bluuebunny/crossref_metadata_2025 huggingface dataset:
Fluorescence angiography-assisted debridement of critically perfused glabrous skin in degloving foot injuries
Authors: Vasella Mauro , Guidi Marco , Waldner Matthias , Calcagni Maurizio , Giovanoli Pietro , Frueh Florian S.
Published: June 2021

Rationale:

Degloving foot injuries are challenging to treat and associated with life-long sequelae for patients. An appropriate debridement of ischemic soft tissues with maximal preservation of glabrous skin is key during the reconstruction of these injuries. Indocyanine green (ICG) fluorescence angiography is an established technique for the intraoperative evaluation of tissue perfusion.

Patient concerns:

Two patients sustained complex foot injuries in traffic accidents, including multiple fracture dislocations and extensive degloving of the plantar skin.

Diagnosis:

Clinical inspection revealed significant degloving of the glabrous skin in both patients.

Interventions:

After fracture fixation, ICG fluorescence angiography-assisted debridement with immediate latissimus dorsi free flap reconstruction was performed.

Outcomes:

In both cases, this technique allowed a precise debridement with maximal preservation of the glabrous skin. The healing of the remaining glabrous skin was uneventful and the 6-month follow-up was characterized by stable soft tissues and satisfying ambulation.

Lessons:

ICG fluorescence angiography is a safe, user-friendly, and quick procedure with minimal risks, expanding the armamentarium of the reconstructive surgeon. It is highly useful for the debridement of extensive plantar degloving injuries and may also help to minimize the number of procedures and the risk of infection.
Transient oculomotor paralysis after cerebral angiography
Authors: Qiu Tao , Dai Xiaoyan , Gong Qingping , Pu Rongmei , Xiao Hua , Shi Qiang , Deng Xiaoyong , Chen Ming , Guo Zhaoyun
Published: June 2021

Rationale:

A special case of transient oculomotor nerve palsy after cerebral angiography.

Patient concerns:

A 55-year-old man developed oculomotor nerve dysfunction after right radial artery puncture angiography.

Diagnoses:

Cerebral angiography-induced oculomotor nerve palsy.

Interventions:

According to the patient's disease state, intravenous drip of dexamethasone 10 mg/d.

Outcomes:

Magnetic resonance imaging (MRI) showed no abnormalities, and the patient recovered completely after 48 hours of hormone therapy.

Lessons:

Transient eye palsy caused by contrast agent encephalopathy is a clinically rare neurological dysfunction caused by adverse effects of contrast agents. Early prevention and correct treatment are critical.
Open total dislocation of ankle joint without fractures
Authors: Chi Yu-lei , Gao Xu , Xu Ying-jie , Bu Xian-min , Han Liang , Zhang Xu , Gao Long-fei , Tian Rong-hua , Wang Hai-bin , Wu Bin
Published: June 2021

Rationale:

Open total dislocation of ankle joint is rare and often caused by high-energy injury. The present study describes a patient with open total lateral dislocation of ankle joint without fractures and obtained a satisfactory clinical result following early debridement and irrigation, one-stage repairment of ligaments, and plaster external fixation.

Patient concerns:

The patient, a 45-year-old male, complained of right foot pain with bleeding and limited motion. Physical examination showed a 15-cm open wound at the medial ankle region, with soft tissues impaired and ankle bones exposed. The 3 dimensional reconstruction computed tomography (CT) examination showed an open total dislocation of ankle joint without concomitant fractures.

Diagnoses:

open total lateral dislocation of ankle joint without fractures

Interventions:

Early modern wound care including thorough debridement and irrigation on the wound was performed to remove contaminated soft tissues. Subsequently, the dislocated ankle joint was reduced by hand and the medial and lateral collateral ligaments were repaired using wire anchors.

Outcomes:

The medial wound healed at 2 weeks after surgery, and several common complications such as infection and skin necrosis did not occur. The last follow-up showed a good range of metatarsal flexion and extension of the injured foot, and obvious signs of traumatic arthritis were not observed. According to Kaikkonen ankle function score, the patient was assessed with 90 points.

Lessons:

For open total dislocation of ankle joint, early treatment should focus on debridement and irrigation, reduction and fixation of the dislocated ankle, protection of the weak soft tissues, and stable external fixation to promote wound healing and reduce the incidence of related complications.
Is higher-level trauma center care associated with better outcomes in patients injured by low-energy trauma?
Authors: Tonkins Michael , Bradbury Daniel , Bramley Paul , Sabir Lisa , Wilkinson Anna , Lecky Fiona
Published: June 2021

Background

In high-income countries trauma patients are becoming older, more likely to have comorbidities, and are being injured by low-energy mechanisms, chiefly ground-level falls. It is currently unknown whether existing trauma systems improve the outcomes of these patients. This systematic review investigates the association between higher-level trauma center care and outcomes of adult patients who were admitted to hospital due to injuries sustained following low-energy trauma.

Methods

A pre-registered systematic review (CRD42020211652) of subject databases and grey literature, supplemented by targeted manual searching, was conducted in January 2021. Studies were eligible if they reported outcomes in adults admitted to hospital due to low-energy trauma. Studies were excluded if participants were not adults or were not admitted to hospital. Studies in lower- and middle-income settings were excluded due to differences in demographics and healthcare systems. Risk of bias was assessed by independent reviewers using the Robins-I tool. In the presence of study heterogeneity a narrative synthesis was pre-specified.

Results

Three observational studies were included from 2,898 unique records. The studies’ risk of bias was moderate-to-serious due to potential residual confounding and selection bias. All studies compared outcomes among adults injured by ground-level falls treated in trauma centers verified by the American College of Surgeons in the USA. The studies reported divergent results. One demonstrated improved outcomes in level 3 or 4 trauma centers (Observed: Expected Mortality 0.973, 95%CI 0.971-0.975), one demonstrated improved outcomes in level 1 trauma centers (Adjusted Odds Ratio 0.71, 95%CI 0.56-0.91), and one demonstrated no difference between level 1 or 2 and level 3 or 4 trauma center care (Adjusted Odds Ratio 0.91 (0.80-1.04).

Conclusions

There is currently no strong evidence for the efficacy of major trauma centers in caring for adult patients injured by a ground-level fall. Further studies at lower risk of bias and studies conducted outwith the USA are required.

Level of Evidence

Level III systematic review and meta-analysis
Temporally-Informed Random Forests for Suicide Risk Prediction
Authors: Bayramli Ilkin , Castro Victor , Barak-Corren Yuval , Madsen Emily M. , Nock Matthew K. , Smoller Jordan W. , Reis Ben Y.
Published: June 2021

Background

Suicide is one of the leading causes of death worldwide, yet clinicians find it difficult to reliably identify individuals at high risk for suicide. Algorithmic approaches for suicide risk detection have been developed in recent years, mostly based on data from electronics health records (EHRs). These models typically do not optimally exploit the valuable temporal information inherent in these longitudinal data.

Methods

We propose a temporally enhanced variant of the Random Forest model - Omni-Temporal Balanced Random Forests (OTBRFs) - that incorporates temporal information in every tree within the forest. We develop and validate this model using longitudinal EHRs and clinician notes from the Mass General Brigham Health System recorded between 1998 and 2018, and compare its performance to a baseline Naive Bayes Classifier and two standard versions of Balanced Random Forests.

Results

Temporal variables were found to be associated with suicide risk. RF models were more accurate than Naive Bayesian classifiers at predicting suicide risk in advance (AUC=0.824 vs. 0.754 respectively). The OT-BRF model performed best among all RF approaches (0.339 sensitivity at 95% specificity), compared to 0.290 and 0.286 for the other two RF models. Temporal variables were assigned high importance by the models that incorporated them.

Discussion

We demonstrate that temporal variables have an important role to play in suicide risk detection, and that requiring their inclusion in all random forest trees leads to increased predictive performance. Integrating temporal information into risk prediction models helps the models interpret patient data in temporal context, improving predictive performance.
Establishing consensus on emergency department interventions that could be conducted in sub-acute care settings for non-emergent paramedic transported visits: A RAND/UCLA modified Delphi study
Authors: Strum Ryan P , Tavares Walter , Worster Andrew , Griffith Lauren E , Costa Andrew P
Published: June 2021

Background

Patients transported by paramedics for non-emergent conditions are increasing in Ontario and contribute to an emergency department (ED) crisis. Redirecting certain patients to sub-acute healthcare may be beneficial and suitable. We examined if ED interventions conducted on non-emergent paramedic transported patients could be conducted in sub-acute health centres.

Methods

A RAND/UCLA modified Delphi study was conducted. Twenty emergency and primary care physicians rated the suitability of the 150 most frequently recorded interventions for completion in sub-acute healthcare centres and provided comments to augment ratings. Interventions were performed on non-emergent adult patients transported by paramedics to an ED, and abstracted from the National Ambulatory Care Reporting System database (January 1, 2014 to March 31, 2018). We used two rounds of a modified Delphi process and set consensus at 70% agreement.

Results

Consensus was reached on 146 (97.3%) interventions; 103 interventions (68.7%) were suitable for sub-acute centres, 43 (28.7%) for ED only; 4 (2.6%) did not receive consensus. For sub-acute centres, all 103 interventions were rated for urgent care centres; walk-in medical centres were applicable for 46 (30.6%) and nurse practitioner-led clinics for 47 (31.3). Diagnostic imaging availability, physician preferences and staffing were determining factors for discrepancies in sub-acute centre ratings.

Interpretation

The majority of included ED interventions performed on non-emergent patients transported by paramedics were identified as suitable for urgent care clinics, with one-third being suitable for either walk-in medical centres or nurse practitioner-led clinics. In combination with additional patient details and supports, knowledge of interventions suitable for sub-acute healthcare centres will inform a patient classification model for paramedic-initiated redirection of patients from ED.

Study registration

IDISRCTN22901977.
Genotype-stratified GWAS meta-analysis reveals novel loci associated with alcohol consumption
Authors: Koyanagi Yuriko N. , Nakatochi Masahiro , Ito Hidemi , Kasugai Yumiko , Narita Akira , Kawaguchi Takahisa , Ikezaki Hiroaki , Hishida Asahi , Hara Megumi , Takezaki Toshiro , Koyama Teruhide , Mikami Haruo , Suzuki Sadao , Katsuura-Kamano Sakurako , Kuriki Kiyonori , Nakamura Yasuyuki , Takeuchi Kenji , Hozawa Atsushi , Kinoshita Kengo , Sutoh Yoichi , Tanno Kozo , Shimizu Atsushi , Oze Isao , Kawakatsu Yukino , Taniyama Yukari , Imoto Issei , Tabara Yasuharu , Takahashi Meiko , Setoh Kazuya , Suzuki Shiori , Goto Atsushi , Katagiri Ryoko , Yamaji Taiki , Sawada Norie , Tsugane Shoichiro , Wakai Kenji , Yamamoto Masayuki , Sasaki Makoto , Matsuda Fumihiko , Iwasaki Motoki , Brennan Paul , Matsuo Keitaro
Published: June 2021

An East Asian-specific variant onaldehyde dehydrogenase 2(ALDH2rs671, G>A) is the major genetic determinant of alcohol consumption. We performed an rs671 genotype-stratified genome-wide association study meta-analysis in up to 40,679 individuals from Japanese populations to uncover additional loci associated with alcohol consumption in an rs671-dependent manner. No loci satisfied the genome-wide significance threshold in wild-type homozygotes (GG), but six loci (ADH1B, ALDH1B1, ALDH1A1, ALDH2, GOT2, andMYOM1-MYL12A) did so in heterozygotes (GA). Of these, three loci (ALDH2, GOT2, andMYOM1-MYL12A) were novel, and two (ADH1BandALDH1B1) showed genome-wide significant interaction with rs671. Our results identify a new genetic architecture associated with alcohol consumption, and shed additional light on the genetic characteristics of alcohol consumption among East Asians.
Effectiveness of mRNA COVID-19 Vaccines among Employees in an American Healthcare System
Authors: Shrestha Nabin K. , Nowacki Amy S. , Burke Patrick C. , Terpeluk Paul , Gordon Steven M.
Published: June 2021

Background

The mRNA SARS-CoV-2 vaccines have shown great promise in clinical trials. The purpose of this study was to evaluate the effectiveness of these vaccines under real-world conditions in the USA.

Methods

Employees of the Cleveland Clinic Health System, previously not infected with SARS-CoV-2, and working in Ohio on Dec 16, 2020, the day COVID-19 vaccination began, were included. The cumulative incidence of SARS-CoV-2 infection, over the next 5 months, was compared among those who received the vaccine and those who did not, by modeling vaccination as a time-dependent covariate in Cox proportional hazards regression analyses adjusted for the slope of the epidemic curve as a continuous time-dependent covariate.

Results

Of the 46866 included employees, 28223 (60%) were vaccinated by the end of the study period. The cumulative incidence of SARS-CoV-2 infection was much higher among those not vaccinated than those vaccinated. Only 15 (0.7%) of the 2154 SARS-CoV-2 infections during the study occurred among those vaccinated. After adjusting for the slope of the epidemic curve, age, and job type, vaccination was associated with a significantly reduced risk of SARS-CoV-2 infection (HR 0.03, 95% C.I. 0.02 – 0.06, p < 0.001), corresponding to a vaccine effectiveness rate of 97.1% (95% CI 94.3 – 98.5). Vaccine effectiveness was 89.2% at 7 days and 95.0% at 14 days after the first vaccine dose.

Conclusions

The mRNA SARS-CoV-2 vaccines are over 97% protective against COVID-19 in the working-age population, with substantial protection possibly apparent within a few days of the first dose.

The effectiveness of mRNA SARS-CoV-2 vaccines was evaluated among 46866 employees in an American healthcare system. After adjusting for age, job type, and the phase of the epidemic, vaccination was 97.1% effective in preventing COVID-19 among the fully vaccinated, and 89.2% protective within 7 days of the first dose.
Antibody Response after Second-dose of ChAdOx1-nCOV (Covishield™®) and BBV-152 (Covaxin™®) among Health Care Workers in India: Final Results of Cross-sectional Coronavirus Vaccine-induced Antibody Titre (COVAT) study
Authors: Kumar Singh Awadhesh , Phatak Sanjeev Ratnakar , Singh Ritu , Bhattacharjee Kingshuk , Singh Nagendra Kumar , Gupta Arvind , Sharma Arvind
Published: June 2021

Background

We assessed the humoral immune response after the completion of two doses of both ChAdOx1-nCOV (Covishield™) and BBV-152 (Covaxin™) vaccines in Indian health care workers (HCW).

Method

A Pan-India, Cross-sectional, Coronavirus Vaccine-induced Antibody Titre (COVAT) study was conducted that measured SARS-CoV-2 anti-spike binding antibody quantitatively, 21 days or more after the first and second dose of two vaccines in both severe acute respiratory syndrome (SARS-CoV-2) naïve and recovered HCW. Primary aim was to analyze antibody response (seropositivity rate and median [inter-quartile range, IQR] antibody titre) following each dose of both vaccines and its correlation to age, sex, blood group, body mass index (BMI) and comorbidities. Here we report the final results of anti-spike antibody response after the two completed doses.

Results

Among the 515 HCW (305 Male, 210 Female), 95.0% showed seropositivity after two doses of both vaccines. Of the 425 Covishield and 90 Covaxin recipients, 98.1% and 80.0% respectively, showed seropositivity. However, both seropositivity rate and median (IQR) rise in anti-spike antibody was significantly higher in Covishield vs. Covaxin recipient (98.1 vs. 80.0%; 127.0 vs. 53 AU/mL; both p<0.001). This difference persisted in 457 SARS-CoV-2 naïve cohorts and propensity-matched (age, sex and BMI) analysis of 116 cohorts. While no difference was observed in relation to sex, BMI, blood group and any comorbidities; people with age >60 years or those with type 2 diabetes had a significantly lower seropositivity rates. Both vaccine recipients had similar solicited mild to moderate adverse events and none had severe or unsolicited side effects. In SARS-CoV-2 naïve cohorts, sex, presence of comorbidities, and vaccine type were independent predictors of antibody positivity rate in multiple logistic regression analysis.

Conclusions

Both vaccines elicited good immune response after two doses, although seropositivity rates and median anti-spike antibody titre was significantly higher in Covishield compared to Covaxin arm.

Highlights

This study evaluated the humoral antibody response after 2 doses of SARS-CoV-2 vaccine Covishield™ and Covaxin™ in Indian health-care workers.

Combined results of both vaccines showed 95% seropositivity to anti-spike antibody, 21-36 days after the second completed dose.

Seropositivity rates were higher in Covishield recipients compared to Covaxin in the propensity-matched analysis of SARS-CoV-2 naïve cohorts.

Gender, presence of comorbidities and the type of vaccine received were independent predictors of antibody response after the second dose.
SSMD: Semi-Supervised Medical Image Detection with Adaptive Consistency and Heterogeneous Perturbation
Authors: Zhou Hong-Yu , Wang Chengdi , Li Haofeng , Wang Gang , Zhang Shu , Li Weimin , Yu Yizhou
Published: June 2021

Semi-Supervised classification and segmentation methods have been widely investigated in medical image analysis. Both approaches can improve the performance of fully-supervised methods with additional unlabeled data. However, as a fundamental task, semi-supervised object detection has not gained enough attention in the field of medical image analysis. In this paper, we propose a novel Semi-Supervised Medical image Detector (SSMD). The motivation behind SSMD is to provide free yet effective supervision for unlabeled data, by regularizing the predictions at each position to be consistent. To achieve the above idea, we develop a novel adaptive consistency cost function to regularize different components in the predictions. Moreover, we introduce heterogeneous perturbation strategies that work in both feature space and image space, so that the proposed detector is promising to produce powerful image representations and robust predictions. Extensive experimental results show that the proposed SSMD achieves the state-of-the-art performance at a wide range of settings. We also demonstrate the strength of each proposed module with comprehensive ablation studies.
Efficacy of clarithromycin on COVID-19 pneumonia without oxygen administration; protocol for multicenter, open-label, randomized-controlled, 3-armed parallel group comparison, exploratory trial (CAME COVID study)
Authors: Yamamoto Kazuko , Hosogaya Naoki , Sakamoto Noriho , Yoshida Haruo , Ishii Hiroshi , Yatera Kazuhiro , Izumikawa Koichi , Yanagihara Katsunori , Mukae Hiroshi
Published: June 2021

Introduction

The coronavirus disease 2019 (COVID-19) epidemic has been emerged worldwide. Although several medications have been approved for treating moderate-to-severe COVID-19, no treatment strategy has been established for mild COVID-19 patients who do not require oxygen administration. The spread of SARS -CoV-2 has been mostly through patients with mild COVID-19; therefore, treating patients with mild COVID-19 is critical in society. Clarithromycin is a macrolide antimicrobial agent that has been widely used for bacterial respiratory infectious diseases. Clarithromycin also acts an immunomodulating drug and suppresses cytokine storms in viral respiratory diseases, including influenza infection. In this study, we aimed to evaluate the efficacy of clarithromycin in patients with mild COVID-19.

Methods and analysis

This is a multicenter, open-label, randomized controlled, 3-armed parallel group comparison, exploratory trial. Subjects with mild COVID-19 pneumonia who did not require oxygen administration were enrolled and randomly assigned in a 1:1:1 ratio to Group A (administration of clarithromycin 800 mg/day), Group B (administration of clarithromycin 400 mg/day), or Group C (standard treatment without clarithromycin). The primary endpoint was the number of days required to improve clinical symptoms as measured by the severity score. Secondary endpoints included days to recover the body temperature, proportion of subjects with oxygen administration, inflammatory cytokines, viral load, serum immunoglobulins, peripheral blood lymphocytes, blood biomarkers, and pneumonia infiltrations.

Ethics and dissemination

The study protocol was approved by the Clinical Research Review Board of Nagasaki University in accordance with the Clinical Trials Act in Japan. The study will be conducted in accordance with the Declaration of Helsinki, the Clinical Trials Act, and other current legal regulations in Japan. Written informed consent will be obtained from all participants. The results of this study will be reported as journal publications.

Registration

This study was registered at the Japan Registry of Clinical Trials (registration number: jRCTs071210011).

Strengths and limitations of this study

This is the first randomized controlled trial to evaluate the efficacy of clarithromycin against COVID-19 pneumonia, especially in patients with mild COVID-19 pneumonia who do not require oxygen administration.

To date, no treatment strategy has been established for mild COVID-19 pneumonia.

The major limitations of this study are its exploratory nature and relatively small sample size.

Another limitation is the open-label study design and generalizability because this study was conducted only in Japan with Japanese patients.
A rare variant in D-amino acid oxidase implicates NMDA receptor signaling and cerebellar gene networks in risk for bipolar disorder
Authors: Hasin Naushaba , Riggs Lace M. , Shekhtman Tatyana , Ashworth Justin , Lease Robert , Oshone Rediet T. , Humphries Elizabeth M. , Badner Judith A. , Thompson Pippa A. , Glahn David C. , Craig David W. , Edenberg Howard J. , Gershon Elliot S. , McMahon Francis J. , Nurnberger John I. , Zandi Peter P. , Kelsoe John R. , Roach Jared C. , Gould Todd D. , Ament Seth A.
Published: June 2021

Bipolar disorder is an often-severe mental health disorder characterized by alternation between extreme mood states of mania and depression. Despite strong heritability and the recent identification of 64 loci of small effect, pathophysiological mechanisms and much of the genetic risk remain unknown. Here, through genome sequencing and linkage and association analyses, we found that rare variants co-segregating with bipolar disorder in large multiply affected families cluster within gene networks enriched for synaptic and nuclear functions. The top variant in this analysis prioritized by statistical association, predicted deleteriousness, and network centrality was a missense variant in the gene encodingD-amino acid oxidase (DAOG131V). Heterologous expression of DAOG131Vin human cells resulted in decreased DAO protein abundance and enzymatic activity. In a knock-in mouse harboring this humanDAOG131Vvariant,DaoG130V/+, we similarly found decreased DAO protein abundance, as well as enhanced stress susceptibility and blunted behavioral responses to pharmacological inhibition ofN-methyl-D-aspartate receptors (NMDARs). RNA sequencing of cerebellar tissue revealed thatDaoG130Vresulted in decreased expression of two gene networks that are enriched for synaptic functions and for genes expressed specifically in Purkinje cells and granule neurons. Similar expression changes in both of these gene networks were also identified in the cerebellum of bipolar disorder cases vs. controls. These findings implicate dysregulation of NMDAR signaling and of gene expression in cerebellar neurons in bipolar disorder pathophysiology and provide insight into its genetic architecture.

One Sentence Summary

Functional studies of a rare hypofunctional variant in the D-amino acid oxidase gene implicate stress susceptibility, NMDA receptor signaling, and cerebellar circuits in risk for bipolar disorder.
African swine fever virus structural protein p17 inhibits cGAS-STING signaling pathway through interacting with STING
Authors: Zheng Wanglong , Xia Nengwen , Luo Jia , Jiang Sen , Zhang Jiajia , Wang Hui , Ao Da , Xu Yulin , Liu Xueliang , Shao Qi , Cao Qi , Zhang Youwen , Chen Nanhua , Zhang Quan , Da Jiansen , Chen Hongjun , Guo Xiaoyu , Zhu Hongfei , Meurens François , Zhu Jianzhong
Published: June 2021

African swine fever (ASF) is highly contagious, causes high mortality in domestic and feral swine, and has a significant economic impact on the global swine industry due to the lack of a vaccine or an effective treatment. African swine fever virus (ASFV) encodes more than 150 polypeptides, which may have intricate and delicate interactions with the host for the benefit of the virus to evade the host’s defenses. However, currently, there is still a lack of information regarding the roles of the viral proteins in host cells. Here, our data demonstrated that the p17, encoded by D117L gene could suppress porcine cGAS-STING signaling pathway, exhibiting the inhibitions of TBK1 and IRF3 phosphorylations, downstream promoter activities, cellular mRNA transcriptions and ISG56 induction, and antiviral responses. Further, we found that p17 was located in endoplasmic reticulum (ER) and Golgi apparatus, and interacted with STING, perturbing it in the recruitment of TBK1 and IKKε. Additionally, it appeared that the transmembrane domain (amino acids 39–59) of p17 could be required for interacting with STING and inhibiting cGAS-STING pathway. Taken together, p17 could inhibit the cGAS-STING pathway through its interaction with STING and interference with STING in the recruitment of TBK1 and IKKε.

Importance

African swine fever (ASF) is a highly contagious disease in domestic and feral swine, posing significant economic impacts on the global swine industry, and the pathogen ASFV is a large icosahedral DNA virus. The innate immune cGAS-STING DNA sensing pathway plays a critical role in sensing invading ASFV and triggering antiviral responses. However, there is still a lack of information regarding the molecular mechanisms of ASFV evasion of the cGAS-STING pathway. We have analyzed the effects of whole genomic open reading frames (ORFs) of ASFV China 2018/1 on the activation of cGAS-STING pathway, and found that p17 was able to inhibit cGAS-STING mediated type I IFN production by targeting STING, altering its capacity to recruit both TBK1 and IKKε. Findings presented here will expand our knowledge on the molecular mechanisms by which ASFV counteracts the antiviral innate immunity and provide deep insights into ASF pathogenesis.
The Movember Global Action Plan 1 (GAP1) - Unique Prostate Cancer Tissue Microarray Resource
Authors: Ouellet Véronique , Erickson Andrew , Wiley Kathy , Morrissey Colm , Berge Viktor , Moreno Carlos S. , Tasken Kristin Austlid , Trudel Dominique , True Lawrence D. , Lewis Michael S. , Svindland Aud , Ertunc Onur , Vidal Igor Damasceno , Osunkoya Adeboye O. , Jones Tracy , Bova G. Steven , Lamminen Tarja , Achtman Ariel H. , Buzza Mark , Kouspou Michelle M ,   GAP1 UTMAs Contributing Investigators, Bigler Steven A , Zhou Xinchun , Freedland Stephen J. , Mes-Masson Anne-Marie , Garraway Isla P. , Trock Bruce J. , Taimen Pekka , Saad Fred , Mirtti Tuomas , Knudsen Beatrice S. , De Marzo Angelo M.
Published: June 2021

Background

The need to better understand the molecular underpinnings of the heterogeneous outcomes of patients with prostate cancer is a pressing global problem and a key research priority for Movember. To address this, the Movember Global Action Plan 1 Unique tissue microarray (GAP1-UTMA) project constructed a set of unique and richly annotated TMAs from prostate cancer samples obtained from multiple institutions across several global locations.

Methods

Three separate TMA sets were built that differ by purpose and disease state.

Results

The intended use of TMA1 is to validate biomarkers that help determine which clinically localized prostate cancers with associated lymph node metastasis have a high risk of progression to lethal castration resistant metastatic disease, and to compare molecular properties of high risk index lesions within the prostate to regional lymph node metastases resected at the time of prostatectomy. TMA2 was designed to address questions regarding risk of castration resistant prostate cancer (CRPC) and response to suppression of the androgen receptor/androgen axis, and characterization of the castration-resistant phenotype. TMA3’s intended use is to assess and better understand the heterogeneity of molecular markers across different anatomic sites in lethal prostate cancer metastases.

Conclusion

The GAP1-UTMA project has succeeded in combining a large set of rare tissue specimens from 501 prostate cancer patients with rich clinical annotation.

Impact

This resource is now available to the prostate cancer community as a tool for biomarker validation to address important unanswered clinical questions around disease progression and response to treatment.
Down-regulation of A Human Herpesvirus 1 (HHV-1) MicroRNA in Infected Cells by Goniothalamin Treatment
Authors: Yip Chee Wai , Md Nor Norefrina Shafinaz , Ibrahim Nazlina
Published: June 2021

Goniothalamin (GTN) has been proven to cause cell cycle arrest and apoptosis in human herpesvirus 1 (HHV-1) infected cells, but interestingly our preliminary transcriptomic analysis revealed other possible modes of action. The data showed that GTN treatment of HHV-1 clinical strain infected cells induced expression of theKLHL24gene that encodes the Kelch-like 24 protein (KLHL24), a transcriptional inhibitor of HHV-1 immediate-early and early genes. An miRNA, hsv1-miR-H27, produced by HHV-1 has also been discovered to control the expression of KLHL24. In order to understand the cause ofKLHL24up-regulation, a time point study was conducted to investigate the effect of GTN onKLHL24and hsv1-miR-H27 expression. Through RT-qPCR analysis, we found that HHV-1 down-regulatedKLHL24significantly (p < 0.05) starting from 12 hpi, while a significant up-regulation (p < 0.05) was observed upon GTN treatment of the infected cells at 4 and 8 hpi. For protein level analysis, significant down-regulation of KLHL24 (p < 0.05) was observed at all time points in HHV-1 infected cells. Intriguingly, treatment with GTN on HHV-1 infected cells showed no significant changes in protein expression compared to cells without any treatment. In addition, the miRNA hsv1-miR-H27 was detected from 16 hpi and treatment with GTN on infected cells showed down-regulation of the miRNA. This was in congruity with the recovery ofKLHL24down-regulation in GTN treated HHV-1 infected cells, confirming that GTN caused down-regulation of hsv1-miR-H27 that governs the expression ofKLHL24. This study provides insights that GTN could be a potential multifaceted antiviral.

Importance

This study provides evidence that GTN possesses a distinct mode of antivirus against HHV-1 compared to currently available antivirals. Our findings showed that GTN caused the down-regulation of a viral miRNA, which inhibits the expression of a cellular protein known as KLHL24. This protein serves as a transcriptional inhibitor of HHV-1 immediate-early and early genes. The down-regulation of this miRNA lead to the up-regulation of KLHL24 and eventually halted HHV-1 replication. With the previously reported antiviral mechanism and the outcome of this study, GTN is a potential multifaceted anti-HHV-1 agent.
Fungal extracellular vesicles are involved in intraspecies intracellular communication
Authors: Bitencourt Tamires A. , Hatanaka Otavio , Pessoni Andre M. , Freitas Mateus S. , Trentin Gabriel , Santos Patrick , Rossi Antonio , Martinez-Rossi Nilce M. , Alves Lysangela L. , Casadevall Arturo , Rodrigues Marcio L. , Almeida Fausto
Published: June 2021

Fungal infections are associated with high mortality rates in humans. The risk of fungal diseases creates the urgent need to broaden the knowledge base regarding their pathophysiology. In this sense, the role of extracellular vesicles (EVs) has been described to convey biological information and participate in the fungal-host interaction process. EVs play many roles, including cellular physiology, responding to environmental cues, mediating a complex circuit of cellular communication in bidirectional crosstalk with other organisms, and the communication between fungal cells has been speculated. This study demonstrated the intra species uptake of EVs in fungi, including Candida albicans, Aspergillus fumigatus, and Paracoccidioides brasiliensis, and the effects triggered by EVs in fungal cells. In C. albicans, we evaluated the involvement of EVs in yeast to hyphae transition, whilst in P. brasiliensis and A. fumigatus the function of EVs as stress transducers was investigated. Both P. brasiliensis and A. fumigatus were exposed to an inhibitor of glycosylation or UV light, respectively. The results demonstrated the role of EVs in regulating the expression of target genes and phenotype features. The EVs treatment induced cellular proliferation and boosted the transition yeast to hyphal transition in C. albicans, while they enhanced stress signals in A. fumigatus and P. brasiliensis, establishing a role for EVs in fungal intra species communication. Thus, fungal EVs regulate the virulence and adaptive traits in fungal interaction systems as potent message effectors, and understanding their effects and mechanism(s) of action could be exploited in antifungal therapies.

Author Summary

Extracellular vesicles (EVs) play an important role in export systems. They act as vehicles for the transference of complex cargoes with broad biological functions, such as proteins, carbohydrates, pigments, nucleic acids, and lipids. EVs can contribute to fungal infection outcomes. The EV content exerts immunomodulatory functions during fungus-host interactions. Furthermore, the participation of EVs in communication between fungal cells has been speculated. This study investigated the capacity of EVs to mediate intra-species in three genera of human pathogenic fungi and established a regulatory function of EVs. We also assessed the features of this regulation by analyzing the cellular morphological aspects of fungi after stimulation with EVs. Our data suggest fungal EVs can function as potent signal mediators that mediate virulence and adaptive responses.
A Prospective Observational Study to Investigate Performance of a Chest X-ray Artificial Intelligence Diagnostic Support Tool Across 12 U.S. Hospitals
Authors: Sun Ju , Peng Le , Li Taihui , Adila Dyah , Zaiman Zach , Melton Genevieve B. , Ingraham Nicholas , Murray Eric , Boley Daniel , Switzer Sean , Burns John L. , Huang Kun , Allen Tadashi , Steenburg Scott D. , Gichoya Judy Wawira , Kummerfeld Erich , Tignanelli Christopher
Published: June 2021

Importance

An artificial intelligence (AI)-based model to predict COVID-19 likelihood from chest x-ray (CXR) findings can serve as an important adjunct to accelerate immediate clinical decision making and improve clinical decision making. Despite significant efforts, many limitations and biases exist in previously developed AI diagnostic models for COVID-19. Utilizing a large set of local and international CXR images, we developed an AI model with high performance on temporal and external validation.

Objective

Investigate real-time performance of an AI-enabled COVID-19 diagnostic support system across a 12-hospital system.

Design

Prospective observational study.

Setting

Labeled frontal CXR images (samples of COVID-19 and non-COVID-19) from the M Health Fairview (Minnesota, USA), Valencian Region Medical ImageBank (Spain), MIMIC-CXR, Open-I 2013 Chest X-ray Collection, GitHub COVID-19 Image Data Collection (International), Indiana University (Indiana, USA), and Emory University (Georgia, USA)

Participants

Internal (training, temporal, and real-time validation): 51,592 CXRs; Public: 27,424 CXRs; External (Indiana University): 10,002 CXRs; External (Emory University): 2002 CXRs

Main Outcome and Measure

Model performance assessed via receiver operating characteristic (ROC), Precision-Recall curves, and F1 score.

Results

Patients that were COVID-19 positive had significantly higher COVID-19 Diagnostic Scores (median .1 [IQR: 0.0-0.8] vs median 0.0 [IQR: 0.0-0.1], p < 0.001) than patients that were COVID-19 negative. Pre-implementation the AI-model performed well on temporal validation (AUROC 0.8) and external validation (AUROC 0.76 at Indiana U, AUROC 0.72 at Emory U). The model was noted to have unrealistic performance (AUROC > 0.95) using publicly available databases. Real-time model performance was unchanged over 19 weeks of implementation (AUROC 0.70). On subgroup analysis, the model had improved discrimination for patients with “severe” as compared to “mild or moderate” disease, p < 0.001. Model performance was highest in Asians and lowest in whites and similar between males and females.

Conclusions and Relevance

AI-based diagnostic tools may serve as an adjunct, but not replacement, for clinical decision support of COVID-19 diagnosis, which largely hinges on exposure history, signs, and symptoms. While AI-based tools have not yet reached full diagnostic potential in COVID-19, they may still offer valuable information to clinicians taken into consideration along with clinical signs and symptoms.
Prior induction of cellular antiviral pathways limits frog virus 3 replication in two permissive Xenopus laevis skin epithelial-like cell lines
Authors: Bui-Marinos Maxwell P. , Todd Lauren A. , Wasson Marie-Claire D. , Morningstar Brandon E. E. , Katzenback Barbara A.
Published: June 2021

Frog virus 3 (FV3) causes mortality in a range of amphibian species. Despite the importance of the skin epithelium as a first line of defence against FV3, the interaction between amphibian skin epithelial cells and FV3 remains largely uncharacterized. Here, we used newly established Xenopus laevis skin epithelial-like cell lines, Xela DS2 and Xela VS2, to study the susceptibility and permissiveness of frog skin epithelial cells to FV3, and the innate immune antiviral and proinflammatory gene regulatory responses of these cells to FV3. Both cell lines are susceptible and permissive to FV3, yet do not exhibit appreciable transcript levels of scavenger receptors recently demonstrated to be used by FV3 for cellular entry. Xela DS2 and Xela VS2 upregulate antiviral and proinflammatory cytokine transcripts in response to poly(I:C) but not to FV3 or UV-inactivated FV3. Poly(I:C) pretreatment limited FV3 replication and FV3-induced cytopathic effects in both cell lines. Thus, Xela DS2 and Xela VS2 can support FV3 propagation, represent in vitro systems to investigate antiviral responses of frog skin epithelial cells, and are novel tools for screening compounds that initiate effective antiviral programs to limit FV3 replication.
Connectivity profile laterality in corticostriatal functional circuitry: a fingerprinting approach
Authors: Korponay Cole , Stein Elliot A , Ross Thomas J
Published: June 2021

An abnormal magnitude of hemispheric difference (i.e. laterality) in corticostriatal circuits is a shared feature of numerous neurodevelopmental and psychiatric disorders. Detailed quantitation and regional localization of corticostriatal laterality in normative samples stands to further the understanding of hemispheric differences in healthy and disease states. Here, we used a fingerprinting approach to quantify “functional connectivity profile laterality” – the overall magnitude by which a voxel’s profile of connectivity with homotopic regions of the ipsilateral and contralateral cortex differs – in the striatum. Laterality magnitude heatmaps revealed “laterality hotspots” – constituting outliers in the voxel-wise distribution –in the right ventrolateral putamen and left central caudate. Findings were replicated in an independent sample, with significant (p<0.05) spatial overlap observed between the location of the laterality hotspots across samples, as measured via Dice coefficients. At both hotspots, a primary driver of overall laterality was the difference in striatal connectivity strength with the right and left pars opercularis of the inferior frontal gyrus. Right and left striatum laterality magnitude maps were found to significantly differ (p<0.05) at the hotspot locations. Moreover, using subjects’ left, but not right, striatum laterality magnitude maps, a support vector machine trained on a discovery sample (n=77) and tested on a replication sample (n=77) significantly predicted (r=0.25, p=0.028) subject performance on a language task, known for its lateralized nature. Laterality magnitude maps remained consistent across different cortical atlas parcellations and did not differ significantly between right-handed and left-handed individuals. In sum, meaningful variation in functional connectivity profile laterality – both spatially within the striatum and across subjects – is evident in corticostriatal circuits. Findings provide a basis to examine corticostriatal connectivity profile laterality in psychiatric illness.
Biallelic loss-of-function OBSCN variants predispose individuals to severe, recurrent rhabdomyolysis
Authors: Cabrera-Serrano Macarena , Caccavelli Laure , Savarese Marco , Vihola Anna , Jokela Manu , Johari Mridul , Capiod Thierry , Madrange Marine , Bugiardini Enrico , Brady Stefen , Quinlivan Rosaline , Merve Ashirwad , Scalco Renata , Hilton-Jones David , Houlden Henry , Aydin Halil , Ceylaner Serdar , Vockley Jerry , Taylor Rhonda L , Goullee Hayley , Ylikallio Emil , Auranen Mari , Tyynismaa Henna , Udd Bjarne , Forrest Alistair RR , Davis Mark R , Bratkovic Drago , Manton Nicholas , Robertson Thomas , McCombe Pamela , Laing Nigel G , Phillips Liza , de Lonlay Pascale , Ravenscroft Gianina
Published: June 2021

Rhabdomyolysis is the acute breakdown of skeletal myofibres in response to an initiating factor, most commonly toxins and over exertion. A variety of genetic disorders predispose to rhabdomyolysis through different pathogenic mechanisms, particularly in patients with recurrent episodes. However, the majority of cases remain without a genetic diagnosis. Here we present six patients who presented with severe and recurrent rhabdomyolysis, usually with onset in the teenage years; other features included a history of myalgia and muscle cramps. We identified ten bi-allelic loss-of-function variants in the gene encoding obscurin (OBSCN) co-segregating with disease. We show reduced expression of OBSCN and loss of obscurin protein in patient muscle. Obscurin is proposed to be involved in SR function and Ca2+ handling. Patient cultured myoblasts appear more susceptible to starvation as evidenced by a greater decreased in SR Ca2+ content compared to control myoblasts. This likely reflects a lower efficiency when pumping Ca2+ back into the SR and/or a decrease in Ca2+ SR storage ability when metabolism is diminished. OSBCN variants have previously been associated with cardiomyopathies. None of the patients presented with a cardiomyopathy and cardiac examinations were normal in all cases in which cardiac function was assessed. There was also no history of cardiomyopathy in first degree relatives, in particular in any of the carrier parents. This cohort is relatively young, thus follow-up studies and the identification of additional cases with bi-allelic null OBSCN variants will further delineate OBSCN-related disease and the clinical course of disease.
Modeling sequence-space exploration and emergence of epistatic signals in protein evolution
Authors: Bisardi Matteo , Rodriguez-Rivas Juan , Zamponi Francesco , Weigt Martin
Published: June 2021

During their evolution, proteins explore sequence space via an interplay between random mutations and phenotypic selection. Here we build upon recent progress in reconstructing data-driven fitness landscapes for families of homologous proteins, to propose stochastic models of experimental protein evolution. These models predict quantitatively important features of experimentally evolved sequence libraries, like fitness distributions and position-specific mutational spectra. They also allow us to efficiently simulate sequence libraries for a vast array of combinations of experimental parameters like sequence divergence, selection strength and library size. We showcase the potential of the approach in re-analyzing two recent experiments to determine protein structure from signals of epistasis emerging in experimental sequence libraries. To be detectable, these signals require sufficiently large and sufficiently diverged libraries. Our modeling framework offers a quantitative explanation for the variable success of recently published experiments. Furthermore, we can fore-cast the outcome of time- and resource-intensive evolution experiments, opening thereby a way to computationally optimize experimental protocols.
Topographically organized representation of space and context in the medial prefrontal cortex
Authors: Sauer Jonas-Frederic , Folschweiller Shani , Bartos Marlene
Published: June 2021

Spatial tuning of neocortical pyramidal cells has been observed in diverse cortical regions and is thought to rely primarily on input from the hippocampal formation. Despite the well-studied hippocampal place code, many properties of the neocortical spatial tuning system are still insufficiently understood. In particular, it has remained unclear how the topography of direct anatomical connections from hippocampus to neocortex affects spatial tuning depth, and whether the dynamics of spatial coding in the hippocampal output region CA1 such as remapping in novel environments is transmitted to the neocortex. Using mice navigating through virtual environments we addressed these questions in the mouse medial prefrontal cortex, which receives direct input from the hippocampus. We find a rapidly emerging prefrontal representation of space in the absence of task rules, which discriminates familiar from novel environments and is reinstated upon re-exposure to the same familiar environment. Topographical analysis revealed a dorso-ventral gradient in the representation of the own position, which runs opposite to the innervation density of hippocampal inputs. Jointly, these results reveal a dynamically emerging and topographically organized prefrontal place code during spontaneous locomotion.

Significance Statement

The neocortex is composed of areas with specialized function (e.g. sensory vs. associational). Despite this functional diversity, emerging evidences suggest that the encoding of space might be a universal feature of cortical circuits. Here, we identified a gradient of spatial tuning depth along the dorso-ventral axis. A complex topography of spatial tuning properties might support a division of labor among medial prefrontal cortical subnetworks to support local circuit computation relevant for the execution of context-dependent behavioral outcomes.