ebiowei S.F. , Samad Mohammed A. , Rahman Md. Tanvir , Zaman Muhammad H. , Wirtz Veronika J.
Published: October 2021

Poor-quality medicines lead to large individual, health systems and national economic losses. Most low- and middle-income countries (LMICs) lack the robust regulatory quality assurance system necessary to contain the spread of poor-quality medicines. Innovations in regulatory systems strengthening are needed to protect public health. In this study, we assessed the integrity of the antimicrobial supply chain in Bangladesh and suggest innovations. We employed a qualitative methodology comprising a policy content analysis, and literature and database reviews. Bangladesh was chosen as a model LMIC because of its pharmaceuticals production capacity. Using a framework modified from the World Health Organization’s and the United States Pharmacopoeia’s, the Bangladesh National Drug Policy (BNDP) was evaluated for provisions on quality assurance mechanisms that match regulatory functions. Newspaper, peer-reviewed and post-marketing surveillance reports were used to assess the extent of poor-quality antimicrobials in circulation. There are provisions for quality assurance in the BNDP. Newspaper reports identified the circulation of substandard antimicrobials and reported on actions by the government to seize fraudulent/falsified and expired products. Only six peer-review studies testing antimicrobial product quality were identified; the three studies with the larger sample size (over 10 samples tested) reported results of out-of-specifications products. This assessment found evidence of regulatory actions against poor-quality antimicrobials as well as news reports and studies suggesting quality concerns, but no current rigorous assessment of the extent in Bangladesh. We suggest a multi-pronged approach to regulatory system strengthening comprising three strategies: community-based surveillance, task-shifting, and technology-enabled consumer participation.
Vaccination of COVID-19 Convalescent Plasma Donors Increases Binding and Neutralizing Antibodies Against SARS-CoV-2 Variants
Authors: Germanio Clara Di , Simmons Graham , Thorbrogger Chloe , Martinelli Rachel , Stone Mars , Gniadek Thomas , Busch Michael P
Published: October 2021

Background

COVID-19 convalescent plasma (CCP) was widely used as passive immunotherapy during the first waves of SARS-CoV-2 infection in the US. However, based on observational studies and randomized controlled trials, beneficial effects of CCP were limited, and its use was virtually discontinued early in 2021, in concurrence with increased vaccination rates and availability of monoclonal antibody (mAb) therapeutics. However, as new variants of the SARS-CoV-2 spread, interest in CCP derived from vaccine-boosted CCP donors is resurging. The effect of vaccination of previously infected CCP donors on antibodies against rapidly spreading variants of concern (VOC) is still under investigation.

Study Design/Methods

In this study, paired samples from 11 CCP donors collected before and after vaccination were tested to measure binding antibodies levels and neutralization activity against the ancestral and SARS-CoV-2 variants (Wuhan-Hu-1, B.1.1.7, B.1.351, P.1, D614G, B.1.617.2, B.1.427) on the Ortho Vitros Spike Total Ig and IgG assays, the MSD V-PLEX SARS-CoV-2 Panel 6 arrays for IgG binding and ACE2 inhibition, and variant-specific Spike Reporter Viral Particle Neutralization (RVPN) assays.

Results/Findings

Binding and neutralizing antibodies were significantly boosted by vaccination, with several logs higher neutralization for all the variants tested post-vaccination compared to the pre-vaccination samples, with no difference found among the individual variants.

Discussion

Vaccination of previously infected individuals boosts antibodies including neutralizing activity against all SARS-CoV-2 VOC, including the current spreading delta (B.1.617.2) variant. Animal model and human studies to assess clinical efficacy of vaccine boosted CCP are warranted, especially since 15-20% of current donations in the US are from previously infected vaccine-boosted donors.
Identification of COVID-19 and COPD common key genes and pathways using a protein-protein interaction approach
Authors: Thambiraja Thiviya S. , Karuppanan Kalimuthu , Subramaniam Gunasekaran , Kumar Suresh
Published: October 2021

Coronavirus disease (COVID-19) is an extremely contagious and cognitive disease that could cause immense hypoxemia. The rise in critically ill patients in epidemic regions has put enormous pressure on hospitals. There is a need to define extreme COVID-19 clinical determinants to optimize clinical diagnosis and the management system is strong. Chronic obstructive pulmonary disease (COPD) is linked to a rapidly increasing risk of death rates in population pneumonia. In this research, a network of protein-protein interaction (PPI) was developed using constructed datasets of COVID-19 and COPD genes to define the interrelationship between COVID-19 and COPD, how it affects each other, and the genes that are responsible for the process. The PPI network shows the top 10 common overlapping genes, which include IL10, TLR4, TNF, IL6, CXCL8, IL4, ICAM1, IFNG, TLR2, and IL18. These are the genes that COVID-19 and high-risk COPD patients are known to be expressed. These important genes shared by COVID-19 and COPD are involved in pathways such as malaria, African trypanosomiasis, inflammatory bowel disease, Chagas disease, influenza, and tuberculosis.
Optimal Design of Stochastic DNA Synthesis Protocols based on Generative Sequence Models
Authors: Weinstein Eli N. , Amin Alan N. , Grathwohl Will , Kassler Daniel , Disset Jean , Marks Debora S.
Published: October 2021

Generative probabilistic models of biological sequences have widespread existing and potential applications in analyzing, predicting and designing proteins, RNA and genomes. To test the predictions of such a model experimentally, the standard approach is to draw samples, and then synthesize each sample individually in the laboratory. However, often orders of magnitude more sequences can be experimentally assayed than can affordably be synthesized individually. In this article, we propose instead to use stochastic synthesis methods, such as mixed nucleotides or trimers. We describe a black-box algorithm for optimizing stochastic synthesis protocols to produce approximate samples from any target generative model. We establish theoretical bounds on the method’s performance, and validate it in simulation using held-out sequence-to-function predictors trained on real experimental data. We show that using optimized stochastic synthesis protocols in place of individual synthesis can increase the number of hits in protein engineering efforts by orders of magnitude, e.g. from zero to a thousand.
Intracellular pH dynamics regulates intestinal stem cell lineage specification
Authors: Liu Yi , Reyes Efren , Castillo-Azofeifa David , Klein Ophir D. , Barber Diane L. , Nystul Todd
Published: October 2021

Intracellular pH (pHi) dynamics is increasingly recognized to regulate myriad cell behaviors, including proliferation, migration, differentiation, and transformation. Here we report a new finding that pHi dynamics also regulates adult stem cell lineage specification. In mouse small intestinal organoids, we identify a pHi gradient along the crypt axis, lower at the crypt base and higher toward the villus, and find that dissipating this gradient by inhibiting Na+-H+exchanger 1 (NHE1) activity genetically or pharmacologically abolishes crypt budding. Using single-cell RNA sequencing and lineage tracing we demonstrate that pHi dynamics acts downstream of ATOH1, with increased pHi promoting differentiation toward the secretory lineage, while reduced pHi biases differentiation into the absorptive lineage. Consistent with these results, disrupting the pHi gradient blocks new Paneth cell differentiation. Paneth cells provide an essential WNT signal to ISCs in organoids, and we find that the loss of crypt budding with inhibiting NHE1 activity is rescued with exogenous WNTs. Our findings indicate that pHi dynamics is tightly regulated in the ISC lineage and that an increase in pHi is required for the specification of secretory lineage, including Paneth cell differentiation that contributes to crypt maintenance. These observations reveal a previously unreported role for pHi dynamics in cell fate decisions within an adult stem cell lineage.
Generating and testing the efficacy of transgenic Cas9 inTribolium castaneum
Authors: Rylee Johnathan C. , Nin-Velez Alexandra , Mahato Simpla , Helms Kennedy J. , Wade Michael J. , Zentner Gabriel E. , Zelhof Andrew C.
Published: October 2021

CRISPR/Cas9 genome editing has now expanded to many insect species, includingTribolium castaneum. However, compared toDrosophila melanogaster, the CRISPR toolkit ofT. castaneumis limited. A particularly apparent gap is the lack of Cas9 transgenic animals, which generally offer higher editing efficiency. We address this by creating and testing transgenic beetles expressing Cas9. We generated two different constructs bearing basal heat shock promoter-driven Cas9, two distinct 3’ UTRs, and one containing Cas9 fused to EGFP by a T2A peptide. For each construct, we were able to generate a line that is homozygous viable, though variable reductions in reproductive success with each construct were noted. Analyses of Cas9 activity in each transgenic line demonstrated that both designs are capable of inducing CRISPR-mediated changes in the genome in the absence of heat induction. Overall, these resources enhance the accessibility of CRISPR/Cas9 genome editing for theTriboliumresearch community and provide a benchmark against which to compare future transgenic Cas9 lines.
Systems-based approach for optimization of a scalable bacterial ST mapping assembly-free algorithm
Authors: Pavlovikj Natasha , Gomes-Neto Joao Carlos , Deogun Jitender S. , Benson Andrew K.
Published: November 2021

Epidemiological surveillance of bacterial pathogens requires real-time data analysis with a fast turn-around, while aiming at generating two main outcomes: 1) Species level identification; and 2) Variant mapping at different levels of genotypic resolution for population-based tracking, in addition to predicting traits such as antimicrobial resistance (AMR). With the recent advances and continual dissemination of whole-genome sequencing technologies, large-scale population-based genotyping of bacterial pathogens has become possible. Since bacterial populations often present a high degree of clonality in the genomic backbone (i.e., low genetic diversity), the choice of genotyping scheme can even facilitate the understanding of ancestral relationships and can be used for prediction of co-inherited traits such as AMR. Multi-locus sequence typing (MLST) fits that purpose and can identify sequence types (ST) based on seven ubiquitous genome-scattered loci that aid in genotyping isolates beneath the species level. ST-based mapping also standardizes genotyping across laboratories and is used by laboratories worldwide. However, algorithms for inferring ST from Illumina paired-end sequencing data typically rely on genome assembly prior to classification. Genome assembly is computationally intensive and is a bottleneck for speed and scalability, which are important aspects of genomic epidemiology. The stringMLST program uses an assembly-free, kmer-based algorithm for inferring STs, which can overcome the speed and scalability bottlenecks. Here we have systematically studied the accuracy and scalability of stringMLST relative to the standard MLST program across a wide array of phylogenetically divergent Public Health-relevant bacterial pathogens. Our data shows that optimal kmer length for stringMLST is species-specific and that genome-intrinsic and -extrinsic features can affect performance and accuracy of the program. While suitable parameters could be identified for most organisms, there were a few instances where this program may not be directly deployable in its current format. More importantly, we integrated stringMLST into our freely available and scalable hierarchical-based population genomics platform, ProkEvo, and further demonstrated how the implementation facilitates automated, reproducible bacterial population analysis. The ProkEvo implementation provides a rapidly deployable genomic epidemiology tool for ST mapping along with other pan-genomic data mining strategies, while providing specific guidance on how to optimize stringMLST performance for a wide variety of bacterial pathogens.