bluuebunny/crossref_metadata_2025 huggingface dataset:
PET/CT for Brain Amyloid
Authors: Lee Sangwon , Jung Jin Ho , Kim Dongwoo , Lim Hyun Keong , Park Mi-Ae , Kim Garam , So Minjae , Yoo Sun Kook , Ye Byoung Seok , Choi Yong , Yun Mijin
Published: January 2021

Purpose

This study was to develop a convolutional neural network (CNN) model with a residual learning framework to predict the full-time 18F-florbetaben (18F-FBB) PET/CT images from corresponding short-time scans.

Methods

In this retrospective study, we enrolled 22 cognitively normal subjects, 20 patients with mild cognitive impairment, and 42 patients with Alzheimer disease. Twenty minutes of list-mode PET/CT data were acquired and reconstructed as the ground-truth images. The short-time scans were made in either 1, 2, 3, 4, or 5 minutes. The CNN with a residual learning framework was implemented to predict the ground-truth images of 18F-FBB PET/CT using short-time scans with either a single-slice or a 3-slice input layer. Model performance was evaluated by quantitative and qualitative analyses. Additionally, we quantified the amyloid load in the ground-truth and predicted images using the SUV ratio.

Results

On quantitative analyses, with increasing scan time, the normalized root-mean-squared error and the SUV ratio differences between predicted and ground-truth images gradually decreased, and the peak signal-to-noise ratio increased. On qualitative analysis, the predicted images from the 3-slice CNN model showed better image quality than those from the single-slice model. The 3-slice CNN model with a short-time scan of at least 2 minutes achieved comparable, quantitative prediction of full-time 18F-FBB PET/CT images, with adequate to excellent image quality.

Conclusions

The 3-slice CNN model with a residual learning framework is promising for the prediction of full-time 18F-FBB PET/CT images from short-time scans.
Prognostic Significance of Pretreatment 18F-FDG PET/CT Volumetric Parameters in Patients With Colorectal Liver Metastasis
Authors: Kim Yong-il , Lee Hyo Sang , Choi Joon Young
Published: January 2021

Purpose

Colorectal liver metastasis (CRLM) remains a clinical challenge due to the lack of reliable prognostic parameters. We performed a systematic review and meta-analysis of the prognostic value of pretreatment 18F-FDG PET/CT volumetric parameters for hepatic metastatic lesions (HMLs) in patients with CRLM.

Methods

A systematic search was performed using the following combination of keywords: CRLM, FDG, PET, and prognosis. The inclusion criteria were studies using 18F-FDG PET/CT as an imaging tool before treatment, including volumetric parameters (metabolic tumor volume [MTV] and total lesion glycolysis [TLG]) for HMLs, and reported survival data. Event-free survival and overall survival were considered as survival markers. The effect on survival was determined by the effect size of the hazard ratio (HR) with 95% confidence interval (CI).

Results

Our systematic search identified 668 records, and a total of 10 studies comprising 494 patients were included. The pooled HRs of the prognostic value of the MTV and TLG for event-free survival were 1.55 (95% CI, 1.21–1.99; P = 0.0006) and 1.64 (95% CI, 1.23–2.19; P = 0.0009) with significance, respectively. The pooled HRs of the prognostic value of the MTV and TLG for overall survival were 1.72 (95% CI, 1.32–2.23; P < 0.0001) and 2.09 (95% CI, 1.48–2.96; P < 0.0001) with significance, respectively.

Conclusions

Higher MTV and TLG for HMLs before treatment were identified as worse prognostic parameters in patients with CRLM. The MTV and TLG of 18F-FDG PET/CT could be used as predictors of prognosis.
Endotracheal, Endobronchial, and Vocal Cords Metastases From Lung Cancer Detected by 18F-FDG PET/CT
Authors: Xiao JingXing , Su Min , Wang Dong
Published: January 2021

A 61-year-old man with a history of lung cancer initially treated 3 years prior presented with a new onset of cough for 1-month and 2-week hoarseness. FDG PET/CT revealed multiple hypermetabolic lesions in the endotracheal, endobronchial, and vocal cords. Subsequently, immunostaining confirmed that all lesions were metastatic squamous cell carcinomas originating from the patient’s primary lung squamous cell carcinoma.
Acute Brain Stroke Evolution Detected by 18F-FDG PET/CT and MRI Justifies the Discordance of Lesions in a Patient With Lymphoproliferative Syndrome
Authors: Fernández-Rodríguez Paula , Tamayo Carabaño Daniella , Fernández López Rosa , Piñero González de la Peña Pilar , Borrego Dorado Isabel
Published: January 2021

A 50-year-old man with angioimmunoblastic T-cell lymphoma in complete response to treatment presented new hypermetabolic brain lesions on 18F-FDG PET/CT suggestive of malignancy. These findings were correlated by MRI that showed cortical-subcortical peripheral lesions typical of acute ischemic infarction. A restaging 18F-FDG PET/CT showed that hypermetabolic lesions were replaced by ametabolic areas, supporting chronic infarction. Early ischemia presents transitory FDG increase. Brain lymphomas are highly FDG avid and difficult to differentiate from acute cerebral infarction. In view of the discordance of abnormal areas of intracranial uptake on PET FDG, MRI confirmation is required to avoid misinterpretation.
The “Safe Index” Considering Body Surface Area for Prolonged Dexamethasone Regimen in Airway Control After Head and Neck Microsurgical Reconstruction
Authors: Chen Yu-Ting , Cheong David Chon-Fok , Hung Shao-Yu , Kao Huang-Kai , Tsao Chung-Kan
Published: January 2021

Background

Dexamethasone (Dexa) is frequently administrated to patients receiving head and neck microsurgical reconstruction with nasotracheal intubation postoperatively for airway control. Infection is the greatest concern when prolonging the treatment course. We aimed to find out the relationship between flap infection and the safe dose of Dexa.

Materials and Methods

A retrospective review of enrolling total 156 patients underwent microsurgical free flap reconstruction for head and neck cancers with nasotracheal intubation from December 2015 to December 2016 was conducted. Among them, 139 patients had received prolonged Dexa treatment course (>2 days). Safe index was then defined as the total amount of used Dexa (in milligrams) over body weight (in kilograms), body mass index (in kilograms per square meter) and body surface area (BSA, in square meter). Statistics were performed for the cutoff level of the safe index and to find out the independent risk factors.

Results

The cutoff level of the safe index was 0.76 for body weight group, 2.28 (10−3 m2) for body mass index group, and 33.84 mg/m2 for BSA group. Safe index for BSA group also outweighed other risk factors in multivariant analysis (odds ratio = 6.242, 95% confidence interval = 2.292–17.002, P = 0.000), which is the only independent risk factors for flap infection in our cohort.

Conclusions

Throughout our study, the “safe index” helps clinician easily predict flap infection risk when using Dexa as the medication for airway control after head and neck microsurgical reconstruction.
Percutaneous Debridement of and Fibrin Glue Injection Into a Pretibial Morel-Lavallée Lesion
Authors: Pan Chih-Hao , Tu Chih-Peng , Ou Shuan-Yuan , Tung Kwang-Yi , Huang Wen-Chen , Yu Chia-Meng , Tsai Ming-Feng , Yao Wen-Teng , Chen Yu-Fan
Published: January 2021

The Morel-Lavallée lesion (MLL) is a posttraumatic close degloving injury, which is often underdiagnosed at first. Patients with MLLs usually present with tender and enlarging soft tissue swelling with fluctuation, decreased skin sensation, ecchymosis, or even skin necrosis hours to days after the inciting injury. The lesion can lead to intractable morbidity if it remains untreated. There is no consensus regarding the treatment for MLL at present. Here, we report an MLL in the pretibial region of a 43-year-old woman who experienced a low-energy contusion in a motorbike accident. The pretibial lesion was diagnosed using sonography and fine-needle aspiration. We successfully treated the patient by performing percutaneous debridement via a small incision and injections of fibrin after conservative treatment failed. The method we herein propose achieved the goal of open surgical debridement, providing faster recovery and a high degree of patient comfort. We reviewed the available pertinent literature and propose our own treatment protocol with the aim to establish common therapies ofMLL.
Gender Affirming Surgery: A Comprehensive, Systematic Review of All Peer-reviewed Literature and Methods of Assessing Patient-centered Outcomes (Part 1: Breast/Chest, Face, and Voice)
Authors: Oles Norah , Darrach Halley , Landford Wilmina , Garza Matthew , Twose Claire , Park Chanjun S. , Tran Phuong , Schechter Loren S. , Lau Brandyn , Coon Devin
Published: January 2021

Objective:

To perform the first systematic review of all available gender-affirming surgery (GAS) publications across all procedures to assess both outcomes reported in the literature and the methods used for outcome assessment.

Summary of Background Data:

Rapidly increasing clinical volumes of gender-affirming surgeries have stimulated a growing need for high-quality clinical research. Although some procedures have been performed for decades, each individual procedure has limited data, necessitating synthesis of the entire literature to understand current knowledge and guide future research.

Methods:

A systematic review was performed following Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines to identify all outcomes measures in GAS cohorts, including PCOs, complications, and functional outcomes. Outcome data were pooled to assess currently reported complication, satisfaction, and other outcome rates.

Results:

Overall, 15,186 references were identified, 4162 papers advanced to abstract review, and 1826 underwent full-text review. After review, there were 406 GAS cohort publications. Of non-genitoplasty titles, 35 were mastectomy, 6 mammoplasty, 21 facial feminization, and 31 voice/cartilage. Although 59.1% of non-genitoplasty papers addressed PCOs in some form, only 4.3% used instruments partially-validated in transgender patients. Overall, data were reported heterogeneously and were biased towards high-volume centers.

Conclusions:

This study represents the most comprehensive review of GAS literature. By aggregating all previously utilized measurement instruments, this study offers a foundation for discussions about current methodologic limitations and what dimensions must be included in assessing surgical success. We have assembled a comprehensive list of outcome instruments; this offers an ideal starting basis for emerging discussions between patients and providers about deficiencies which new, better instruments and metrics must address. The lack of consistent use of the same outcome measures and validated GAS-specific instruments represent the 2 primary barriers to high-quality research where improvement efforts should be focused.
Intraoperative Colonoscopy During Colorectal Surgery Does Not Increase Postoperative Complications: An Assessment From the ACS-NSQIP Procedure-targeted Cohort
Authors: Tatar Cihad , Benlice Cigdem , Rencuzogullari Ahmet , Church James , Ozuner Gokhan , Liska David , Steele Scott R. , Gorgun Emre
Published: January 2021

Intraoperative colonoscopy (IOC) is an adjunct in colorectal surgery to detect the location of the lesions and assessing anastomotic integrity. The authors aimed to evaluate the safety and feasibility and postoperative morbidity of IOC in left-sided colectomy patients for colorectal cancer. Patients undergoing elective left-sided colectomy without any proximal diversion for colorectal cancer between 2013 and 2016 were reviewed from the American College of Surgeons National Surgical Quality Improvement Program procedure-targeted database. Demographics, comorbidities, short-term outcomes, and postoperative morbidity of patients were evaluated. A total of 8811 patients were identified and IOC was performed for 1143 (12.97%) patients. There was no significant difference in postoperative complications between the IOC and non-IOC groups. Patients with IOC had shorter total hospital length of stay. The use of IOC does not adversely affect short-term outcomes after colorectal resections. Surgeons may utilize IOC liberally for left-sided colorectal resections.
Enhanced Recovery Program for Outpatient Female Pelvic Reconstructive Surgery
Authors: Trowbridge Elisa R. , Vollum Kathryn G. , Sarosiek Bethany M. , Chang Eric S. , Hullfish Kathie L.
Published: January 2021

Objectives

Enhanced recovery programs (ERPs) are evidence-based perioperative interventions designed to reduce narcotic use, decrease hospital length of stay, decrease medical costs, and improve patient satisfaction. Given the increase in outpatient procedures in female pelvic medicine and reconstructive surgery, we sought to compare patient outcomes before and after implementation of an ERP for women undergoing outpatient pelvic reconstructive surgery.

Methods

This was a prospective nonrandomized cohort quality improvement practice initiative. The ERP intervention group included consecutive patients (n = 66) undergoing elective outpatient pelvic reconstructive surgery from March 2016 to October 2016. Historical controls were consecutive patients (n = 124) who had undergone outpatient pelvic reconstructive surgery in the same period a year before ERP implementation. Our primary outcome was opioid use and postoperative pain scores. Secondary outcomes included procedure time, use of intravenous fluids, time to discharge, and total hospital cost.

Results

There was an observed reduction in opioid use between the ERP patients and historic controls as measured by intraoperative morphine milligram equivalents (MMEs) and total MMEs, with no difference in postoperative pain scores or postoperative MME. In addition, reduction in length of procedure (P = 0.03), intraoperative intravenous fluids (P < 0.0001), and total hospital cost (P ≤ 0.01) was noted between the ERP patients and historic controls.

Conclusions

Implementation of an outpatient ERP for female pelvic reconstructive surgery was associated with decreased intraoperative and total MMEs, decreased length of procedure, decreased administration of intravenous fluids, and decreased total hospital cost without changing postoperative pain scores.
Virtual Interviews During COVID-19 Pandemic: A Survey of Applicants to Fellowships in Female Pelvic Medicine and Reconstructive Surgery
Authors: Gaigbe-Togbe Bertille H.A. , Menhaji Kimia , Tran Ann D. , Bui Anthony H. , Ascher-Walsh Charles , Dabney Lisa , Hardart Anne
Published: January 2021

Objectives

The objective was to assess female pelvic medicine and reconstructive surgery (FPMRS) fellowship applicants’ perspectives on the effectiveness of the virtual interview format for creating their rank lists.

Methods

This was an anonymous internet-based survey study of applicants to the FPMRS fellowships in the United States, conducted from July 21, 2020, to August 5, 2020. A 34-item questionnaire queried applicants on satisfaction with interviews, comfort with creating a rank list and time, and financial cost of interviews. Applicants were invited to complete the survey via standardized emails distributed via the REDCap secure database.

Results

Forty-two (56.7%) of 74 applicants completed the survey. The majority of respondents were somewhat satisfied or very satisfied (92.9%) with the virtual interview process and felt comfortable ranking the programs (83.3%). A total of 9.8% of respondents found virtual interviews somewhat or much better than in-person interviews with regards to being informative and helpful, whereas 61% found them to be about the same. A majority (75.6%) found virtual interviews somewhat or much less stressful compared with in-person interviews. The majority (97.5%) spent less than $2,000 during the application process compared with more than $4,000 (87.8%) that they had anticipated spending if the interviews were in person.

Conclusions

Our data revealed that FPMRS applicants overall had a positive experience with the virtual interview platform and felt comfortable creating a rank list of programs based on those interviews.
Parosmia in Right-lateralized Semantic Variant Primary Progressive Aphasia
Authors: Joo Jae Young , Kim Hyug-Gi , Lee Kyung Mi , Ko Seok Hoon , Rhee Hak Young , Park Key-Chung , Lee Jin San
Published: January 2021

Parosmia, defined as the distorted perception of an odor stimulus, has been reported to be associated with head trauma, upper respiratory tract infections, sinonasal diseases, and toxin/drug consumption. To date, little is known about parosmia in right-lateralized semantic variant primary progressive aphasia. A 60-year-old right-handed man presented with a 2-year history of parosmia and prosopagnosia. Brain magnetic resonance imaging demonstrated severe atrophy of the right anterior and mesial temporal lobe, particularly in the fusiform cortex and the regions known as the primary olfactory cortex. 18F-fluorodeoxyglucose position emission tomography showed asymmetric hypometabolism of the bilateral temporal lobes (right > left). We clinically diagnosed him with right-lateralized semantic variant primary progressive aphasia. As the right hemisphere is known to be more involved in the processing of pleasant odors than the left hemisphere, we speculate that the unique manifestation of parosmia observed in this patient might be associated with the lateralization of the olfactory system.
Botulinum Toxin Monotherapy for the Treatment of Essential Tremor: Life Quality Effect
Authors: Demiryurek Bekir Enes
Published: January 2021

Aim

This study aims to evaluate the effectiveness of botulinum toxin therapy, as a monotherapy, and its effect on quality of life in patients with essential tremor (ET) who are resistant to medical treatment or cannot tolerate optimum drug doses in the population.

Method

This retrospective research was conducted between February 2019 and December 2019 with 15 adult patients (9 men and 6 women) in the 50-to-70 age group, who had a definite diagnosis of ET as evaluated by the same clinician. With the help of electroneuromyography, intramuscular onabotulinum toxin A (BoNT-A) injection was administered to the related muscles, not exceeding 100 U in total. Demographic characteristics and duration of disease of all patients were recorded. The tremor severity of patients before the injection, 1 month after the injection, and 3 months after the injection was assessed by the Fahn-Tolosa-Marín Tremor Rating Scale (FTM-TRS), applied by the same clinician during the face-to-face interviews, in addition to the Questionnaire for Essential Tremor (QUEST), which was filled out by participants.

Results

The first month and third month mean QUEST and FTM-TRS scores were statistically lower than that before the procedure in patients with ET after BoNT-A injection (P = 0.001, P = 0.001, P = 0.001, and P = 0.001). In addition, the mean FTM-TRS and QUEST scores for the first month after the procedure were significantly lower than the mean FTM-TRS and QUEST scores for the third month (P = 0.005 and P = 0.007).

Conclusion

We believe that our study is valuable because there is no research on the effect of BoNT-A administration on ET treatment in the our country population and because the effect of BoNT-A treatment on quality of life in patients with ET was evaluated using the ET-specific QUEST scale.
Improving Detection of Hippocampal Epileptiform Activity Using Magnetoencephalography
Authors: Sidler Elaine , Greiner Hansel , Mangano Francesco , Skoch Jesse , Arya Ravindra , Holland Katherine , Aungaroon Gewalin , Arthur Todd , Fujiwara Hisako , Horn Paul , Tenney Jeffrey
Published: January 2021

Purpose:

Magnetoencephalography (MEG) defines the spike-generating zone and provides targets for invasive monitoring with stereotactic electroencephalography. This retrospective, blinded, cross-sectional study determined whether MEG virtual sensors could identify hippocampal epileptiform activity.

Methods:

Using MEG beamformer analysis, virtual sensors were manually placed in bilateral hippocampi and corresponding virtual sensor waveforms were analyzed for the presence of epileptiform activity. These findings were compared with hippocampal stereotactic electroencephalography in the same patients. Concordance was determined using sensitivity and specificity.

Results:

Thirty patients (mean age 12.5 ± 5.9 years) and 35 hippocampi were included. Patients were also placed into subgroups based on conventional MEG analysis: temporal (n = 19), extratemporal (n = 10), and normal (n = 1). Overall, sensitivity and specificity were 57.9% and 50.0%, respectively (n = 35). Patients with temporal sources based on conventional MEG analysis had sensitivity and specificity of 80.0% and 36.4%, respectively (n = 21). Those with extratemporal sources based on conventional MEG had sensitivity and specificity of 42.9% and 80.0%, respectively (n = 12).

Conclusions:

When grouped by conventional MEG analysis, virtual sensors can be useful to confirm mesial temporal dipoles seen with conventional analysis.

Significance:

This work may help support the use of MEG for the detection of epileptiform activity in the hippocampus and influence the planning of invasive electrode placement.
Association of homelessness with COVID-19 positivity among individuals visiting a testing center
Authors: Kiran Tara , Craig-Neil Amy , Das Paul , Lockwood Joel , Wang Ri , Nathanielsz Nikki , Rosenthal Esther , Hwang Stephen W.
Published: January 2021

We conducted a chart audit of all patients attending an inner-city COVID-19 testing centre in Toronto, Canada between March and April 2020. Of the 2050 unique individuals tested, 214 (10.4%) were homeless. People experiencing homelessness were more likely to test positive for COVID-19 compared to those not experiencing homelessness even after adjustment for age, sex, and the presence of any medical co-morbidity (15.4% vs. 6.7%, p<0.001; OR 2.41, 95% CI 1.51 to 3.76, p<0.001).
Immunogenicity and Protective Efficacy of an Intranasal Live-attenuated Vaccine Against SARS-CoV-2 in Preclinical Animal Models
Authors: Park Jun-Guy , Oladunni Fatai S. , Rohaim Mohammed A. , Whittingham-Dowd Jayde , Tollitt James , Assas Bakri M , Alhazmi Wafaa , Almilaibary Abdullah , Iqbal Munir , Chang Pengxiang , Escalona Renee , Shivanna Vinay , Torrelles Jordi B. , Worthington John J , Jackson-Jones Lucy H. , Martinez-Sobrido Luis , Munir Muhammad
Published: January 2021

The global deployment of an effective and safe vaccine is currently a public health priority to curtail the coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Here, we evaluated a Newcastle disease virus (NDV)-based intranasal vectored-vaccine in mice and hamsters for its immunogenicity, safety and protective efficacy in challenge studies with SARS-CoV-2. The recombinant (r)NDV-S vaccine expressing spike (S) protein of SARS-CoV-2 administrated via intranasal route in mice induced high levels of SARS-CoV-2-specific neutralizing immunoglobulin A (IgA) and IgG2a antibodies and T cell-mediated immunity. Hamsters vaccinated with two doses of vaccine showed complete protection from clinical disease including lung infection, inflammation, and pathological lesions after SARS-CoV-2 challenge. Importantly, a single or double dose of intranasal rNDV-S vaccine completely blocked SARS-CoV-2 shedding in nasal turbinate and lungs within 4 days of vaccine administration in hamsters. Taken together, intranasal administration of rNDV-S has the potential to control infection at the site of inoculation, which should prevent both the clinical disease and transmission to halt the spread of the COVID-19 pandemic.
The landscape of human brain immune response in patients with severe COVID-19
Authors: Fullard John F. , Lee Hao-Chih , Voloudakis Georgios , Suo Shengbao , Shao Zhiping , Peter Cyril , Javidfar Behnam , Zhang Wen , Jiang Shan , Corvelo André , Woodoff-Leith Emma , Purohit Dushyant P. , Hoffman Gabriel E. , Akbarian Schahram , Fowkes Mary , Crary John , Yuan Guo-Cheng , Roussos Panos
Published: January 2021

In coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, the relationship between brain tropism, neuroinflammation and host immune response has not been well characterized. We analyzed 68,557 single-nucleus transcriptomes from three brain regions (dorsolateral prefrontal cortex, medulla oblongata and choroid plexus) and identified an increased proportion of stromal cells and monocytes in the choroid plexus of COVID-19 patients. Differential gene expression, pseudo-temporal trajectory and gene regulatory network analyses revealed microglial transcriptome perturbations, mediating a range of biological processes, including cellular activation, mobility and phagocytosis. Quantification of viral spike S1 protein and SARS-CoV-2 transcripts did not support the notion of brain tropism. Overall, our findings suggest extensive neuroinflammation in patients with acute COVID-19.

One Sentence Summary

Single-nucleus transcriptome analysis suggests extensive neuroinflammation in human brain tissue of patients with acute coronavirus disease 2019.
The Ecological Structure of Mosquito Population Seasonal Dynamics
Authors: Whittaker Charles , Winskill Peter , Sinka Marianne , Pironon Samuel , Massey Claire , Weiss Daniel J , Nguyen Michele , Gething Peter W , Kumar Ashwani , Ghani Azra , Bhatt Samir
Published: January 2021

Understanding the temporal dynamics of mosquito populations underlying malaria transmission is key to optimising control strategies. We collate mosquito time-series catch data spanning 40 years and 117 locations across India to understand the factors driving these dynamics. Our analyses reveal pronounced variation in dynamics across locations and between species. Many mosquito populations lacked the often-assumed positive relationship with rainfall, instead displaying patterns of abundance that were only weakly or even negatively correlated with precipitation and highlighting the role of temperature, proximity to perennial bodies of water and patterns of land use in shaping the dynamics and seasonality of mosquito populations. We show that these diverse dynamics can be clustered into “dynamical archetypes”, each characterised by distinct temporal properties and driven by a largely unique set of environmental factors. These results highlight that a complex interplay of factors, rather than rainfall alone, shape the timing and extent of mosquito population seasonality.
24-Nor-Ursodeoxycholic acid reshapes immunometabolism in CD8+T cells and alleviates hepatic inflammation
Authors: Zhu Ci , Boucheron Nicole , Müller André C. , Májek Peter , Claudel Thierry , Halilbasic Emina , Baazim Hatoon , Lercher Alexander , Viczenczova Csilla , Hainberger Daniela , Preglej Teresa , Sandner Lisa , Alteneder Marlis , Gülich Alexandra F. , Khan Matarr , Hamminger Patricia , Remetic Jelena , Ohradanova-Repic Anna , Schatzlmaier Philipp , Donner Clemens , Fuchs Claudia D. , Stojakovic Tatjana , Scharnagl Hubert , Sakaguchi Shinya , Weichhart Thomas , Bergthaler Andreas , Stockinger Hannes , Ellmeier Wilfried , Trauner Michael
Published: January 2021

Background & Aims

24-NorUrsodeoxycholic acid (NorUDCA) is novel therapy for immune-mediated liver diseases such as primary sclerosing cholangitis (PSC) where dysregulated T cells including CD8+T cells cause liver immunopathology. We hypothesized that NorUDCA may directly modulate CD8+T cell effector function thus contributing to its therapeutic efficacy independent of anti-cholestatic effects.

Methods

NorUDCA effects on CD8+T cell functionin vivowere investigated in a hepatic injury model system induced by excessive CD8+T cell immune response upon non-cytolytic lymphocytic choriomeningitis virus (LCMV) infection. Mechanistic studies included molecular and biochemical approaches, flow cytometry and metabolic assays in mouse CD8+T cellsin vitro. Mass spectrometry (MS) was used to identify potential targets modulated by NorUDCA in CD8+T cells. NorUDCA signaling effects observed in murine systems were validated in peripheral T cells from healthy volunteers and PSC patients.

Results

In vivoNorUDCA ameliorated hepatic injury and systemic inflammation upon LCMV infection. Mechanistically, NorUDCA demonstrated a strong immunomodulatory efficacy in CD8+T cells affecting lymphoblastogenesis, mTORC1 signaling and glycolysis of CD8+T cells. With MS, we identified that NorUDCA regulates CD8+T cells via targeting mTORC1. NorUDCA’s impact on mTORC1 signaling was further confirmed in circulating human CD8+T cells.

Conclusions

NorUDCA possesses a yet-unrecognized direct modulatory potency on CD8+T cells and attenuates excessive CD8+T cell hepatic immunopathology. These findings may be relevant for treatment of immune-mediated liver diseases such as PSC and beyond.
Epidemiological impact of prioritizing SARS-CoV-2 vaccination by antibody status: Mathematical modeling analyses
Authors: Ayoub Houssein H. , Chemaitelly Hiam , Makhoul Monia , Kanaani Zaina Al , Kuwari Einas Al , Butt Adeel A. , Coyle Peter , Jeremijenko Andrew , Kaleeckal Anvar Hassan , Latif Ali Nizar , Shaik Riyazuddin Mohammad , Rahim Hanan F. Abdul , Nasrallah Gheyath K. , Yassine Hadi M. , Kuwari Mohamed G. Al , Romaihi Hamad Eid Al , Al-Thani Mohamed H. , Bertollini Roberto , Khal Abdullatif Al , Raddad Laith J. Abu
Published: January 2021

Background

Vaccines against SARS-CoV-2 have been developed, but their availability falls far short of global needs. This study aimed to investigate the impact of prioritizing available doses on the basis of recipient antibody status, that is by exposure status, using Qatar as an example.

Methods

Vaccination impact was assessed under different scale-up scenarios using a deterministic meta-population mathematical model describing SARS-CoV-2 transmission and disease progression in the presence of vaccination.

Results

For a vaccine that protects against infection with an efficacy of 95%, half as many vaccinations were needed to avert one infection, disease outcome, or death by prioritizing antibody-negative individuals for vaccination. Prioritization by antibody status reduced incidence at a faster rate and led to faster elimination of infection and return to normalcy. Further prioritization by age group amplified the gains of prioritization by antibody status. Gains from prioritization by antibody status were largest in settings where the proportion of the population already infected at the commencement of vaccination was 30-60%, which is perhaps where most countries will be by the time vaccination programs are up and running. For a vaccine that only protects against disease and not infection, vaccine impact was reduced by half, whether this impact was measured in terms of averted infections or disease outcomes, but the relative gains from using antibody status to prioritize vaccination recipients were similar.

Conclusions

Major health, societal, and economic gains can be achieved more quickly by prioritizing those who are antibody-negative while doses of the vaccine remain in short supply.
The hyperlipidaemic drug fenofibrate significantly reduces infection by SARS-CoV-2 in cell culture models
Authors: Davies Scott P. , Mycroft-West Courtney J. , Pagani Isabel , Hill Harriet J. , Chen Yen-Hsi , Karlsson Richard , Bagdonaite Ieva , Guimond Scott E. , Stamataki Zania , De Lima Marcelo Andrade , Turnbull Jeremy E. , Yang Zhang , Vicenzi Elisa , Skidmore Mark A. , Khanim Farhat , Richardson Alan
Published: January 2021

The SARS-CoV-2 pandemic has caused a significant number of fatalities and worldwide disruption. To identify drugs to repurpose to treat SARS-CoV-2 infections, we established a screen to measure dimerization of ACE2, the primary receptor for the virus. This screen identified fenofibric acid, the active metabolite of fenofibrate. Fenofibric acid also destabilized the receptor binding domain (RBD) of the viral spike protein and inhibited RBD binding to ACE2 in ELISA and whole cell binding assays. Fenofibrate and fenofibric acid were tested by two independent laboratories measuring infection of cultured Vero cells using two different SARS-CoV-2 isolates. In both settings at drug concentrations which are clinically achievable, fenofibrate and fenofibric acid reduced viral infection by up to 70%. Together with its extensive history of clinical use and its relatively good safety profile, these studies identify fenofibrate as a potential therapeutic agent requiring urgent clinical evaluation to treat SARS-CoV-2 infection.

Teaser

The approved drug fenofibrate inhibits infection by SARS-COV-2
Characterization of cephalic and non-cephalic sensory cell types provides insight into joint photo- and mechanoreceptor evolution
Authors: Revilla-i-Domingo Roger , Veedin Rajan Vinoth Babu , Waldherr Monika , Prohaczka Günther , Musset Hugo , Orel Lukas , Gerrard Elliot , Smolka Moritz , Farlik Matthias , Lucas Robert J. , Raible Florian , Tessmar-Raible Kristin
Published: January 2021

Rhabdomeric Opsins (r-Opsins) are light-sensors in cephalic eye photoreceptors, but also function in additional sensory organs. This has prompted questions on the evolutionary relationship of these cell types, and if ancient r-Opsins cells were non-photosensory. Our profiling of cephalic and non-cephalic r-opsin1-expressing cells of the marine bristlewormPlatynereis dumeriliireveals shared and distinct features. Non-cephalic cells possess a full set of phototransduction components, but also a mechanosensory signature. We determine that Pdu-r-Opsin1 is a Gαq-coupled blue-light receptor. Profiling of cells fromr-opsin1mutants versus wild-types, and a comparison under different light conditions reveals that in the non-cephalic cells, light – mediated by r-Opsin1 – adjusts the expression level of a calcium transporter relevant for auditory mechanosensation in vertebrates. We establish a deep learning-based quantitative behavioral analysis for animal trunk movements, and identify a light-and r-Opsin-1-dependent fine-tuning of the worm’s undulatory movements in headless trunks, which are known to require mechanosensory feedback.

Our results suggest an evolutionary concept in which r-Opsins act as ancient, light-dependent modulators of mechanosensation, and suggest that light-independent mechanosensory roles of r-Opsins likely evolved secondarily.
Biophysical investigation of the dual binding surfaces of human transcription factors FOXO4 and p53
Authors: Kim Jinwoo , Ahn Dabin , Park Chin-Ju
Published: January 2021

Cellular senescence is protective against external oncogenic stress, but its accumulation causes aging-related diseases. Forkhead box O4 (FOXO4) and p53 are human transcription factors known to promote senescence by interacting each other and activating p21 transcription. Inhibition of the interaction is a strategy for inducing apoptosis of senescent cells, but the binding surfaces that mediate the FOXO4-p53 interaction remain elusive. Here, we investigated two binding sites involved in the interaction between FOXO4 and p53 by NMR spectroscopy. NMR chemical shift perturbation analysis showed that the binding between FOXO4’s forkhead domain (FHD) and p53’s transactivation domain (TAD), and between FOXO4’s C-terminal transactivation domain (CR3) and p53’s DNA binding domain (DBD), mediate the FOXO4-p53 interaction. Isothermal titration calorimetry data showed that both interactions have micromolar Kdvalues, and FOXO4 FHD-p53 TAD interaction has a higher binding affinity. Also, we showed that the FOXO4 CR3-binding surface of FOXO4 FHD interacts with p53 TAD2, and FOXO4 CR3 interacts with the DNA/p53 TAD-binding surface of p53 DBD, suggesting a network of potentially competitive and/or coordinated interactions. Based on the results, we propose that the dual interaction contributes to two TF’s proper location on the p21 promoter site and consequently promotes p21 transcription and cell senescence. This work provides structural information at the molecular level that is key to understanding the interplay of two proteins responsible for cellular senescence.

Conflicts of interest

None
High-content single-cell combinatorial indexing
Authors: Mulqueen Ryan M. , Pokholok Dmitry , O’Connell Brendan L. , Thornton Casey A. , Zhang Fan , O’Roak Brian J. , Link Jason , Yardmici Galip Gurkan , Sears Rosalie C. , Steemers Frank J. , Adey Andrew C.
Published: January 2021

Single-cell genomics assays have emerged as a dominant platform for interrogating complex biological systems. Methods to capture various properties at the single-cell level typically suffer a tradeoff between cell count and information content, which is defined by the number of unique and usable reads acquired per cell. We and others have described workflows that utilize single-cell combinatorial indexing (sci)1, leveraging transposase-based library construction2to assess a variety of genomic properties in high throughput; however, these techniques often produce sparse coverage for the property of interest. Here, we describe a novel adaptor-switching strategy, ‘s3’, capable of producing one-to-two order-of-magnitude improvements in usable reads obtained per cell for chromatin accessibility (s3-ATAC), whole genome sequencing (s3-WGS), and whole genome plus chromatin conformation (s3-GCC), while retaining the same high-throughput capabilities of predecessor ‘sci’ technologies. We apply s3 to produce high-coverage single-cell ATAC-seq profiles of mouse brain and human cortex tissue; and whole genome and chromatin contact maps for two low-passage patient-derived cell lines from a primary pancreatic tumor.
Toward Optimized and Predictive Connectomics at Scale
Authors: Moon Joseph Y. , Mukherjee Pratik , Madduri Ravi K. , Markowitz Amy J. , Palacios Eva M. , Manley Geoffrey T. , Bremer Peer-Timo
Published: January 2021

Probabilistic MRI diffusion tractography is a sophisticated technique to investigate structural connectomes, but its steep computational cost prevents application to broader research and clinical settings. Major speedup can be achieved by reducing the number of tractography streamlines. To ensure this does not degrade connectome quality, we calculate the identifiability of connectomes between test and retest MRI as a proxy for information content. We find that reducing streamline count by up to two orders of magnitude from prevailing levels in literature has no significant impact on identifiability. Incidentally, we also observe that Jaccard similarity is more effective than Pearson correlation in achieving identifiability.

This document was prepared as an account of work sponsored by an agency of the United States government. Neither the United States government nor Lawrence Livermore National Security, LLC, nor any of their employees makes any warranty, expressed or implied, or assumes any legal liability or responsibility for the accuracy, completeness, or usefulness of any information, apparatus, product, or process disclosed, or represents that its use would not infringe privately owned rights. Reference herein to any specific commercial product, process, or service by trade name, trademark, manufacturer, or otherwise does not necessarily constitute or imply its endorsement, recommendation, or favoring by the United States government or Lawrence Livermore National Security, LLC. The views and opinions of authors expressed herein do not necessarily state or reflect those of the United States government or Lawrence Livermore National Security, LLC, and shall not be used for advertising or product endorsement purposes.
Spatial Transcriptomics to define transcriptional patterns of zonation and structural components in the liver
Authors: Hildebrandt Franziska , Andersson Alma , Saarenpää Sami , Larsson Ludvig , Van Hul Noémi , Kanatani Sachie , Masek Jan , Ellis Ewa , Barragan Antonio , Mollbrink Annelie , Andersson Emma R. , Lundeberg Joakim , Ankarklev Johan
Published: January 2021

Reconstruction of heterogeneity through single-cell transcriptional profiling has greatly advanced our understanding of the spatial liver transcriptome in recent years. However, global transcriptional differences across lobular units remain elusive in physical space. Here, we implement Spatial Transcriptomics to perform transcriptomic analysis across sectioned liver tissue. We confirm that the heterogeneity in this complex tissue is predominantly determined by lobular zonation. By introducing novel computational approaches, we enable transcriptional gradient measurements between tissue structures, including several lobules in a variety of orientations. Further, our data suggests the presence of previously transcriptionally uncharacterized structures within liver tissue, contributing to the overall spatial heterogeneity of the organ. This study demonstrates how comprehensive spatial transcriptomic technologies can be used to delineate extensive spatial gene expression patterns in the liver, indicating its future impact for studies of liver function, development and regeneration as well as its potential in pre-clinical and clinical pathology.
Low oxygen arrestsBabesia duncanischizonts and leads to increased drug susceptibilities in hamster erythrocytes
Authors: Zhang Yumin , Alvarez-Manzo Hector , Zhang Ying
Published: January 2021

We studied the effect of oxygen concentrations on the in vitro growth and drug susceptibility ofBabesia duncani. We found that the growth ofB. duncanirequired high level oxygen and the culture condition at ambient aerobic condition (21% O2) was optimal. Compared with ambient air, our results further showed that low oxygen (6-16%) could arrestB. duncanischizonts and lead to high susceptibilities to antiparasitic drugs atovaquone, pyrimethamine, quinine, and chloroquine at certain concentrations in vitro. Drug susceptibilities of otherBabesiaspp impacted by O2levels need to be studied in the future, and this study indicates that culturing conditions ofBabesiaspp should be considered and reestablished for generating more comparable and reliable results in drug research in the future.

Graphical abstract

Highlights

The in vitro growth ofB. duncanirequires high level oxygen and the culture condition of 5% CO2ambient air is optimal

Low level oxygen resultsB. duncaniin low growth rate and high schizont ratio in vitro

Compared with 5% CO2ambient air, in vitro drug susceptibilities ofB. duncanican be significantly increased when cultured in microaerobic condition
A Simple Parametric Representation of the Hodgkin-Huxley Model
Authors: Rodríguez-Collado Alejandro , Rueda Cristina
Published: January 2021

The Hodgkin-Huxley model, decades after its first presentation, is still a reference model in neuroscience as it has successfully reproduced the electrophysiological activity of many organisms. The primary signal in the model represents the membrane potential of a neuron. A parametric and simple representation of this signal is presented in this paper.

The new proposal is an adapted Frequency Modulated Möbius multicomponent model defined as a flexible decomposition in waves that describe the signal morphology. A specific feature of the new model is that the parameters are subject to interpretable restrictions.

A broad simulation experiment is conducted to show the new model accurately represents the simulated Hodgkin-Huxley signal. Moreover, the model potential to predict the neuron’s relevant characteristics, described with parameters of the Hodgkin Huxley model, is shown using different Machine Learning methods. The proposed model is also validated with real data from Squid Giant Axons. The comparison of the parameter configuration between the simulated and real data demonstrated the flexibility of the model as well as interesting differences.

Author summary

Alejandro Rodríguez-Collado. I received the double degree in Statistics and Computer Engineering and the Master’s degree in Business Intelligence and Big Data from the Universidad de Valladolid in 2019 and 2020, respectively. I work as researcher and Professor for the Department of Statistics and Operational Research at the Universidad de Valladolid. My main research interests include oscillatory signal processing, neuroscience, multivariate data analysis and supervised learning.

Cristina Rueda. I received the BS degree in mathematics from the Universidad de Valladolid in 1987 and the PhD degree in statistical science from the Universidad de Valladolid in 1989. I am currently Professor in the Department of Statistics and Operational Research at the Universidad de Valladolid. My main research interests include statistical inference methods under restrictions, circular data, computational biology, and statistical methods for signal analysis.
A flexible micro-piston device for mechanical cell stimulation and compression in microfluidic settings
Authors: Onal Sevgi , Alkaisi Maan M. , Nock Volker
Published: January 2021

Evidence continues to emerge that cancer is not only a disease of genetic mutations, but also of altered mechanobiological profiles of the cells and microenvironment. This mutation-independent element might be a key factor in promoting development and spread of cancer. Biomechanical forces regulate tumor microenvironment by solid stress, matrix mechanics, interstitial pressure and flow. Compressive stress by tumor growth and stromal tissue alters the cell deformation, and recapitulates the biophysical properties of cells to grow, differentiate, spread or invade. Such a solid stress can be introduced externally to change the cell response and to mechanically induce cell lysis by dynamic compression. In this work we report a microfluidic cell-culture platform with an integrated, actively-modulated actuator for the application of compressive forces on cancer cells. Our platform is composed of a control microchannel in a top layer for introducing external force and a polydimethylsiloxane (PDMS) membrane with monolithically integrated actuators. The integrated actuator, herein called micro-piston, was used to apply compression on SKOV-3 ovarian cancer cells in a dynamic and controlled manner by modulating applied gas pressure, localization, shape and size of the micro-piston. We report fabrication of the platform, characterization of the mechanical actuator experimentally and computationally, as well as cell loading and culture in the device. We further show use of the actuator to perform both, repeated dynamic cell compression at physiological pressure levels, and end-point mechanical cell lysis, demonstrating suitability for mechanical stimulation to study the role of compressive forces in cancer microenvironments.
COVID-19 Severity Is Associated with Differential Antibody Fc-mediated Innate Immune Functions
Authors: Adeniji Opeyemi S. , Giron Leila B. , Zilberstein Netanel F , Shaikh Maliha W. , Balk Robert A , Moy James N , Forsyth Christopher B. , Keshavarzian Ali , Landay Alan , Abdel-Mohsen Mohamed
Published: January 2021

Beyond neutralization, antibodies elicit several innate immune functions including complement deposition (ADCD), phagocytosis (ADCP), and cytotoxicity (ADCC). These functions can be both beneficial (by clearing pathogens) and/or detrimental (by inducing inflammation). We tested the possibility that qualitative differences in SARS-CoV-2 specific antibody-mediated innate immune functions contribute to Coronavirus disease 2019 (COVID-19) severity. We found that antibodies from hospitalized COVID-19 patients elicited higher ADCD but lower ADCP compared to antibodies from non-hospitalized COVID-19 patients. Consistently, higher ADCD was associated with higher systemic inflammation during COVID-19. Our study points to qualitative, differential features of anti-SARS-CoV-2 antibodies as potential contributors to COVID-19 severity.