bluuebunny/crossref_metadata_2025 huggingface dataset:
Vestibular mapping assessment in idiopathic sudden sensorineural hearing loss
Authors: Seo Hee Won , Chung Jae Ho , Byun Hayoung , Lee Seung Hwan
Published: September 2021

Objective:

The aim of this study was to investigate patterns of semicircular canal (SCC) and otolith organ dysfunction by vestibular mapping, and to determine the clinical implications of treatment outcomes in idiopathic sudden sensorineural hearing loss (ISSNHL).

Methods:

We retrospectively reviewed 135 consecutive patients diagnosed with ISSNHL from January 2016 to December 2020. Patients underwent video-head impulse tests (vHIT) for each SCC, cervical vestibular-evoked myogenic potential test for the saccules, ocular vestibular-evoked myogenic potential test for the utricles, and hearing tests. Hearing outcomes were evaluated according to the American Academy of Otolaryngology-Head and Neck Surgery criteria and factors associated with prognosis were assessed. We also conducted vestibular mapping assessments and hierarchical cluster analysis.

Results:

Overall, utricular impairment (76, 56.3%) was the most frequent diagnosis in the 135 ISSNHL patients, followed by saccular impairment (59, 43.7%) and posterior SCC impairment (30, 22.2%). The mean number of affected end organs was 1.37 ± 1.24, with higher numbers in the complete recovery group than in the partial/no recovery groups. In a multivariate analysis, higher initial hearing level and abnormal vHIT results in the posterior SCC were associated with poor prognosis in ISSNHL. In hierarchical cluster analysis, horizontal SCC and anterior SCC showed the highest similarity but were in different clusters than posterior SCC, and the saccule and utricle were in separate clusters from the three SCCs.

Conclusions:

The vestibular end organ showed various patterns of dysfunction in patients with ISSNHL. Of the five vestibular end organs, only abnormal posterior SCC was associated with poor prognosis for hearing recovery.
Comparative Effectiveness and Functional Outcome of C2 Dome-like Expansive Versus C2 Expansive Open-door Laminoplasty for Upper Cervical Ossification of the Posterior Longitudinal Ligament
Authors: Yu Chengcheng , Wu Yinan , Zhang Zengjie , Zhang Ning , Yu Xinning , Li Fangcai , Chen Weishan , Chen Qixin , Li Wanli
Published: September 2021

Study Design.

Retrospective Cohort Study.

Objectives.

This study compared the function and radiographical outcomes of the patients who underwent C2 dome-like expansive laminoplasty to those C2 expansive open-door laminoplasty for the treatment of OPLL with C2 involved.

Summary of Background Data.

There are few comparative studies of these two surgical methods. C2 dome-like and C2 expansive open-door laminoplasty are posterior approaches for posterior longitudinal ligament ossification with C2 level and above.

Methods.

This study performed a retrospective cohort analysis of 59 patients with OPLL up to C2 which cause compression symptoms. 31 patients underwent C2 dome-like expansive laminoplasty with C3-7 expansive open-door laminoplasty (Group Dom) and 28 underwent C2-7 expansive open-door laminoplasty (Group Exp). The preoperative and postoperative space available for cord (SAC) of C2 segment, cervical curvature index of C2-7, C2-7 range of motion, Japanese orthopedic association (JOA) score, visual analog scale (VAS) score, and neck disability index (NDI) were used to assess clinical out-comes and statistically analyzed.

Results.

The cervical curvature index, JOA score, and NDI significantly changed at the final follow-up in two groups with no significant intergroup differences. There were no significant differences in preoperative SAC and VAS between the two groups. At the final follow-up, the SAC of C2/3 in Group Exp was significantly larger than Group Dom, while the VAS and range of motion of Group Dom became significantly better than Group Exp.

Conclusion.

The C2 dome-like expansive laminoplasty can reduce postoperative neck pain more obviously and achieve better cervical curvature. C2 expansive open-door laminoplasty can get more adequate decompression in the spinal canal, which may be recommend to the patients with OPLL occupying more than 50% of the vertebral canal at C2/3, or with developmental spinal stenosis.

Level of Evidence.

3
Late Awakening Is Common in Settings Without Withdrawal of Life-Sustaining Therapy in Out-of-Hospital Cardiac Arrest Survivors Who Undergo Targeted Temperature Management*
Authors: Lee Dong Hun , Cho Yong Soo , Lee Byung Kook , Lee Hyoung Youn , Jeung Kyung Woon , Jung Yong Hun , Park Kyu Nam , Kim Youn-Jung , Chae Minjung Kathy , Seo Dong-Woo ,   on behalf of the Korean Hypothermia Network (KORHN) Investigators
Published: September 2021

OBJECTIVES:

We investigated awakening time and characteristics of awakening compared nonawakening and factors contributing to poor neurologic outcomes in out-of-hospital cardiac arrest survivors in no withdrawal of life-sustaining therapy settings.

DESIGN:

Retrospective analysis of the Korean Hypothermia Network Pro registry.

SETTING:

Multicenter ICU.

PATIENTS:

Adult (≥ 18 yr) comatose out-of-hospital cardiac arrest survivors who underwent targeted temperature management at 33–36°C between October 2015 and December 2018.

INTERVENTIONS:

None.

MEASUREMENTS AND MAIN RESULTS:

We measured the time from the end of rewarming to awakening, defined as a total Glasgow Coma Scale score greater than or equal to 9 or Glasgow Coma Scale motor score equals to 6. The primary outcome was awakening time. The secondary outcome was 6-month neurologic outcomes (poor outcome: Cerebral Performance Category 3–5). Among 1,145 out-of-hospital cardiac arrest survivors, 477 patients (41.7%) regained consciousness 30 hours (6–71 hr) later, and 116 patients (24.3%) awakened late (72 hr after the end of rewarming). Young age, witnessed arrest, shockable rhythm, cardiac etiology, shorter time to return of spontaneous circulation, lower serum lactate level, absence of seizures, and multisedative requirement were associated with awakening. Of the 477 who woke up, 74 (15.5%) had poor neurologic outcomes. Older age, liver cirrhosis, nonshockable rhythm, noncardiac etiology, a higher Sequential Organ Failure Assessment score, and higher serum lactate levels were associated with poor neurologic outcomes. Late awakeners were more common in the poor than in the good neurologic outcome group (38/74 [51.4%] vs 78/403 [19.4%]; p < 0.001). The awakening time (odds ratio, 1.005; 95% CIs, 1.003–1.008) and late awakening (odds ratio, 3.194; 95% CIs, 1.776–5.746) were independently associated with poor neurologic outcomes.

CONCLUSIONS:

Late awakening after out-of-hospital cardiac arrest was common in no withdrawal of life-sustaining therapy settings and the probability of awakening decreased over time.
Lower melanoma pulmonary metastatic burden in obese mice: role of FGF-21
Authors: Fonseca Magda , Soares Raquel , Coelho Pedro
Published: September 2021

Obesity is a risk factor for malignant melanoma. The lungs are main target organs for metastization and their immune response is a key modulator of this mechanism. The concept that the metastatic potential of some types of cancer is reduced or inhibited by obesity, known as the obesity paradox, drives major concerns on the prognosis of metastasized patients. The aim of this study was to investigate how high-fat diet (HFD)-induced obesity affects melanoma metastization. C57Bl6/J mice were fed with HFD or standard diet for 180 days and inoculated intravenously with B16F10 melanoma cells. Upon 21 days of inoculation, lung tissue of overweight and lean mice was assessed for histology and immunohistochemistry assays. Adipokine antibody arrays were performed in mice serum. In vitro RAW 264.7 macrophage cultures were established and incubated with FGF-21 and/or lipopolysaccharide (LPS). Conditioned media was added to B16F10 cells for viability quantification. HFD-fed mice presented a reduced number of metastases with lower proliferative rates. The high content of inflammatory foci observed in noninoculated obese mice was significantly decreased upon B16F10 inoculation, concurrent with a slight fibrosis reduction. Plasma levels of fibroblast growth factor-21 (FGF-21), an endocrine regulator, were elevated in noninoculated HFD mice and the expression of FGF receptor 1 (FGFR-1) was significantly upregulated after inoculation. FGF-21 reduced melanoma viability in LPS-stimulated macrophages. Altogether, these findings suggest that higher amounts of FGF-21 are able to counterbalance the proinflammatory effects associated with obesity, protecting the lungs from melanoma metastization.
CircRNA MFACR Is Upregulated in Myocardial Infarction and Downregulates miR-125b to Promote Cardiomyocyte Apoptosis Induced by Hypoxia
Authors: Wang Shujuan , Li Long , Deng Weijie , Jiang Minhua
Published: September 2021

Circular RNA (circRNA) MFACR promotes cardiomyocyte death that leads to myocardial infarction (MI). This study aimed to explore the role of MFACR in MI. T-qPCRs were performed to measure the expression levels of MFACR and miR-125b in plasma samples from both MI patients (n = 61) and healthy controls (n = 61). MFACR or miR-125b was overexpressed in AC16 cells (cardiomyocytes) to explore the interaction between them. Methylation of miR-125b gene in cells with the overexpression of MFACR was detected by methylation-specific PCR. Cell apoptosis after transfections was detected by cell apoptosis assay. MI model was constructed to further demonstrate the effect of MFACR in vivo. We found that MFACR was upregulated in MI and inversely correlated with miR-125b. In AC16 cells, hypoxia treatment increased the expression levels of MFACR and decreased the expression levels of miR-125b. In AC16 cells, overexpression of MFACR decreased the expression levels of miR-125b and increased the methylation of miR-125b gene. Under hypoxia treatment, overexpression of MFACR increased AC16 cell apoptosis, and overexpression of miR-125b decreased cell apoptosis. In addition, overexpression of miR-125b reversed the effects of overexpression of MFACR on cell apoptosis both in vivo and in vitro.
Combined Usage of Trimetazidine With 3-Bromopyruvate May Lead to Cardiotoxicity by Activating Oxidative Stress and Apoptosis in Rats
Authors: Zheng Min , Zhan Chengchuang , Bai Nan , Bai Juncai , Nie Chaoqun , Chi Jing , Ding Xue , Liu Jiaren , Yang Wei
Published: September 2021

The energy used by the heart is generated mainly by the metabolism of fatty acids and glucose. Trimetazidine (TMZ) inhibits fatty acid metabolism and is used for the treatment of heart diseases such as heart failure. 3-Bromopyruvate (3-BrPA) can suppress glucose metabolism, and it is considered a promising candidate agent for tumor therapy. Because TMZ and 3-BrPA can separately inhibit the 2 main cardiac energy sources, it is necessary to investigate the effects of 3-BrPA combined with TMZ on the heart. Forty male Wistar rats were randomly divided into 4 groups: a control group, a TMZ group, a 3-BrPA group, and a 3-BrPA + TMZ group. Weight was recorded every day, and echocardiography was performed 14 days later. Heart function, the levels of adenosine triphosphate, oxidative stress-related factors (ROS, glutathione, oxidized glutathione, malondialdehyde, superoxide dismutase and total antioxidant capacity), and apoptosis in heart tissues were assessed to evaluate the effects of 3-BrPA and TMZ on the heart. In our study, no obvious changes occurred in the 3-BrPA group or the TMZ group compared with the control group. The combination of 3-BrPA and TMZ worsened heart function, decreased adenosine triphosphate levels, and increased oxidative stress and myocardial apoptosis. In conclusion, 3-BrPA and TMZ are not recommended for concurrent use.
Examining the Use of Web-Based Health Education and Information Among Ambulatory Care Clinic Diabetic Patients
Authors: Robinson Tanya D. , Pollard Theresa , Sarver Wendy L.
Published: September 2021

Web-based health education provides access to information and better coordination of care. Demographic and geographical factors may impact use and effectiveness of these services. The purpose of this study was to identify factors associated with use of web-based health education programs among diabetic patients at ambulatory clinics of a safety-net hospital. This was a retrospective chart review. Total sample size was 300. Patients who completed a web-based video were younger, Caucasian, living outside inner city core, users of patient portal, and more likely to complete annual diabetic eye examination. Web-based education may empower patients to manage health conditions and improve health outcomes. Health care organizations must consider barriers to use of these tools.
Can 3D artificial intelligence models outshine 2D ones in the detection of intracranial metastatic tumors on magnetic resonance images?
Authors: Sun Ying-Chou , Hsieh Ang-Ting , Fang Ssu-Ting , Wu Hsiu-Mei , Kao Liang-Wei , Chung Wen-Yuh , Chen Hung-Hsun , Liou Kang-Du , Lin Yu-Shiou , Guo Wan-Yuo , Lu Henry Horng-Shing
Published: September 2021

Background:

This study aimed to compare the prediction performance of two-dimensional (2D) and three-dimensional (3D) semantic segmentation models for intracranial metastatic tumors with a volume ≥ 0.3 mL.

Methods:

We used postcontrast T1 whole-brain magnetic resonance (MR), which was collected from Taipei Veterans General Hospital (TVGH). Also, the study was approved by the institutional review board (IRB) of TVGH. The 2D image segmentation model does not fully use the spatial information between neighboring slices, whereas the 3D segmentation model does. We treated the U-Net as the basic model for 2D and 3D architectures.

Results:

For the prediction of intracranial metastatic tumors, the area under the curve (AUC) of the 3D model was 87.6% and that of the 2D model was 81.5%.

Conclusion:

Building a semantic segmentation model based on 3D deep convolutional neural networks might be crucial to achieve a high detection rate in clinical applications for intracranial metastatic tumors.
Latinx Sexual Minority Men's Access to HIV and Behavioral Health Services in South Florida During COVID-19: A Qualitative Study of Barriers, Facilitators, and Innovations
Authors: Harkness Audrey , Weinstein Elliott R. , Atuluru Pranusha , Mayo Daniel , Vidal Ronald , Rodríguez-Díaz Carlos E. , Safren Steven A.
Published: September 2021

Despite the availability of HIV prevention and treatment tools, HIV disparities continue to affect Latinx sexual minority men (LSMM). Behavioral health concerns further exacerbate HIV disparities among LSMM. This study used rapid qualitative analysis to understand factors influencing LSMM's access to HIV and behavioral health services during coronavirus disease 2019 (COVID-19). Participants included LSMM with (n = 10) and without HIV (n = 10). The analysis identified 15 themes. Themes revealed that LSMM's access was disrupted by new and worsening barriers resulting from COVID-19, such as anxiety about COVID-19 exposure, confusion and disruptions to services, and new structural challenges. Other themes highlight positive changes, such as telehealth and relaxed clinic protocols, which enhanced LSMM's access to services during COVID-19. The findings suggest the need for HIV and behavioral health clinics to innovate and ensure LSMM's continued access to services during and beyond COVID-19.
Potential of Medical Management to Mitigate Suction Events in Ventricular Assist Device Patients
Authors: Rocchi Maria , Fresiello Libera , Jacobs Steven , Dauwe Dieter , Droogne Walter , Meyns Bart
Published: September 2021

Ventricular suction is a common adverse event in ventricular assist device (VAD) patients and can be due to multiple underlying causes. The aim of this study is to analyze the potential of different therapeutic interventions to mitigate suction events induced by different pathophysiological conditions. To do so, a suction module was embedded in a cardiovascular hybrid (hydraulic-computational) simulator reproducing the entire cardiovascular system. An HVAD system (Medtronic) was connected between a compliant ventricular apex and a simulated aorta. Starting from a patient profile with severe dilated cardiomyopathy, four different pathophysiological conditions leading to suction were simulated: hypovolemia (blood volume: −900 ml), right ventricular failure (contractility −70%), hypotension (systemic vascular resistance: 8.3 Wood Units), and tachycardia (heart rate:185 bpm). Different therapeutic interventions such as volume infusion, ventricular contractility increase, vasoconstriction, heart rate increase, and pump speed reduction were simulated. Their effects were compared in terms of general hemodynamics and suction mitigation. Each intervention elicited a different effect on the hemodynamics for every pathophysiological condition. Pump speed reduction mitigated suction but did not ameliorate the hemodynamics. Administering volume and inducing a systemic vasoconstriction were the most efficient interventions in both improving the hemodynamics and mitigating suction. When simulating volume infusion, the cardiac powers increased, respectively, by 38%, 25%, 42%, and 43% in the case of hypovolemia, right ventricular failure, hypotension, and tachycardia. Finally, a management algorithm is proposed to identify a therapeutic intervention suited for the underlying physiologic condition causing suction.
Is Ignorance Bliss? Examining the Effect of News Media Exposure on Anxiety and Depression During the COVID-19 Pandemic
Authors: Hoyt Danielle L. , Hiserodt Michele , Gold Alexandra K. , Milligan Megan A. , Otto Michael W.
Published: September 2021

There has been a widespread increase in affective disorders after the emergence of the COVID-19 pandemic. In the current study, we investigated the effects of exposure to and perceived accuracy of news media and demographic characteristics on anxiety and depressive symptoms. We conducted an online survey of US adults (N = 480) using hierarchical linear regression models to understand the predictive roles of duration and frequency of news media exposure, as well as the perceived accuracy of COVID-19 portrayal by the news media, on anxiety and depression. Increased exposure duration predicted greater anxiety, and decreased frequency of exposure and perceived overreaction in the news media coverage of COVID-19 were linked to greater anxiety and depression. Perceived accuracy moderated the relationship of exposure frequency to both affective outcomes. Accordingly, our data support the importance of adequate levels of accurate and trusted information to help mitigate the overall mental health burden of the pandemic.
Expanded use of tranexamic acid is safe and decreases transfusion rates in patients with geriatric hip fractures
Authors: Kahan Joseph B. , Morris Jensa , Li Don , Moran Jay , O’Connor Mary I.
Published: September 2021

Objectives:

To determine the effect of a standardized tranexamic acid (TXA) protocol on red blood cell transfusions and adverse events in fragility hip fracture patients.

Design:

Retrospective cohort study.

Setting:

Academic Tertiary Care Center.

Patients/Participants:

Series of 209 patients with fragility hip fractures treated operatively from April 1, 2019 to September 30, 2019.

Intervention:

Eligible patients received 4 intravenous doses of TXA. Some patients missed doses and only received between 1 and 3 doses of TXA: Ineligible patients received no TXA. Patients with medical conditions precluding the use of TXA were deemed ineligible: allergy to TXA; creatinine clearance <30 mL/min; active malignancy; vascular event in the past year; anticoagulant use; fracture > 48 hours prior to presentation.

Main Outcome Measures:

Red blood cell transfusion; major adverse vascular events; minor drug related adverse events.

Results:

Patients who received all 4 doses of TXA (n = 70) had a significantly lower transfusion rate compared to those who did not receive any TXA (7.1% vs 28.1%, P = .003). There were no significant differences in the number of major or minor adverse events between the 2 groups.

Conclusions:

The use of a standardized TXA protocol of 4 doses significantly decreases transfusion rates in eligible patients undergoing operative intervention for fragility hip fracture without an increase in major or minor adverse events. These findings are even more pronounced in patients with decreased preoperative hemoglobin.

Level of Evidence: Prognostic Level III
Treatment of a Case of Toe Hair-Thread Tourniquet Syndrome With Hirasè Technique
Authors: Tamborini Federico , Sallam Davide , Maggiulli Francesca , Pellegatta Igor , Corno Martina , Cherubino Mario , Valdatta Luigi
Published: September 2021

Hair-thread tourniquet syndrome (HTTS) is an uncommon condition that affects mostly babies, usually a few months old. It happens when a strand of hair or cloth fiber encircles an appendage causing a condition of total or subtotal ischemia (West J Med 1976;125:335–336). This condition has been described several times in the recent literature. Appendages involved include toes, fingers, genitalia, uvula, and neck (N Engl J Med 1965;273:866–867). The mechanism of injury usually involves the fiber cutting the skin deeply through soft tissues, veins, and arteries. As HTTS occurs in small babies and hidden parts of the body, sometimes this event can be very difficult to detect and irritability may be the only symptom. The treatment consists of releasing the circumferential constriction and restoring the arteriovenous flow also with microsurgical techniques if vessel interruption is present. Unfortunately, the fiber or the thread often penetrates so deep that, once an HTTS is recognized, it may be very challenging to identify and trim. The authors present a case of HTTS of the second toe of the right foot in a 2-month-old baby treated with surgical release and Hirasè technique. After the thread was successfully cut and removed, the forefoot was covered with aluminum foil, and a bag with ice was immediately put all around. After 3 days, we observed a complete survival of the toe without any sign of necrosis. Later control at 6 months showed complete restitutio ad integrum of the affected digit with a normal perfusion and absence of any onychopathy. Hirasè technique represents a simple, safe, and low-cost option of treatment for HTTS.
Incidental Detection of Sacral Insufficiency Fracture on 68Ga-FAPI PET/MR
Authors: Lv Yuhu , Lan Xiaoli , Qin Chunxia
Published: September 2021

A 61-year-old woman with low-set rectal adenocarcinoma (cT4bN1Mx) received radiotherapy and chemotherapy for 4 months, and then she underwent 18F-FDG PET/CT and 68Ga-FAPI PET/MR. Obviously increased 68Ga-FAPI uptake was unexpectedly revealed on both sides of the sacrum with low 18F-FDG uptake, which was diagnosed as insufficiency fracture based on the imaging features, advanced patient age, and radiotherapy history. The possibility of insufficiency fracture should be considered when accidental, symmetrically increased sacral 68Ga-FAPI uptake appears in cancer patients, and differential diagnosis should be carefully made.
Colin James Pennycuick. 11 June 1933—9 December 2019
Authors: Spedding Geoffrey , Hedenström Anders
Published: September 2021

Colin Pennycuick was almost single-handedly responsible for the successful, and continuing, merger of the engineering and mathematical sciences of aerodynamics and flight mechanics with ornithology, ecology and bird flight behaviour. He developed a mathematical/ aerodynamical/ecological model of bird flight that could explain and predict bird body and wing shapes and sizes, and hence flight behaviour over a broad range of length- and time-scales, for real birds. He sought to bring rigorous quantitative methods to the people, and insisted that no matter how complex and sophisticated a theoretical model may be, unless it showed some improvement and advance in its practical utility, then it was of questionable value. He similarly insisted that model predictions be testable, and that results be openly and quantifiably given. His approach was marked by two distinct characteristics: first he pioneered the use of small aircraft and powered and unpowered gliders to follow soaring and migrating birds in their natural environment, exploiting his top-level pilot skills; second, he invented, designed and built novel instrumentation for making hitherto unheard-of laboratory and field measurements. The most well-known were his tilting wind tunnels, in which birds and bats could be trained to perform steady gliding flight. His intellectually and geographically-broad range of interests and contacts led to his being a giant influence in theoretical and practical bird flight mechanics and behaviour, one that is likely to stay with us for many decades.
Emergence of SARS-CoV-2 Resistance with Monoclonal Antibody Therapy
Authors: Choudhary Manish C. , Chew Kara W. , Deo Rinki , Flynn James P. , Regan James , Crain Charles R. , Moser Carlee , Hughes Michael , Ritz Justin , Ribeiro Ruy M. , Ke Ruian , Dragavon Joan A. , Javan Arzhang C. , Nirula Ajay , Klekotka Paul , Greninger Alexander L. , Fletcher Courtney V. , Daar Eric S. , Wohl David A. , Eron Joseph J. , Currier Judith S. , Parikh Urvi M. , Sieg Scott F. , Perelson Alan S. , Coombs Robert W. , Smith Davey M. , Li Jonathan Z. ,   for the ACTIV-2/A5401 Study Team
Published: September 2021

Resistance mutations to monoclonal antibody (mAb) therapy has been reported, but in the non-immunosuppressed population, it is unclear if in vivo emergence of SARS-CoV-2 resistance mutations alters either viral replication dynamics or therapeutic efficacy. In ACTIV-2/A5401, non-hospitalized participants with symptomatic SARS-CoV-2 infection were randomized to bamlanivimab (700mg or 7000mg) or placebo. Treatment-emergent resistance mutations were significantly more likely detected after bamlanivimab 700mg treatment than placebo (7% of 111 vs 0% of 112 participants, P=0.003). There were no treatment-emergent resistance mutations among the 48 participants who received bamlanivimab 7000mg. Participants with emerging mAb resistant virus had significantly higher pre-treatment nasopharyngeal and anterior nasal viral load. Intensive respiratory tract viral sampling revealed the dynamic nature of SARS-CoV-2 evolution, with evidence of rapid and sustained viral rebound after emergence of resistance mutations, and worsened symptom severity. Participants with emerging bamlanivimab resistance often accumulated additional polymorphisms found in current variants of concern/interest and associated with immune escape. These results highlight the potential for rapid emergence of resistance during mAb monotherapy treatment, resulting in prolonged high level respiratory tract viral loads and clinical worsening. Careful virologic assessment should be prioritized during the development and clinical implementation of antiviral treatments for COVID-19.
Localising Vaccination Services: Qualitative Insights on an Orthodox Jewish Collaboration with Public health during the UK coronavirus Vaccine Programme
Authors: Kasstan Ben , Mounier-Jack Sandra , Letley Louise , Gaskell Katherine M , Roberts Chrissy H , Stone Neil RH , Lal Sham , Eggo Rosalind M , Marks Michael , Chantler Tracey
Published: September 2021

Ethnic and religious minorities have been disproportionately affected by the SARS-CoV-2 pandemic and are less likely to accept coronavirus vaccinations. Orthodox (Haredi) Jewish neighbourhoods in England experienced high incidences of SARS-CoV-2 in 2020-21 and measles outbreaks (2018-19) due to suboptimal childhood vaccination coverage. The objective of our study was to explore how the coronavirus vaccination programme (CVP) was co-delivered between public health services and an Orthodox Jewish health organisation.

Methods included 28 semi-structured interviews conducted virtually with public health professionals, community welfare and religious representatives, and household members. We examined CVP delivery from the perspectives of those involved in organising services and vaccine beneficiaries. Interview data was contextualised within debates of the CVP in Orthodox (Haredi) Jewish print and social media. Thematic analysis generated five considerations: i) Prior immunisation-related collaboration with public health services carved a role for Jewish health organisations to host and promote coronavirus vaccination sessions, distribute appointments, and administer vaccines ii) Public health services maintained responsibility for training, logistics, and maintaining vaccination records; iii) The localised approach to service delivery promoted vaccination in a minority with historically suboptimal levels of coverage; iv) Co-delivery promoted trust in the CVP, though a minority of participants maintained concerns around safety; v) Provision of CVP information and stakeholders’ response to situated (context-specific) challenges and concerns.

Drawing on this example of CVP co-delivery, we propose that a localised approach to delivering immunisation programmes could address service provision gaps in ways that involve trusted community organisations. Localisation of vaccination services can include communication or implementation strategies, but both approaches involve consideration of investment, engagement and coordination, which are not cost-neutral. Localising vaccination services in collaboration with welfare groups raises opportunities for the on-going CVP and other immunisation programmes, and constitutes an opportunity for ethnic and religious minorities to collaborate in safeguarding community health.
Vascular flow simulations using SimVascular and OpenFOAM
Authors: Yogeswaran Swetha , Liu Fei
Published: September 2021

Applications of computational fluid dynamics (CFD) techniques to aid in the diagnosis and treatment of cardiovascular disease have entered the research domain in recent years, due to their ability to provide valuable patient-specific information without risks associated with highly invasive procedures. SimVascular [1] [2] is an open-source software which allows streamlined processing and CFD blood flow analysis of medical imaging data. OpenFOAM [3] is a proven open-source software which allows for versatile modeling of various fluid dynamics phenomena. In this study, both SimVascular and OpenFOAM simulations are set up with identical computational mesh, similar numerical schemes, boundary conditions, and material properties, to model blood flow in the coronary artery of a 10 year old patient with Coarctation of the Aorta (CoA) who underwent end-to-side anastomosis. Difference in the flow fields such as flow rate, pressure, vorticity, and wall shear stress between SimVascular and OpenFOAM are analyzed. Similar results are obtained in both simulations up to a certain model time, before the results become drastically different. Both the similarities and differences are documented and discussed.
Bacterial and Fungal Co-Infections among ICU COVID-19 Hospitalized Patients in a Palestinian Hospital: Incidence and Antimicrobial Stewardship
Authors: Naseef Hani A. , Mohammad Ula , Al-Shami Nimeh , Sahoury Yousef , Abukhalil Abdallah D. , Farraj Mohammad
Published: September 2021

Diagnosis of co-infections with multiple pathogens among hospitalized COVID-19 patients can be jointly challenging and very essential for appropriate treatment, shortening hospital stay and preventing antimicrobial resistance. This study proposes to investigate the burden of bacterial and fungal co-infections outcomes on COVID-19 patients. It is a single centre cross-sectional study of hospitalized COVID-19 patients at Beit-Jala hospital in Palestine. The study included 321 hospitalized patients admitted to the ICU between June 2020 and March 2021 aged ≥ 20 years, with a confirmed diagnosis of COVID-19 via RT-PCR conducted on a nasopharyngeal swab. The patient’s information was gathered using graded data forms from electronic medical reports. The diagnosis of bacterial and fungal infection was proved through the patient’s clinical presentation and positive blood or sputum culture results. All cases had received empirical antimicrobial therapy before the ICU admission, and different regimens during the ICU stay. The rate of bacterial co-infection was 51.1%, mainly from gram-negative isolates (Enterobacter species and K.pneumoniae). The rate of fungal co-infection caused by A.fumigatus was 48.9%, and the mortality rate was 8.1%. However, it is unclear if it had been attributed to SARS-CoV-2 or coincidental.
Causal reasoning over knowledge graphs leveraging drug-perturbed and disease-specific transcriptomic signatures for drug discovery
Authors: Domingo-Fernández Daniel , Gadiya Yojana , Patel Abhishek , Mubeen Sarah , Rivas-Barragan Daniel , Diana Chris W. , Misra Biswapriya B. , Healey David , Rokicki Joe , Colluru Viswa
Published: September 2021

Network-based approaches are becoming increasingly popular for drug discovery as they provide a systems-level overview of the mechanisms underlying disease pathophysiology. They have demonstrated significant early promise over other methods of biological data representation, such as in target discovery, side effect prediction and drug repurposing. In parallel, an explosion of -omics data for the deep characterization of biological systems routinely uncovers molecular signatures of disease for similar applications. Here, we present RPath, a novel algorithm that prioritizes drugs for a given disease by reasoning over causal paths in a knowledge graph (KG), guided by both drug-perturbed as well as disease-specific transcriptomic signatures. First, our approach identifies the causal paths that connect a drug to a particular disease. Next, it reasons over these paths to identify those that correlate with the transcriptional signatures observed in a drug-perturbation experiment, and anti-correlate to signatures observed in the disease of interest. The paths which match this signature profile are then proposed to represent the mechanism of action of the drug. We demonstrate how RPath consistently prioritizes clinically investigated drug-disease pairs on multiple datasets and KGs, achieving better performance over other similar methodologies. Furthermore, we present two applications showing how one can deconvolute the predictions made by RPath as well as predict novel targets. Finally, we have made the source code and data publicly available at https://github.com/enveda/RPath.
Maximized redundant and synergistic information transfers predict the rise in the output gene expression noise in a generic class of coherent type-1 feed-forward loop networks
Authors: Aziz Momin Md Sorique , Biswas Ayan
Published: September 2021

We apply the partial information decomposition principle to a generic coherent type-1 feed-forward loop (C1-FFL) motif with tunable direct and indirect transcriptional regulations of the output gene product and quantify the redundant, synergistic, and unique information transfers from the regulators to their target output species. Our results which are obtained within the small-noise regime of a Gaussian framework reveal that the redundant and synergistic information transfers are antagonistically related to the output noise. Most importantly, these two information flavors are maximized prior to the minimization and subsequent growth of the output noise. Therefore, we hypothesize that the dynamic information redundancy and synergy maxima may possibly be utilized as efficient statistical predictors to forecast the increasing trend of the fluctuations associated with the output gene expression dynamics in the C1-FFL class of network motifs. Our core analytical finding is supported by exact stochastic simulation data and furthermore validated for a diversified repertoire of biologically plausible parameters. Since, the output gene product serves essential physiological purposes in the cell, a predictive estimate of its noise level is supposed to be of considerable biophysical utility.
Hobotnica: exploring molecular signature quality
Authors: Stupnikov Alexey , Sizykh Alexey , Favorov Alexander , Afsari Bahman , Wheelan Sarah , Marchionni Luigi , Medvedeva Yulia A.
Published: September 2021

A Molecular Features Set (MFS), is a result of vast diversity of bioinformatics pipelines. In case when MFS is used for further analysis to distinguish between phenotypes, it is often referred to as a signature. Lack of the “gold standard” for most experimental data modalities makes it hard to provide valid estimation for a particular MFS’s quality. Yet, this goal can partially be achieved by analyzing inner-sample Distance Matrix (DM) and their power to distinguish between phenotypes.

The quality of a DM can be assessed by summarizing its power to quantify the differences of inner-phenotype and outer-phenotype distances. This estimation of the DM quality can be construed as a measure of the MFS’s quality.

Here we propose Hobotnica, an approach to estimate MFS’s quality by their ability to stratify data, and assign them significance scores, that allows for collating various signatures and comparing their quality for contrasting groups.
Angiotensin II Inhibits the A-type K+ Current of Hypothalamic Paraventricular Nucleus Neurons in Rats with Heart Failure: Role of MAPK-ERK1/2 Signaling
Authors: Roy Ranjan K. , Ferreira-Neto Hildebrando Candido , Felder Robert B. , Stern Javier E.
Published: September 2021

ANGII-mediated sympathohumoral activation constitutes a key pathophysiological mechanism in heart failure (HF). While the hypothalamic paraventricular nucleus (PVN) is recognized as a major site mediating ANGII effects in HF, the precise mechanisms by which ANGII influences sympathohumoral outflow from the PVN remain unknown. ANGII activates the ubiquitous intracellular MAPK signaling cascades and recent studies revealed a key role for ERK1/2 MAPK signaling in ANGII-mediated sympathoexcitation in HF rats. Importantly, ERK1/2 was reported to inhibit the transient outward potassium current (IA) in hippocampal neurons. Given that IA is a critical determinant of the PVN neuronal excitability, and that downregulation of IA in the brain has been reported in cardiovascular disease states, including HF, we investigated here whether ANGII modulates IA in PVN neurons via the MAPK-ERK pathway, and, whether these effects are altered in HF rats. Patch-clamp recordings from identified magnocellular neurosecretory (MNNs) and presympathetic (PS) PVN neurons revealed that ANGII inhibited IA in both PVN neuronal types, both in sham and HF rats. Importantly, ANGII effects were blocked by inhibiting MAPK-ERK signaling as well as by inhibiting EGFR, a gateway to MAPK-ERK signaling. While no differences in basal IA magnitude were found between sham and HF rats under normal conditions, MAPK-ERK blockade resulted in significantly larger IA in both PVN neuronal types in HF rats. Taken together, our studies show that ANGII-induced ERK1/2 activity inhibits IA and increases the excitability of presympathetic and neuroendocrine PVN neurons, contributing to the neurohumoral overactivity than promotes progression of the HF syndrome.

GRAPHICAL ABSTRACT
Injury-induced Erk1/2 signaling enhances Ca2+ activity and is necessary for regeneration of spinal cord and skeletal muscle
Authors: Levin Jacqueline B. , Borodinsky Laura N.
Published: September 2021

The transition of stem cells from quiescence to proliferation enables tissues to self-repair. The signaling mechanisms driving these stem-cell-status decisions are still unclear. Ca2+ and the extracellular signal-regulated kinase (Erk1/2) are two signaling pathways that have the potential to coordinate multiple signals to promote a specific cellular response. They both play important roles during development but their roles during regeneration are not fully deciphered. Here we show in Xenopus laevis larvae that both Ca2+ and Erk1/2 signaling pathways are activated after tail amputation. In response to injury, we find that Erk1/2 signaling is activated in neural and muscle stem cells and is necessary for spinal cord and skeletal muscle regeneration. Finally, we show in vivo that Erk1/2 action is necessary for an injury-induced increase in intracellular store-dependent Ca2+ dynamics in skeletal muscle-associated tissues but that in spinal cord, injury increases Ca2+ influx-dependent Ca2+ activity independent of Erk1/2 signaling. This study suggests that precise temporal and tissue-specific activation of Ca2+ and Erk1/2 pathways is essential for regulating tissue regeneration.
Brain stimulation boosts perceptual learning by altering sensory GABAergic plasticity and functional connectivity
Authors: Karlaftis Vasilis M , Frangou Polytimi , Higgins Cameron , Vidaurre Diego , Ziminski Joseph J , Stagg Charlotte J , Emir Uzay E , Kourtzi Zoe
Published: September 2021

Interpreting cluttered scenes —a key skill for successfully interacting with our environment— relies on our ability to select relevant sensory signals while filtering out noise. Training is known to improve our ability to make these perceptual judgements by altering local processing in sensory brain areas. Yet, the brain-wide network mechanisms that mediate our ability for perceptual learning remain largely unknown. Here, we combine transcranial direct current stimulation (tDCS) with multi-modal brain measures to modulate cortical excitability during training on a signal-in-noise task (i.e. detection of visual patterns in noise) and test directly the link between processing in visual cortex and its interactions with decision-related areas (i.e. posterior parietal cortex). We test whether brain stimulation alters inhibitory processing in visual cortex, as measured by magnetic resonance spectroscopy (MRS) of GABA and functional connectivity between visual and posterior parietal cortex, as measured by resting state functional magnetic resonance imaging (rs-fMRI). We show that anodal tDCS during training results in faster learning and decreased GABA+ during training, before these changes occur for training without stimulation (i.e. sham). Further, anodal tDCS decreases occipito-parietal interactions and time-varying connectivity across the visual cortex. Our findings demonstrate that tDCS boosts learning by accelerating visual GABAergic plasticity and altering interactions between visual and decision-related areas, suggesting that training optimises gain control mechanisms (i.e. GABAergic inhibition) and functional inter-areal interactions to support perceptual learning.
Proteome signatures of reductive stress cardiomyopathy
Authors: Sunny Sini , David Cynthia L. , Parsawar Krishna , Jones Dean P. , Rajasekaran Namakkal S.
Published: September 2021

Nuclear factor erythroid 2-related factor 2 (NRF2), a redox sensor, is vital for cellular redox homeostasis. We reported that transgenic mice expressing constitutively active Nrf2 (CaNrf2-TG) exhibit reductive stress (RS). In this study, we identified novel protein biomarkers for RS-induced cardiomyopathy using Tandem Mass Tag (TMT) proteomic analysis in heart tissues of TG (CaNrf2-TG) and non-transgenic (NTg) mice at 6-7 months of age (N= 4/group). A total of 1105 proteins were extracted from 22544 spectra. Of note, about 560 proteins were differentially expressed in TG vs. NTg hearts, indicating a global impact of RS on myocardial proteome. From a closer analysis of the proteome datasets, we identified over 32 proteins that were significantly altered in response to RS. Among these, 20 were upregulated and 12 were downregulated in the hearts of TG vs. NTg mice, suggesting that these proteins could be putative signatures of RS. Scaffold analysis revealed a clear distinction between TG vs NTg hearts. Of note, we observed several proteins with redox (#185; cysteine residues), NEM-adducts (#81), methionine-loss (#21) and acetylation (#1) modifications in TG vs. NTg hearts due to chronic RS. The majority of the differentially expressed proteins (DEPs) that are significantly altered in RS mice were found to be involved in stress related pathways such as antioxidants, NADPH, protein quality control (PQC), etc. Interestingly, proteins that were involved in mitochondrial respiration, lipophagy and cardiac rhythm were dramatically decreased in TG hearts. Of note, we identified the glutathione family of proteins as the significantly changed subset of the proteome in TG heart. Surprisingly, our comparative analysis of NGS based transcriptome and TMT-proteome indicated ∼50% of the altered proteins in TG myocardium was found to be negatively correlated with their transcript levels. Modifications at cysteine/NEM-adducts (redox), methionine or lysine residues in multiple proteins in response to chronic RS might be associated with impaired PQC mechanisms, thus causing pathological cardiac remodeling.

Graphical Abstract
Forkhead transcription factor FKH-8 is a master regulator of primary cilia in C. elegans
Authors: Brocal-Ruiz Rebeca , Esteve-Serrano Ainara , Mora-Martinez Carlos , Swoboda Peter , Tena Juan , Flames Nuria
Published: September 2021

Cilia, either motile or non-motile (a.k.a primary or sensory), are complex evolutionary conserved eukaryotic structures composed of hundreds of proteins required for their assembly, structure and function that are collectively known as the ciliome. Ciliome mutations underlie a group of pleiotropic genetic diseases known as ciliopathies. Proper cilium function requires the tight coregulation of ciliome gene transcription, which is only fragmentarily understood. RFX transcription factors (TF) have an evolutionarily conserved role in the direct activation of ciliome genes both in motile and non-motile cilia cell types. In vertebrates, FoxJ1 and FoxN4 Forkhead (FKH) TFs work with RFX in the direct activation of ciliome genes, exclusively in motile cilia cell-types. No additional TFs have been described to act together with RFX in primary cilia cell-types in any organism. Here we describe FKH-8, a FKH TF, as master regulator of the primary ciliome in Caenorhabditis elegans. fkh-8 is expressed in all ciliated neurons in C. elegans, binds the regulatory regions of ciliome genes, regulates ciliome gene expression, cilium morphology and a wide range of behaviours mediated by sensory cilia. Importantly, we find FKH-8 function can be replaced by mouse FOXJ1 and FOXN4 but not by members of other mouse FKH subfamilies. In conclusion, our results show that RFX and FKH TF families act as master regulators of ciliogenesis also in sensory ciliated cell types and suggest that this regulatory logic could be an ancient trait predating functional cilia sub-specialization.
The snoGloBe interaction predictor reveals a broad spectrum of C/D snoRNA RNA targets
Authors: Deschamps-Francoeur Gabrielle , Couture Sonia , Abou-Elela Sherif , Scott Michelle S.
Published: September 2021

Box C/D small nucleolar RNAs (snoRNAs) are a conserved class of RNA known for their role in guiding ribosomal RNA 2’-O-ribose methylation. Recently, C/D snoRNAs were also implicated in regulating the expression of non-ribosomal genes through different modes of binding. Large scale RNA-RNA interaction datasets detect many snoRNAs binding messenger RNA, but are limited by specific experimental conditions. To enable a more comprehensive study of C/D snoRNA interactions, we created snoGloBe, a human C/D snoRNA interaction predictor based on a gradient boosting classifier. SnoGloBe considers the target type, position and sequence of the interactions, enabling it to outperform existing predictors. Interestingly, for specific snoRNAs, snoGloBe identifies strong enrichment of interactions near gene expression regulatory elements including splice sites. Abundance and splicing of predicted targets were altered upon the knockdown of their associated snoRNA. Strikingly, the predicted snoRNA interactions often overlap with the binding sites of functionally related RNA binding proteins, reinforcing their role in gene expression regulation. SnoGloBe is also an excellent tool for discovering viral RNA targets, as shown by its capacity to identify snoRNAs targeting the heavily methylated SARS-CoV-2 RNA. Overall, snoGloBe is capable of identifying experimentally validated binding sites and predicting novel sites with shared regulatory function.