bluuebunny/crossref_metadata_2025 huggingface dataset:
The Long-Term Analgesic Effectiveness of Platelet-Rich Plasma Injection for Carpal Tunnel Syndrome: A Cross-Sectional Cohort Study
Authors: Lai Chia-Ying , Li Tsung-Ying , Lam King Hei Stanley , Chou Yu-Ching , Hueng Dueng-Yuan , Chen Liang-Cheng , Wu Yung-Tsan
Published: January 2022

Objective

Interest in perineural platelet-rich-plasma (PRP) injections for the treatment of carpal tunnel syndrome (CTS) has increased in recent years. However, evidence supporting the long-term effectiveness of PRP is lacking. Therefore, the aim of our cross-sectional cohort study was to investigate the long-term results of PRP injections for CTS.

Methods

Eighty-one patients diagnosed with CTS of any grade who received a single PRP injection at least 2 years prior were enrolled. Through structured telephone interviews, all patients were asked of their post-injection outcomes compared to their pre-injection condition. Symptom relief ≥50%, compared to the pre-injection condition, was considered an effective outcome. Binary logistic regression was applied to analyze each baseline variable as a regressor for determining the prognostic outcome factors.

Results

In total, 70% of patients reported positive outcomes ≥2 years post-injection. Shorter duration of symptoms before treatment (odds ratio: 0.991; 95% confidence interval [CI] 0.983–0.999; P = .023) and lower electrodiagnostic severity of CTS were the main prognostic factors for an effective outcome (mild grade vs severe grade, odds ratio: 17.652; 95% CI 1.43–221.1; P = .025). Although there was a trend toward positive outcomes at longer follow-up durations (2–3 years vs 3–4 years vs 4–5 years), the difference was not statistically significant.

Conclusions

A single perineural PRP injection has a long-term analgesic effect on CTS, especially in mild-to-moderate cases.
The stability and dynamics of computationally designed proteins
Authors: Gonzalez Natali A , Li Brigitte A , McCully Michelle E
Published: January 2022

Protein stability, dynamics and function are intricately linked. Accordingly, protein designers leverage dynamics in their designs and gain insight to their successes and failures by analyzing their proteins’ dynamics. Molecular dynamics (MD) simulations are a powerful computational tool for quantifying both local and global protein dynamics. This review highlights studies where MD simulations were applied to characterize the stability and dynamics of designed proteins and where dynamics were incorporated into computational protein design. First, we discuss the structural basis underlying the extreme stability and thermostability frequently observed in computationally designed proteins. Next, we discuss examples of designed proteins, where dynamics were not explicitly accounted for in the design process, whose coordinated motions or active site dynamics, as observed by MD simulation, enhanced or detracted from their function. Many protein functions depend on sizeable or subtle conformational changes, so we finally discuss the computational design of proteins to perform a specific function that requires consideration of motion by multi-state design.
Impact of COVID-19 pandemic outbreak on mental health of the hospital front-line healthcare workers in Chile: a difference-in-differences approach
Authors: Olivares-Tirado Pedro , Zanga-Pizarro Rosendo
Published: January 2022

Background

Most of the evidence about impact of COVID-19 pandemic on the mental health of healthcare workers (HCWs) comes from symptom questionnaires. It is important to evaluate main mental health diagnoses in hospital front-line HCW’s during the early acute phase of the COVID-19 pandemic in Chile.

Methods

An individual-level cross-sectional study using administrative data was conducted. A Difference-in-Difference (DiD) approach was used to estimate the impact of the COVID-19 pandemic on sick leave rates of depression, anxiety and acute stress reaction among hospital front-line HCW’s in comparison with other private insured workers.

Results

DiD estimates showed a significant reduction of depression (17%), anxiety (8%) and acute stress reaction (8%) sick leave rate, in the front-line HCWs during the COVID-19 pandemic. Reduction of the three mental disorders sick leave rates was higher in men than women. Except for depression, front-line HCW’s from the Santiago region’s sick leave rates of anxiety and acute stress reaction decreased more than other regions’.

Conclusion

Opposite to our hypothesis the results suggests a remarkable resilience level and compromise of front-line HCW’s. To address threats to the mental health of HCW’s is key to promotes programs for their psychological well-being and safety.
War, Socialism, and the Rise of Fascism: an Empirical Exploration
Authors: Acemoglu Daron , De Feo Giuseppe , De Luca Giacomo , Russo Gianluca
Published: January 2022

The recent ascent of right-wing populist movements in several countries has rekindled interest in understanding the causes of the rise of fascism in the interwar years. In this article, we argue that there was a strong link between the surge of support for the Socialist Party after World War I and the subsequent emergence of fascism in Italy. We first develop a source of variation in socialist support across Italian municipalities in the 1919 election based on war casualties from the area. We show that these casualties are unrelated to a battery of political, economic, and social variables before the war and had a major effect on socialist support (partly because the socialists were the main antiwar political movement). Our main result is that this boost to socialist support (that is “exogenous” to the prior political leaning of the municipality) led to greater local fascist activity as measured by local party branches and fascist political violence, and to significantly larger vote share of the Fascist Party in the 1921 and 1924 elections. We provide evidence that landowner associations and greater presence of local elites played an important role in the rise of fascism. Finally, we find greater likelihood of Jewish deportations in 1943–45 and lower vote share for Christian Democrats after World War II in areas with greater early fascist activity.
Concordance between myositis autoantibodies and anti-nuclear antibody patterns in a real-world, Australian cohort
Authors: He Jianna , Wei Xiumei , Sturgess Allan
Published: January 2022

Objectives

Myositis autoantibodies (MAs) were traditionally used as a diagnostic biomarker for idiopathic inflammatory myopathy (IIM). Its clinical utility had recently expanded to include interstitial lung disease (ILD) diagnosis. Depending on the patient cohort, MAs false positives can be common. Correlation between ANA indirect immunofluorescent (IIF) pattern and MAs may improve its positive predictive value (PPV). The aim of our study was to determine the PPV of MAs in IIM and ILD in a real-world patient cohort. We also assessed whether concordance between MAs and ANA IIF pattern can improve the PPV of positive MA results.

Methods

Patients with positive MAs and corresponding ANA IIF pattern were identified from Sutherland Centre of Immunology, New South Wales Health Pathology, Australia. The corresponding health records were reviewed to identify each patient’s primary diagnosis. χ2 test was used to compare the PPV between MA-ANA concordant and discordant groups.

Results

Between January 2016 and July 2019, 118 patients were positive for at least one MA (mean age 66.7 years, 55% female). The most frequently detected autoantibodies were Ro52, anti-synthetase antibodies and PM-Scl. The PPV of MAs for IIM or ILD was 47.4%. The overall concordance rate of MAs and ANA IIF pattern was 70.2%. Patients with concordant MA-ANA results were more likely to have true clinical disease (64.1% vs 17.8%, P <0.001).

Conclusion

Myositis autoantibodies have a low PPV for IIM and ILD in a real-world patient cohort. A positive concordance with ANA IIF pattern can improve MA test accuracy.
Stem Cell Therapy for Neuroprotection in the Growth-Restricted Newborn
Authors: Chand Kirat , Nano Rachel , Wixey Julie , Patel Jatin
Published: January 2022

Fetal growth restriction (FGR) occurs when a fetus is unable to grow normally due to inadequate nutrient and oxygen supply from the placenta. Children born with FGR are at high risk of lifelong adverse neurodevelopmental outcomes, such as cerebral palsy, behavioral issues, and learning and attention difficulties. Unfortunately, there is no treatment to protect the FGR newborn from these adverse neurological outcomes. Chronic inflammation and vascular disruption are prevalent in the brains of FGR neonates and therefore targeted treatments may be key to neuroprotection. Tissue repair and regeneration via stem cell therapies have emerged as a potential clinical intervention for FGR babies at risk for neurological impairment and long-term disability. This review discusses the advancement of research into stem cell therapy for treating neurological diseases and how this may be extended for use in the FGR newborn. Leading preclinical studies using stem cell therapies in FGR animal models will be highlighted and the near-term steps that need to be taken for the development of future clinical trials.
Using caloric efficiency to estimate the net energy value of expelled, extruded soybean meal relative to dehulled, solvent-extracted soybean meal and its effects on growth performance of nursery pigs,
Authors: Blomme Allison K , Wecker Haley K , Tokach Mike D , Woodworth Jason C , Stark Charles R , Paulk Chad B
Published: January 2022

This study aimed to estimate the net energy (NE) value of expelled, extruded soybean meal (MSBM) relative to dehulled, solvent-extracted soybean meal (SSBM) and determine its effects on growth performance of late nursery pigs. A total of 297 pigs (DNA 241 × 600) were weaned (BW 5.10 kg) and placed into 60 pens (2 rooms of 30 pens) with 5 pigs per pen balanced by gender and weaning weight. Pigs were fed a common diet for 21 d. Then, pens of pigs (BW 9.3 kg) were randomly assigned to one of five treatments to provide 12 replications per treatment. Treatments consisted of increasing amounts of MSBM replacing SSBM in the diet (0%, 25%, 50%, 75%, and 100%). All diets were fed for 28 d and were formulated to 1.30% standardized ileal digestible lysine and met or exceeded requirements for amino acids, calcium, and phosphorus. The SSBM diet was formulated to 2,421 kcal/kg and NE was not balanced between diets. Analyzed values for CP, EE, CF, and total lysine for the SSBM were 47.28%, 0.47%, 3.80%, and 3.00%, whereas the MSBM contained 47.41%, 6.88%, 5.32%, and 2.99%, respectively. The MSBM had increased values for KOH solubility and trypsin inhibitor (83.62% and 7,026 TIU/g) compared to the SSBM (73.05% and 3,011 TIU/g), whereas urease activity was similar between the two (0.03 and 0.02 Δ pH, respectively). Data were analyzed using Proc GLIMMIX (SAS 9.4; Cary, NC) with pen as the experimental unit and room as the blocking factor. There was no evidence of differences in ADG and ADFI in pigs fed diets with increasing concentrations of MSBM. Pigs fed diets with increasing concentrations of MSBM had improved (linear, P < 0.001) G:F and caloric efficiency on an NE basis. Using caloric efficiency to estimate NE of the MSBM relative to SSBM, MSBM was estimated to have a value of 2,566 kcal/kg. In conclusion, MSBM contains approximately 123% of the energy of SSBM, which improved feed efficiency when fed to nursery pigs.
Ameliorative impacts of chrysin against gibberellic acid-induced liver and kidney damage through the regulation of antioxidants, oxidative stress, inflammatory cytokines, and apoptosis biomarkers
Authors: Soliman Mohamed Mohamed , Aldhahrani Adil , Gaber Ahmed , Alsanie Walaa F , Mohamed Wafaa Abdou , Metwally Mohamed M M , Elbadawy Mohamed , Shukry Mustafa
Published: January 2022

Gibberellic acid (GA3), a widely known plant growth regulator, has been mostly used in agriculture. Little is known regarding its toxicity or the impact of its metabolic mechanism on human health. The current study examined the protective impact of chrysin against GA3-induced liver and kidney dysfunctions at biochemical, molecular, and histopathological levels. Forty male albino rats were allocated into 4 groups. The control group received saline; the chrysin group received 50 mg/kg/BW orally daily for 4 weeks; the GA3 group received 55 mg/kg/BW GA3 via daily oral gavage for 4 weeks, and the protective group (chrysin + GA3) was administered both chrysin and GA3 at the same dosage given in chrysin and GA3 groups. Chrysin was administered 1 h earlier than GA3. The GA3 induced liver and kidney injuries as proven by the elevation of hepatic and renal markers with a significant increase in malondialdehyde levels. Furthermore, a decrease of catalase and glutathione was reported in the GA3-administered rats. Pre-administration of chrysin significantly protected the hepatorenal tissue against the deleterious effects of GA3. Chrysin restored the hepatorenal functions and their antioxidant ability to normal levels. Moreover, chrysin modulated the hepatorenal toxic effects of GA3 at the molecular level via the upregulation of the antiapoptotic genes, interleukin-10 (IL-10), hemoxygenase-1, and nuclear factor erythroid 2-related factor 2 expressions; the downregulation of the kidney injury molecule-1 and caspase-3 mRNA expressions; and a decrease in IL-1β and tumor necrosis factor-α secretions. Additionally, the pre-administration of chrysin effectively attenuated the GA3-induced hepatorenal histopathological changes by regulating the immunoexpression of cytochrome P450 2E1 (CYP2E1) and pregnane X receptor, resulting in normal values at the cellular level. In conclusion, chrysin attenuated GA3-induced oxidative hepatorenal injury by inhibiting free-radical production and cytokine expression as well as by modulating the antioxidant, apoptotic, and antiapoptotic activities. Chrysin is a potent hepatorenal protective agent to antagonize oxidative stress induced by GA3.
Brain differential gene expression and blood cross-validation of a molecular signature of patients with major depressive disorder
Authors: Gomez Rueda Hugo , Bustillo Juan
Published: January 2022

Introduction

The agreement between clinicians diagnosing major depressive disorder (MDD) is poor. The objective of this study was to identify a reproducible and robust gene expression marker capable of differentiating MDD from healthy control (HC) subjects.

Materials and methods

Brain and blood gene expression datasets were searched, which included subjects with MDD and HC. The largest database including different areas of brain samples (GSE80655) was used to identify an initial gene expression marker. Tests of robustness and reproducibility were then implemented in 13 brain and 7 blood independent datasets. Correlations between expression in brain and blood samples were also examined. Finally, an enrichment analysis to explore the marker biological meaning was completed.

Results

Twenty-eight genes were differentially expressed in GSE80655, of which 23 were critical to differentiate MDD from HC. The accuracy obtained using the 23 genes was 0.77 and 0.8, before and after the forward selection model, respectively. The gene marker’s robustness and reproducibility were between the range of 0.46 and 0.63 in the other brain datasets and between 0.45 and 0.78 for the blood datasets. Brain and blood expression tended to correlate in some samples. Thirteen of the 23 genes were related to stress and immune response.

Conclusion

A 23 gene expression marker was able to distinguish subjects with MDD from HC, with adequate reproducibility and low robustness in the independent databases investigated. This gene set was similarly expressed in the brain and blood and involved genes related to stress and immune response.
Network-based integrative analysis of lithium response in bipolar disorder using transcriptomic and GWAS data
Authors: Niemsiri Vipavee , Rosenthal Sarah Brin , Nievergelt Caroline M. , Maihofer Adam X. , Marchetto Maria C. , Santos Renata , Shekhtman Tatyana , Alliey-Rodriguez Ney , Anand Amit , Balaraman Yokesh , Berrettini Wade H. , Bertram Holli , Burdick Katherine E. , Calabrese Joseph R. , Calkin Cynthia V. , Conroy Carla , Coryell William H. , DeModena Anna , Feeder Scott , Fisher Carrie , Frazier Nicole , Frye Mark A. , Gao Keming , Garnham Julie , Gershon Elliot S. , Goes Fernando , Goto Toyomi , Harrington Gloria J. , Jakobsen Petter , Kamali Masoud , Kelly Marisa , Leckband Susan G. , Lohoff Falk , McCarthy Michael J. , McInnis Melvin G. , Craig David , Millett Caitlin E. , Mondimore Francis , Morken Gunnar , Nurnberger John I. , Donovan Claire O’ , Øedegaard Ketil J. , Ryan Kelly , Schinagle Martha , Shilling Paul D. , Slaney Claire , Stapp Emma K. , Stautland Andrea , Tarwater Bruce , Zandi Peter P. , Alda Martin , Fisch Kathleen M. , Gage Fred H. , Kelsoe John R.
Published: January 2022

Lithium (Li) is one of the most effective drugs for treating bipolar disorder (BD), however, there is presently no way to predict response to guide treatment. The aim of this study is to identify functional genes and pathways that distinguish BD Li responders (LR) from BD Li non-responders (NR). An initial Pharmacogenomics of Bipolar Disorder study (PGBD) GWAS of lithium response did not provide any significant results. As a result, we then employed network-based integrative analysis of transcriptomic and genomic data. In transcriptomic study of iPSC-derived neurons, 41 significantly differentially expressed (DE) genes were identified in LR vs NR regardless of lithium exposure. In the PGBD, post-GWAS gene prioritization using the GWA- boosting (GWAB) approach identified 1119 candidate genes. Following DE-derived network propagation, there was a highly significant overlap of genes between the top 500- and top 2000-proximal gene networks and the GWAB gene list (Phypergeometric=1.28E- 09 and 4.10E-18, respectively). Functional enrichment analyses of the top 500 proximal network genes identified focal adhesion and the extracellular matrix (ECM) as the most significant functions. Our findings suggest that the difference between LR and NR was a much greater effect than that of lithium. The direct impact of dysregulation of focal adhesion on axon guidance and neuronal circuits could underpin mechanisms of response to lithium, as well as underlying BD. It also highlights the power of integrative multi-omics analysis of transcriptomic and genomic profiling to gain molecular insights into lithium response in BD.
DNA methylation meta-analysis confirms the division of the genome into two functional groups
Authors: Salnikov Lev , Goldberg Saveli , Sukumaran Parvathy , Pinsky Eugene
Published: January 2022

Based on a meta-analysis of human genome methylation data, we tested a theoretical model in which aging is explained by the redistribution of limited resources in cells between two main tasks of the organism: its self-sustenance based on the function of the housekeeping gene group (HG) and functional differentiation, provided by the (IntG) integrative gene group. A meta-analysis of methylation of 100 genes, 50 in the HG group and 50 in IntG, showed significant differences (p<0.0001) between our groups in the level of absolute methylation values of genes bodies and its promoters. We showed a reliable decrease of absolute methylation values in IntG with rising age in contrast to HG, where this level remained constant. The one-sided decrease in methylation in the IntG group is indirectly confirmed by the dispersion data analysis, which also decreased in the genes of this group. The imbalance between HG and IntG in methylation levels suggests that this IntG-shift is a side effect of the ontogenesis grownup program and the main cause of aging. The theoretical model of functional genome division also suggests the leading role of slow dividing and post mitotic cells in triggering and implementing the aging process.
Price elasticity of demand for new and recurring opioid prescriptions
Authors: Harris Rebecca Arden
Published: January 2022

Objective

Several U.S. states have recently enacted excise taxes to curb prescription opioid use and other states are considering similar measures. We assessed the effects of increasing out-of-pocket costs (OPC) on new and recurring opioid fills.

Methods

We conducted a retrospective cohort study of opioid-naive individuals presenting with acute back pain using data from a nationwide claims repository. We estimated the effect of OPC on the initiation of opioid treatment in logistic regressions, controlling for socio-demographics, medical history, healthcare utilization, insurance type, and region. With the same covariates plus morphine milligram equivalents and days supplied, we estimated the effect of OPC on the number of opioid fills in negative binomial regressions. We report the price elasticity of demand (PED) for prescription opioids, defined as the percentage change in outcome resulting from a two-fold increase in OPC.

Results

Of 25,531 adults diagnosed with acute back pain in Q1 of 2018, 2,451 (9.6%) filled at least one opioid prescription. In multivariable regression, the association between OPC and initiating opioid treatment was not significant (PED= -1.9%; 95% CI: -5.5%, 1.7%). However, by region, the PED was -10.3% (95% CI: -18.1%, -2.4%) in the coastal states and 1.6% (95% CI: -2.5%, 5.7%) in the central-southern states. The PED for the number of prescription fills was -3.7% (95% CI: -7.3%, -0.1%), which also differed by region. In the coastal states, the PED was -15.2% (95% CI: -24.7%, -5.7%) and in the central-southern states -1.5% (95% CI: -5.4%, 2.4%).

Conclusions

Opioid fills were price sensitive in the coastal states but not in the central-southern states. Policies that would increase OPC might have a restraining effect on opioid consumption in parts, but not all of the U.S.
Hydroxychloroquine/Chloroquine in COVID-19 With Focus on Hospitalized Patients – A Systematic Review
Authors: Freilich Daniel , Victory Jennifer , Gadomski Anne
Published: January 2022

Background

In the beginning of the COVID-19 pandemic, many hospitalized patients received empiric hydroxychloroquine/chloroquine (HC/CQ). Although some retrospective-observational trials suggested potential benefit, all subsequent randomized clinical trials (RCTs) failed to show benefit and use generally ceased. Herein, we summarize key studies that clinicians advising patients on HC/CQ’s efficacy:safety calculus in hospitalized COVID-19 patients would want to know about in a practical one-stop-shopping source.

Methods

Pubmed and Google were searched on November 4, 2021. Search words included: COVID-19, hydroxychloroquine, chloroquine, in vitro, animal studies, clinical trials, and meta-analyses. Studies were assessed for import and included if considered impactful for benefit:risk assessment.

Results

These searches led to inclusion of 12 in vitro and animal reports; 12 retrospective-observational trials, 19 interventional clinical trials (17 RCTs, 1 single-arm, 1 controlled but unblinded), and 51 meta-analyses in hospitalized patients.

Inconsistent efficacy was seen in vitro and in animal studies for coronaviruses and nil in SARS-CoV-2 animal models specifically. Most retrospective-observational studies in hospitalized COVID-19 patients found no efficacy; QT prolongation and increased adverse events and mortality were reported in some. All RCTs and almost all meta-analyses provided robust data showing no benefit in overall populations and subgroups, yet concerning safety issues in many.

Conclusions

HC/CQ have inconsistent anti-coronavirus efficacy in vitro and in animal models, and no convincing efficacy yet substantial safety issues in the overwhelming majority of retrospective-observational trials, RCTs, and meta-analyses in hospitalized COVID-19 patients. HC/CQ should not be prescribed for hospitalized COVID-19 patients outside of clinical trials.

Key Summary Points

Preclinical hydroxychloroquine/chloroquine in vitro studies found inconsistent activity against coronaviruses including SARS-CoV-2.

Preclinical hydroxychloroquine/chloroquine animals studies found inconsistent efficacy for coronaviruses in general and none for SARS-CoV-2.

The overhwelming majority of RCTs and retrospective-observational trials found no benefit for hydroxychloroquine/chloroquine in hospitalized COVID-19 patients, and many found concerning safety signals.

The majority of RCTs and retrospective-observational trials found no benefit for hydroxychloroquine/chloroquine in COVID-19 outpatients or for pre- or post-exposure prophylaxis, and some found concerning safety signals.

The overwhelming majority of meta-analyses found no benefit for hydroxychloroquine/chloroquine in COVID-19 inpatients, outpatients, or for prophylaxis, and many found concerning safety signals.
Impaired functional connectivity of the hippocampus in murine models of NMDA-receptor antibody associated pathology
Authors: Kuchling Joseph , Jurek Betty , Kents Mariya , Kreye Jakob , Geis Christian , Wickel Jonathan , Mueller Susanne , Koch Stefan Paul , Boehm-Sturm Philipp , Prüss Harald , Finke Carsten
Published: January 2022

Introduction

While decreased hippocampal connectivity and disruption of functional networks are established MRI features in human anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis, the underlying pathophysiology for brain network alterations remains poorly understood. Application of patient-derived monoclonal antibodies against the NR1 subunit of the NMDAR allows for the investigation of potential functional connectivity alterations in experimental murine NMDAR antibody disease models.

Objective

To explore functional connectivity changes in NR1 antibody mouse models using resting-state functional MRI (rs-fMRI).

Methods

Adult C57BL/6J mice (n=10) were intrathecally injected with a recombinant human NR1 antibody over 14 days and then studied using rs-fMRI at 7 Tesla. In addition, a newly established mouse model with in utero exposure to a human recombinant NR1 antibody characterized by a neurodevelopmental disorder (NR1-offspring) was investigated with rs-fMRI at the age of 8 weeks (n=15) and 10 months (n=14). Mice exposed to isotype-matched control antibodies served as controls. Independent component analysis (ICA) and dual regression analysis were performed to compare functional connectivity between NMDAR antibody mouse models and control mice.

Results

Adult NR1-antibody injected mice showed significantly impaired functional connectivity within the dentate gyrus of the left hippocampus in comparison to controls, resembling impaired hippocampal functional connectivity patterns observed in human patients with NMDAR encephalitis. Similarly, analyses showed significantly reduced functional connectivity in the dentate gyrus in NR1-offspring compared after 8 weeks, and impaired connectivity in the dentate gyrus and CA3 hippocampal subregion in NR1-offspring at the age of 10 months.

Conclusion

Functional connectivity changes within the hippocampus resulting from both direct application and in utero exposure to NMDAR antibodies can be modeled in experimental murine systems. With this translational approach, we successfully reproduced functional MRI alterations previously observed in human NMDAR encephalitis patients. Future experimental studies will identify the detailed mechanisms that cause functional network alterations and may eventually allow for non-invasive monitoring of disease activity and therapeutic effects in autoimmune encephalitis.
Improving the time and space complexity of the WFA algorithm and generalizing its scoring
Authors: Eizenga Jordan M. , Paten Benedict
Published: January 2022

Motivation

Modern genomic sequencing data is trending toward longer sequences with higher accuracy. Many analyses using these data will center on alignments, but classical exact alignment algorithms are infeasible for long sequences. The recently proposed WFA algorithm demonstrated how to perform exact alignment for long, similar sequences in O(sN) time and O(s2) memory, where s is a score that is low for similar sequences (Marco-Sola et al., 2021). However, this algorithm still has infeasible memory requirements for longer sequences. Also, it uses an alternate scoring system that is unfamiliar to many bioinformaticians.

Results

We describe variants of WFA that improve its asymptotic memory use from O(s2) to O(s3/2) and its asymptotic run time from O(sN) to O(s2 + N). We expect the reduction in memory use to be particularly impactful, as it makes it practical to perform highly multithreaded megabase-scale exact alignments in common compute environments. In addition, we show how to fold WFA’s alternate scoring into the broader literature on alignment scores.

Availability

All code is publicly available for use and modification at https://github.com/jeizenga/wfalm.

Contact

jeizenga@ucsc.edu

Supplementary information

Supplementary data are available online.
BlenderPhotonics – an integrated open-source software environment for 3-D meshing and photon simulations in complex tissues
Authors: Zhang Yuxuang , Fang Qianqian
Published: January 2022

Significance

Rapid advances in biophotonics techniques require quantitative, model-based computational approaches to obtain functional and structural information from increasingly complex and multi-scaled anatomies. The lack of efficient tools to accurately model tissue structures and subsequently perform quantitative multi-physics modeling greatly impedes the clinical translation of these modalities.

Aim

While the mesh-based Monte Carlo (MMC) method expands our capabilities in simulating complex tissues by using tetrahedral meshes, the generation of such domains often requires specialized meshing tools such as Iso2Mesh. Creating a simplified and intuitive interface for tissue anatomical modeling and optical simulations is essential towards making these advanced modeling techniques broadly accessible to the user community.

Approach

We responded to the above challenge by combining the powerful, open-source 3-D modeling software, Blender, with state-of-the-art 3-D mesh generation and MC simulation tools, utilizing the interactive graphical user interface (GUI) in Blender as the front-end to allow users to create complex tissue mesh models, and subsequently launch MMC light simulations.

Results

Here we present a tutorial to our newly developed Python-based Blender add-on – BlenderPhotonics – to interface with Iso2Mesh and MMC, allowing users to create, configure and refine complex simulation domains and run hardware-accelerated 3-D light simulations with only a few clicks. We provide a comprehensive introduction to this new tool and walk readers through 5 examples, ranging from simple shapes to sophisticated realistic tissue models.

Conclusion

BlenderPhotonics is user-friendly and open-source, leveraging the vastly rich ecosystem of Blender. It wraps advanced modeling capabilities within an easy-to-use and interactive interface. The latest software can be downloaded at http://mcx.space/bp.
Emergence of two distinct SARS-CoV-2 Gamma variants and the rapid spread of P.1-like-II SARS-CoV-2 during the second wave of COVID-19 in Santa Catarina, Southern Brazil
Authors: Padilha Dayane A. , Benetti-Filho Vilmar , Moreira Renato S. , Soratto Tatiany A. T. , Maia Guilherme A. , Christoff Ana P. , Barazzetti Fernando H. , Schörner Marcos A. , Ferrari Fernanda L. , Martins Carolina L. , Kawagoe Eric K. , Wachter Julia K. , Sacchet Paula , Baptistella Antuani R. , Schlindwein Aline D. , Coelho Bruna K. , Fernandes Sandra B. , Rovaris Darcita B. , Anjos Marlei P. D. , Melo Fernanda R. , Bittencourt Bianca , Cunha Sthefani , Meneghetti Karine L. , Wendt Nestor , Madaloz Tamela Z. , Rodrigues Marcus V. D. , Souza Doris S. M. , Moraes Milene H. , Baptista Rodrigo P. , Toledo-Silva Guilherme , Maciel Guilherme R. , Grisard Edmundo C. , Stoco Patrícia H. , Oliveira Luiz F. V. , Bazzo Maria L. , Fongaro Gislaine , Wagner Glauber
Published: January 2022

The Western mesoregion, the State of Santa Catarina (SC), Southern Brazil, was heavily affected as a whole by the COVID-19 pandemic in early 2021. This study aimed to evaluate the dynamics of the SARS-CoV-2 virus spreading patterns in the SC state through March 2020 to April 2021 using genomic surveillance. During this period, 23 distinct variants, including Beta and Gamma, among which, the Gamma and related lineages were predominant in the second pandemic wave within SC. A regionalization of P.1-like-II in the Western-SC region was observed, concomitant to the increase in cases, mortality, and case fatality rate (CFR) index. This is the first evidence of the regionalization of the SARS-CoV-2 in SC transmission and highlights the importance of tracking variants, dispersion, and impact of SARS-CoV-2 on the public health systems.
Algorithmic Fairness and Bias Mitigation for Clinical Machine Learning: Insights from Rapid COVID-19 Diagnosis by Adversarial Learning
Authors: Yang Jenny , Soltan Andrew A. S. , Yang Yang , Clifton David A.
Published: January 2022

Machine learning is becoming increasingly prominent in healthcare. Although its benefits are clear, growing attention is being given to how machine learning may exacerbate existing biases and disparities. In this study, we introduce an adversarial training framework that is capable of mitigating biases that may have been acquired through data collection or magnified during model development. For example, if one class is over-presented or errors/inconsistencies in practice are reflected in the training data, then a model can be biased by these. To evaluate our adversarial training framework, we used the statistical definition of equalized odds. We evaluated our model for the task of rapidly predicting COVID-19 for patients presenting to hospital emergency departments, and aimed to mitigate regional (hospital) and ethnic biases present. We trained our framework on a large, real-world COVID-19 dataset and demonstrated that adversarial training demonstrably improves outcome fairness (with respect to equalized odds), while still achieving clinically-effective screening performances (NPV>0.98). We compared our method to the benchmark set by related previous work, and performed prospective and external validation on four independent hospital cohorts. Our method can be generalized to any outcomes, models, and definitions of fairness.
Effects of medical school on mental health and sleep habits
Authors: McKinley Blake , Daines Bryan , Allen Mitchell , Pulsipher Kayd , Zapata Isain , Wilde Benjamin
Published: January 2022

BACKGROUND and OBJECTIVES

This study aims to define changes in anxiety and depression among medical students while evaluating the association of sleep habits and other risk factors, including exercise habits and a diagnosis of chronic disease. The effect of the COVID-19 pandemic was also evaluated.

DESIGN

A cohort of first- and second-year medical students was evaluated longitudinally using survey methods to quantify changes from pre-medical school and summer break to each semester in medical school throughout years one and two.

METHODS

Data was analyzed using Generalized Linear Mixed Models (GLMMs) on the numeric responses of General Anxiety Disorder-7 (GAD-7), Patient Health Questionnaire-9 (PHQ-9), and Pittsburg Sleep Quality Index. Additional assessments evaluated exercise habits, chronic disease, and impact of COVID-19 Pandemic.

RESULTS

Depression, anxiety, and sleep habits displayed a cyclical change that was associated with the academic cycle. The COVID-19 pandemic was never significant. Medical students who had a chronic disease diagnosis had increased severity. Exercise did not play a role.

CONCLUSION

The main driver for depression, anxiety, and poor sleep quality was the academic cycle, while the COVID-19 pandemic did not have an impact on mental health.
ExPRSweb - An Online Repository with Polygenic Risk Scores for Common Health-related Exposures
Authors: Ma Ying , Patil Snehal , Zhou Xiang , Mukherjee Bhramar , Fritsche Lars G.
Published: January 2022

Complex traits are influenced by genetic risk factors, lifestyle, and environmental variables, so called exposures. Some exposures, e.g., smoking or lipid levels, have common genetic modifiers identified in genome-wide association studies. Since measurements are often unfeasible, Exposure Polygenic Risk Scores (ExPRSs) offer an alternative to study the influence of exposures on various phenotypes. Here, we collected publicly available summary statistics for 28 exposures and applied four common PRS methods to generate ExPRSs in two large biobanks, the Michigan Genomics Initiative and the UK Biobank. We established ExPRS for 27 exposures and demonstrated their applicability in phenome-wide association studies and as predictors for common chronic conditions. Especially, the addition of multiple ExPRSs showed, for several chronic conditions, an improvement compared prediction models that only included traditional, disease-focused PRSs. To facilitate follow-up studies, we share all ExPRS constructs and generated results via an online repository called ExPRSweb.
Two Pools of ATP Detected in the Brains of Pediatric Patients with Myelin Oligodendrocyte Glycoprotein Antibody Disorders (MOGAD) by 3D31P MR Spectroscopic Imaging (MRSI) at 7T
Authors: Ren Jimin , Yu Fang , Greenberg Benjamin M.
Published: January 2022

Over the past four decades, ATP, the obligatory energy molecule for keeping all cells alive and functioning, was thought to contribute only one set of31P MR signals in the human brain. Here we report for the first time the simultaneous detection of two pools of ATP in the human brain by high-resolution 3D31P MRSI at ultrahigh field 7T. These two ATP pools differ in cytosolic Mg2+concentration (1:0.5 ratio), with a resonance separation of 0.5 ppm at β-ATP, a well-established imaging marker of intracellular Mg2+concentration. Mg2+is a cofactor of ATPase and its deficiency is associated with immune dysfunction, free radical damage, perturbations in Ca2+homeostasis, and development of atherosclerosis, dyslipidemia and a number of neurological disorders, such as cerebral vasospasm, stroke, migraine, Alzheimer’s disease, and Parkinson’s disease. Our study documents reduced Mg levels in the brain of patients with myelin oligodendrocyte glycoprotein antibody disorders (MOGAD), which is an idiopathic, inflammatory, demyelinating condition of the central nervous system (CNS) more common in pediatric patients. Low-Mg2+ATP signals were detected mostly in the white matter regions in MOGAD, suggesting an association between Mg2+deficiency and compromised functions of oligodendrocytes in maintenance and generation of the axonal myelin sheath. This preliminary study demonstrates the utility of the 7T 3D31P MSRI for probing altered energy metabolism at reduced availability of Mg2+rather than ATP itself. The potential correlation between [Mg2+] and disease progression over time should be assessed in larger cohorts.

Author Approval

Yes
Prognostic Value of Serum/Plasma Neurofilament Light Chain for COVID-19 Associated Mortality
Authors: Masvekar Ruturaj R. , Kosa Peter , Jin Kimberly , Dobbs Kerry , Stack Michael A. , Castagnoli Riccardo , Quaresima Virginia , Su Helen C. , Imberti Luisa , Notarangelo Luigi D. , Bielekova Bibiana
Published: January 2022

Given the continued spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), early predictors of coronavirus disease 19 (COVID-19) mortality might improve patients’ outcomes. Increased levels of circulating neurofilament light chain (NfL), a biomarker of neuro-axonal injury, have been observed in patients with severe COVID-19. We investigated whether NfL provides non-redundant clinical value to previously identified predictors of COVID-19 mortality.

We measured serum or plasma NfL concentrations in a blinded fashion in 3 cohorts totaling 338 COVID-19 patients. In cohort 1, we found significantly elevated NfL levels only in critically ill COVID-19 patients compared to healthy controls. Longitudinal cohort 2 data showed that NfL is elevated late in the course of the disease, following two other prognostic markers of COVID-19: decrease in absolute lymphocyte count (ALC) and increase in lactate dehydrogenase (LDH). Significant correlations between LDH and ALC abnormalities and subsequent rise of NfL implicate multi-organ failure as a likely cause of neuronal injury at the later stages of COVID-19. Addition of NfL to age and gender in cohort 1 significantly improved the accuracy of mortality prediction and these improvements were validated in cohorts 2 and 3.

In conclusion, although substantial increase in serum/plasma NfL reproducibly enhances COVID-19 mortality prediction, NfL has clinically meaningful prognostic value only close to death, which may be too late to alter medical management. When combined with other prognostic biomarkers, rising longitudinal NfL measurements triggered by LDH and ALC abnormalities would identify patients at risk of COVID-19 associated mortality who might still benefit from escalated care.
Association of Retinal Age Gap with Arterial Stiffness and Incident Cardiovascular Disease
Authors: Zhu Zhuoting , Chen Yifan , Wang Wei , Wang Yueye , Hu Wenyi , Shang Xianwen , Liao Huan , Shi Danli , Huang Yu , Ha Jason , Tan Zachary , Kiburg Katerina , Zhang Xueli , Tang Shulin , Yu Honghua , Yang Xiaohong , He Mingguang
Published: January 2022

Background

Retinal parameters could reflect systemic vascular changes. With the advances of deep learning technology, we have recently developed an algorithm to predict retinal age based on fundus images, which could be a novel biomarker for ageing and mortality.

Objective

To investigate associations of retinal age gap with arterial stiffness index (ASI) and incident cardiovascular disease (CVD).

Methods

A deep learning (DL) model was trained based on 19,200 fundus images of 11,052 participants without any past medical history at baseline to predict the retinal age. Retinal age gap (retinal age predicted minus chronological age) was generated for the remaining 35,917 participants. Regression models were used to assess the association between retinal age gap and ASI. Cox proportional hazards regression models and restricted cubic splines were used to explore the association between retinal age gap and incident CVD.

Results

We found each one-year increase in retinal age gap was associated with increased ASI (β=0.002, 95% confidence interval [CI]: 0.001-0.003, P<0.001). After a median follow-up of 5.83 years (interquartile range [IQR]: 5.73-5.97), 675 (2.00%) developed CVD. In the fully adjusted model, each one-year increase in retinal age gap was associated with a 3% increase in the risk of incident CVD (hazard ratio [HR]=1.03, 95% CI: 1.01-1.06, P=0.012). In the restricted cubic splines analysis, the risk of incident CVD increased significantly when retinal age gap reached 1.21 (HR=1.05; 95% CI, 1.00-1.10; P-overall <0.0001; P-nonlinear=0.0681).

Conclusion

We found that retinal age gap was significantly associated with ASI and incident CVD events, supporting the potential of this novel biomarker in identifying individuals at high risk of future CVD events.
Characterizing the conformational free-energy landscape of RNA stem-loops using single-molecule field-effect transistors
Authors: Jang Sukjin S. , Dubnik Sarah , Hon Jason , Hellenkamp Björn , Lynall David G. , Shepard Kenneth L. , Nuckolls Colin , Gonzalez Ruben L.
Published: January 2022

We have developed and used high-time-resolution, single-molecule field-effect transistors (smFETs) to characterize the conformational free-energy landscape of RNA stem-loops. Stem-loops are some of the most common RNA structural motifs and serve as building blocks for the formation of more complex RNA structures. Given their prevalence and integral role in RNA folding, the kinetics of stem-loop (un)folding has been extensively characterized using both experimental and computational approaches. Interestingly, these studies have reported vastly disparate timescales of (un)folding, which has been recently interpreted as evidence that (un)folding of even simple stem-loops occurs on a highly rugged conformational energy landscape. Because smFETs do not rely on fluorophore reporters of conformation or on the application of mechanical (un)folding forces, they provide a unique and complementary approach that has allowed us to directly monitor tens of thousands of (un)folding events of individual stem-loops at a 200 μs time resolution. Our results show that under our experimental conditions, stem-loops fold and unfold over a 1-200 ms timescale during which they transition between ensembles of unfolded and folded conformations, the latter of which is composed of at least two sub-populations. The 1-200 ms timescale of (un)folding we observe here indicates that smFETs report on complete (un)folding trajectories in which unfolded conformations of the RNA spend long periods of time wandering the free-energy landscape before sampling one of several misfolded conformations or, alternatively, the natively folded conformation. Our findings demonstrate how the combination of single-molecule sensitivity and high time resolution makes smFETs unique and powerful tools for characterizing the conformational free-energy landscape of RNA and highlight the extremely rugged landscape on which even the simplest RNA structural elements fold.
SH3-domain mutations selectively disrupt Csk homodimerization or PTPN22 binding
Authors: Brian Ben F. , Sjaastad Frances V. , Freedman Tanya S.
Published: January 2022

The kinase Csk is the primary negative regulator of the Src-family kinases (SFKs, e.g., Lck, Fyn, Lyn, Hck, Fgr, Blk, Yes), phosphorylating a tyrosine on the SFK C-terminal tail that mediates autoinhibition. Csk also binds phosphatases, including PTPN12 (PTP-PEST) and immune-cell PTPN22 (LYP/Pep), which dephosphorylate the SFK activation loop to promote autoinhibition. Csk-binding proteins (e.g., CBP/PAG1) oligomerize within membrane microdomains, and high local concentration promotes Csk function. Purified Csk homodimerizes in solution through an interface that overlaps the phosphatase binding footprint. Here we demonstrate that Csk can homodimerize in Jurkat T cells, in competition with PTPN22 binding. We designed SH3-domain mutations in Csk that selectively impair homodimerization (H21I) or PTPN22 binding (K43D) and verified their kinase activity in solution. Disruption of either interaction, however, decreased the negative-regulatory function of Csk in cells. Csk W47A, a substitution previously reported to block PTPN22 binding, also impairs homodimerization. Csk H21I and K43D will be useful tools for dissecting the protein-specific drivers of autoimmunity mediated by the human polymorphism PTPN22 R620W, which impairs interaction with Csk and with the E3 ubiquitin ligase TRAF3. Future investigations of Csk homodimer activity and phosphatase interactions may reveal new facets of SFK regulation in hematopoietic and non-hematopoietic cells.