bluuebunny/crossref_metadata_2025 huggingface dataset:
Inhibition of Notch Intracellular Domain Suppresses Cell Activation and Fibrotic Factors Production in Hypertrophic Scar Fibroblasts Versus Normal Skin Fibroblasts
Authors: Chen Lin , Zhang Xi , Yu Zhou , Song Yajuan , Wang Tong , Yang Kuan , Li Shengxu , Wang Jianzhang , Su Yingjun , Song Baoqiang
Published: September 2020

Background

Hypertrophic scar (HS) is the most common complication after skin injury with unknown etiopathogenesis. There is increasing evidence to suggest that aberrant Notch signaling contributes directly to skin pathogenesis and altered expression of the Notch intracellular domain (NICD) identified in HS. Therefore, the aim of this study was to investigate the effects of Notch signaling pathway in HS pathogenesis.

Methods

Hypertrophic scar and normal skin samples were collected. Notch intracellular domain expression was detected by immunohistochemistry staining and fibroblasts were separated from the samples. We compared fibrotic factors production, cell viability, migration and apoptosis of HS fibroblasts (HFB) versus normal skin fibroblasts (NFB) by real time quantitative polymerase chain reaction, MTS, cell scratch assay and flow cytometry respectively under the impact of inhibition of Notch signaling by NICD-small-interfering RNA (SiRNA).

Results

The results showed that NICD was overexpressed in the dermis of HS tissues. Inhibition of Notch signaling by NICD-SiRNA suppressed the production of the fibrotic factors including collagen 1, collagen 3, α-SMA, and TGF-β1 by HFB and NFB. Cell viability and migration were reduced in NICD-SiRNA–treated NFB and HFB, whereas cell apoptosis was enhanced by NICD-SiRNA.

Conclusions

Conclusively, the study demonstrates a potential role for Notch signaling in HS progression, and targeting this pathway may provide a novel strategy for treatment of HS.
Early Prediction of the Need for Orthognathic Surgery in Patients With Repaired Unilateral Cleft Lip and Palate Using Machine Learning and Longitudinal Lateral Cephalometric Analysis Data
Authors: Lin Guang , Kim Pil-Jong , Baek Seung-Hak , Kim Hong-Gee , Kim Suk-Wha , Chung Jee-Hyeok
Published: August 2020

The purpose of this study was to determine the cephalometric predictors of the future need for orthognathic surgery in patients with repaired unilateral cleft lip and palate (UCLP) using machine learning. This study included 56 Korean patients with UCLP, who were treated by a single surgeon and a single orthodontist with the same treatment protocol. Lateral cephalograms were obtained before the commencement of orthodontic/orthopedic treatment (T0; mean age, 6.3 years) and at at least of 15 years of age (T1; mean age, 16.7 years). 38 cephalometric variables were measured. At T1 stage, 3 cephalometric criteria (ANB ≤ −3°; Wits appraisal ≤ −5 mm; Harvold unit difference ≥34 mm for surgery group) were used to classify the subjects into the surgery group (n = 10, 17.9%) and non-surgery group (n = 46, 82.1%). Independent t-test was used for statistical analyses. The Boruta method and XGBoost algorithm were used to determine the cephalometric variables for the prediction model. At T0 stage, 2 variables exhibited a significant intergroup difference (ANB and facial convexity angle [FCA], all P < 0.05). However, 18 cephalometric variables at the T1 stage and 14 variables in the amount of change (ΔT1−T0) exhibited significant intergroup differences (all, more significant than P < 0.05). At T0 stage, the ANB, PP-FH, combination factor, and FCA were selected as predictive parameters with a cross-validation accuracy of 87.4%. It was possible to predict the future need for surgery to correct sagittal skeletal discrepancy in UCLP patients at the age of 6 years.
Preoperative Management of a Jehovah's Witness Patient Undergoing Head and Neck Surgery With High Risk of Bleeding
Authors: Sergiampietri Marta , Nicastro Viviana , Calvo Alessandro , Galletti Bruno
Published: August 2020

Surgery in head and neck district is often associated with bleeding as major complication and need of blood transfusions. Homologous blood transfusions may be unacceptable to some patient groups such as the Jehovah's Witness (JW) patients. Refusal of potentially life-saving treatment creates ethical dilemmas for treating clinicians.

This is the first report in literature which examines the management and treatment of a female JW patient who underwent major surgical procedure for squamous cell carcinoma of the jaw with a high risk of hemorrage which rejected any possibility of blood and hemocomponent transfusion by virtue of her religious principles.
Common Carotid-to-Internal Jugular Arteriovenous Loop for Single-Stage Microsurgical Reconstruction in the Radiated Vessel-Depleted Neck
Authors: Anderson Spencer R. , Scott Britney A. , Harrison Lucas M. , Wimalawansa Sunishka M. , Kadakia Sameep P.
Published: August 2020

Management of head and neck defects in a radiated field can be quite challenging owing to the dearth of vasculature and significant degree of post-radiation fibrosis. In this setting, arteriovenous (AV) loop vascular grafts can bypass nonviable local vessels to provide viable and reliable inflow and outflow vessels for free tissue transfer in an otherwise hostile environment. Prior reports of the Corlett loop utilizing a cephalic vein transposition has been described however a common carotid-to-internal jugular AV loop has not been recently reported. Three patients underwent carotid artery to internal jugular vein AV loop creation to facilitate free-flap reconstruction secondary to radiation-induced vessel depletion. The specific technique described utilizes the saphenous vein as a donor and spares the cephalic vein for the possibility of flap complication. All three cases resulted in successful reconstruction, maintaining healthy tissue, vascular flow, and flap viability at all follow-up intervals. In our experience, vascular augmentation via AV loop formation provides reliable vascular inflow and outflow in the vessel-depleted neck to facilitate microvascular reconstruction. Sparing the cephalic vein yields an additional salvage mechanism in the event of venous congestion.
Mandibular Reconstruction Using Free Fibular Flap Graft Following Excision of Calcifying Epithelial Odontogenic Tumor
Authors: Li Yu-Yang , Xu Zhi-Min , Zhang Shi-Chen , Tao Bo-Qiang , Xiang Dan-Wei , Liu Wei-Wei
Published: August 2020

The calcifying epithelial odontogenic tumor (CEOT) is a rare benign odontogenic tumor, which usually presents with distension of affected tissues. Radiologically, the lesions are often associated with an unerupted tooth and may have spot calcification shadows. The authors report a case of a CEOT in a 48-year-old male involving the right mandibular jaw bone and mentum soft tissues. The authors performed hemimandibulectomy and enucleation followed by reconstruction of the mandible using a vascularized free fibular flap through a digital surgical technique in order to restore the patient's facial symmetry and prepare the area for functional restorations. The case illustrates who the free fibular flap graft can be used for satisfactory mandibular reconstruction and restoration of the morphology and functions.
Differences of Craniofacial Characteristics in Oral Breathing and Pediatric Obstructive Sleep Apnea
Authors: Feng Guangyao , Gong Xu , Yu Min , Huang Xin , Gao Xuemei
Published: August 2020

Background:

Oral breathing (OB) was considered associated with specific craniofacial structures and same for pediatric obstructive sleep apnea (OSA). This study aimed to investigate the differences of craniofacial structures between OB and OSA.

Methods:

In this retrospective study, 317 children under age 18 years were recruited and divided into OB group, OSA group, and control group. OSA group (15 boys, 4 girls) were referred from qualified sleep center and diagnosed as pediatric OSA with full-night polysomnography. OB group (10 boys, 10 girls) were mostly referral from pediatric or ENT department, some of whom undertook polysomnography and were not OSA. Control group consisted of orthodontic patients within the same period. Lateral cephalograms were obtained in all groups and their parameters were compared with Chinese normal values and each other.

Results:

R-PNS of OB group (18.04 ± 2.49 mm) was greater than OSA group (14.27 ± 4.36 mm) and even control group (16.22 ± 3.91 mm) (P < 0.01). U1-NA was also the greatest in OB group (7.15 ± 2.92 mm), followed by OSA group (4.88 ± 2.66 mm), while control group was the smallest (5.71 ± 2.94 mm) (P < 0.05). In addition, OB group presented the smallest adenoids and tonsils among three groups. Bony nasopharynx development, mandibular length and growth direction of mandible of OB group were all better than OSA group.

Conclusion:

Despite of oral breathing, anatomical morphology (well-developed dentoalveolar structures; mild adenotonsillar hypertrophy) might protect children from developing OSA.
Degloving Approach for the Management of Extensive Mandibular Osteomyelitis
Authors: Shadamarshan R Arunkumar , Sharma Rohit , Grewal Ritu
Published: August 2020

Extensive osteomyelitis of the mandible is usually managed using elaborate procedures including resection and reconstruction of the affected part of the mandible. This brief clinical report, the authors present a case of 75-year old male with extensive osteomyelitis of the mandible, incidentally diagnosed with anemia of chronic disease and Type I diabetes mellitus and managed using an intraoral degloving approach exclusively. This has proved to be a procedure ensuring better blood supply, decreased morbidity, precluding an elaborate reconstruction procedure and an overall reduction in cost. The advantages, scientific basis, rationale and pitfalls have been discussed briefly.
Tranexamic acid administration in the field does not affect admission thromboelastography after traumatic brain injury
Authors: Dixon Alexandra L. , McCully Belinda H. , Rick Elizabeth A. , Dewey Elizabeth , Farrell David H. , Morrison Laurie J. , McMullan Jason , Robinson Bryce R.H. , Callum Jeannie , Tibbs Brian , Dries David J. , Jui Jonathan , Gandhi Rajesh R. , Garrett John S. , Weisfeldt Myron L. , Wade Charles E. , Aufderheide Tom P. , Frascone Ralph J. , Tallon John M. , Kannas Delores , Williams Carolyn , Rowell Susan E. , Schreiber Martin A.
Published: August 2020

BACKGROUND

No Food and Drug Administration–approved medication improves outcomes following traumatic brain injury (TBI). A forthcoming clinical trial that evaluated the effects of two prehospital tranexamic acid (TXA) dosing strategies compared with placebo demonstrated no differences in thromboelastography (TEG) values. We proposed to explore the impact of TXA on markers of coagulation and fibrinolysis in patients with moderate to severe TBI.

METHODS

Data were extracted from a placebo-controlled clinical trial in which patients 15 years or older with TBI (Glasgow Coma Scale, 3–12) and systolic blood pressure of ≥90 mm Hg were randomized prehospital to receive placebo bolus/placebo infusion (placebo), 1 g of TXA bolus/1 g of TXA infusion (bolus maintenance), or 2 g of TXA bolus/placebo infusion (bolus only). Thromboelastography was performed, and coagulation measures including prothrombin time, activated partial thromboplastin time, international ratio, fibrinogen, D-dimer, plasmin-antiplasmin (PAP), thrombin antithrombin, tissue plasminogen activator, and plasminogen activator inhibitor 1 were quantified at admission and 6 hours later.

RESULTS

Of 966 patients receiving study drug, 700 had laboratory tests drawn at admission and 6 hours later. There were no statistically significant differences in TEG values, including LY30, between groups (p > 0.05). No differences between prothrombin time, activated partial thromboplastin time, international ratio, fibrinogen, thrombin antithrombin, tissue plasminogen activator, and plasminogen activator inhibitor 1 were demonstrated across treatment groups. Concentrations of D-dimer in TXA treatment groups were less than placebo at 6 hours (p < 0.001). Concentrations of PAP in TXA treatment groups were less than placebo on admission (p < 0.001) and 6 hours (p = 0.02). No differences in D-dimer and PAP were observed between bolus maintenance and bolus only.

CONCLUSION

While D-dimer and PAP levels reflect a lower degree of fibrinolysis following prehospital administration of TXA when compared with placebo in a large prehospital trial of patients with TBI, TEG obtained on admission and 6 hours later did not demonstrate any differences in fibrinolysis between the two TXA dosing regimens and placebo.

LEVEL OF EVIDENCE

Diagnostic test, level III.
Amyotrophic lateral sclerosis: update on clinical management
Authors: Norris Simone P. , Likanje Marie-France N. , Andrews Jinsy A.
Published: August 2020

Purpose of review

The current review will provide recent updates in the clinical management of amyotrophic lateral sclerosis (ALS).

Recent findings

Although there is no cure for ALS, there are new treatments, growing knowledge of genetics, development of clinical staging systems, and the recent coronavirus disease 2019 pandemic that have recently impacted the clinical management of ALS. Increased understanding of genetics has helped provide insights into pathophysiology, the staging systems and clinical measures help to provide tools for monitoring disease clinically, and the recent coronavirus disease 2019 pandemic has provided opportunities to develop telemedicine and remote monitoring of disease thereby increasing accessibility to care and reducing burden of travel to centers for people living with the disease and their caregivers.

ALS is a progressive neurodegenerative disease that causes degeneration of the motor neurons which leads to paralysis and respiratory failure. Despite the lack of a cure, multidisciplinary care, proactive respiratory management, nutritional care and management of symptoms as well as pharmacological interventions that can improve quality of life and survival.
Hemorrhagic Intracranial Cavernoma Presenting as a Homonymous Horizontal Sectoranopia
Authors: Costello Fiona E. , Starreveld Yves P.
Published: August 2020

Hemorrhagic lateral geniculate nucleus (LGN) insults are rare but have been reported in association with tumors, vascular malformations, and trauma. The localization of LGN lesions is facilitated by recognition of pathognomonic visual field defects. A 21-year old woman developed a sudden onset painless left homonymous horizontal sectoranopia. Magnetic resonance imaging revealed a hemorrhagic cavernous malformation of the right temporal lobe. Optical coherence tomography (OCT) and Humphrey perimetry findings localized the lesion to the right LGN. Specifically, OCT testing revealed a right homonymous sectoranopia pattern of hemi-retinal macular ganglion layer-inner plexiform layer (mGCIPL) thinning contralateral to the left sided visual field defect. The OCT pattern reflected retrograde neuroaxonal degeneration from the right LGN lesion. This case highlights a unique pattern of mGCIPL thinning characteristic for a posterior lateral choroidal artery injury, affecting the LGN. These findings illustrate how functional eloquence correlates with topographical elegance in the afferent visual pathway.
Patterns of Retinal Ganglion Cell Damage in Nonarteritic Anterior Ischemic Optic Neuropathy Assessed by Swept-Source Optical Coherence Tomography
Authors: Jiang Jingjing , Wang Zhijun , Chen Yi , Li Aihong , Sun Chuan , Sun Xinquan
Published: August 2020

Objective:

To evaluate the ability of macular ganglion cell and inner plexiform layer (mGCIPL) and retinal nerve fiber layer (RNFL) thickness measurements by long-wavelength swept-source optical coherence tomography (SS-OCT) to assess retinal ganglion cell (RGC) damage in nonarteritic anterior ischemic optic neuropathy (NAION).

Methods:

A retrospective study of 20 patients with unilateral NAION was performed. SS-OCT scanning of the macular and peripapillary areas was performed to measure the total and six-sector thicknesses of macular RNFL (mRNFL) and mGCIPL, as well as peripapillary RNFL (pRNFL) thicknesses in global and 12 clock-hour sectors. Further comparison of these thicknesses between NAION involved eyes and uninvolved counterparts was performed in 12 of the 20 patients at 4 visits. The thickness map and en face images generated by volume data of the posterior pole over a 12 × 9-mm area were used for RNFL analysis.

Results:

Median time intervals between the visual symptom onset and first thinning occurrences of mGCIPL, mRNFL, and pRNFL were 17 days (95% Confidence Interval [CI] 14–18 days), 43 days (95% CI 32–48 days), and 70 days (95% CI 62–80 days), respectively. The thickness map indicated a significantly reduced pRNFL in the superior temporal sectors or temporal sectors after 9 weeks, and retinal damage corresponded to the superior hemisphere's mRNFL and mGCIPL. En face images showed that the RNFL thinning area gradually expanded along the retinal nerve fiber direction and progressed toward the optic nerve head.

Conclusions:

The patterns of RGC damage in the macular and peripapillary areas of NAION eyes can be revealed by SS-OCT. Objective measurement of SS-OCT is valuable in characterizing NAION.
Paracentral Acute Middle Maculopathy Mimicking Retrobulbar Optic Neuropathy
Authors: Scott Rachel A. , Bhat Nita , Harish Bindiganavile Shruthi , Li Helen K. , Lee Andrew G.
Published: August 2020

A 70-year-old woman presented with acute awareness of decreased color vision in her right eye. Fundus examination and a flash electroretinography (ERG) were both normal. A multifocal ERG (mfERG) however revealed foveal depression, and thinning of inner nuclear layer was noted on macular optical coherence tomography (OCT), and a diagnosis of resolved paracentral acute middle maculopathy was made. Clinicians should be aware of the complementary role of OCT and mfERG in unexplained acute central visual loss to distinguish retinal from neuro-ophthalmic etiologies. Structural ocular imaging with OCT shows features of inner, middle, and outer retinal localizations to the visual loss.
Comitant Ocular Deviation in Myasthenia Gravis
Authors: Pike-Lee Tiffany , Hill Jeremy , Li Jianbo , Kosmorsky Gregory S. , Li Yuebing
Published: August 2020

Background:

Occurrence of comitant ocular deviation in myasthenia gravis (MG) is not well described.

Methods:

A retrospective analysis of patients with ocular or generalized MG evaluated at a neuro-ophthalmology clinic for a 6-year period. Comitant ocular deviation was defined as magnitude of deviations in all planes varying by <20% from the measurement in the primary position.

Results:

Among the 120 patients included, 89 patients had ocular and 31 patients generalized MG. At the initial strabismus testing, comitant ocular deviation was present in 27 (22.5%) patients. Among the 16 patients who had a follow-up, ocular deviation remained comitant in 6 patients and converted to incomitant or no ocular deviation in 10 patients. An additional 7 patients demonstrated comitant ocular deviation at follow-up. Brain MRI was performed in 18 patients with comitant ocular deviation, and none showed abnormalities in the brainstem or cerebellum.

Conclusion:

Comitant ocular deviation can be an ocular manifestation of MG. Its presence does not necessarily indicate a central etiology in patients with MG neither excluding a MG diagnosis.
Delayed-Onset Cranial Nerve Palsy After Transvenous Embolization of Indirect Carotid Cavernous Fistulas
Authors: Wang Arthur , Halbach Van V. , Dowd Christopher F. , Alexander Matthew D. , Hallam Danial K. , Ghodke Basavarj , Moazami Golnaz , Mandigo Grace K. , Lavine Sean D. , Meyers Philip M.
Published: August 2020

Background:

Carotid cavernous fistulas (CCF) often present with diplopia secondary to cranial nerve palsy (CNP). Immediate development of postoperative CNP has been described in the literature. This study described delayed-onset of CNP after complete and reconfirmed obliteration of the CCF and resolution of initial CNP.

Methods:

A retrospective analysis was performed on patients with indirect CCF between 1987 and 2006 at 4 academic endovascular centers. Details of the endovascular procedures, embolic agents used, and complications were studied. Partial or complete obliteration was determined. Immediate and delayed cranial nerve palsies were independently assessed.

Results:

A total of 267 patients with symptomatic indirect CCF underwent transvenous endovascular treatment. Four patients (1.5%) developed delayed abducens nerve (VI) palsy after complete resolution of presenting symptoms after embolization. Delayed presentation ranged between 3 and 13 months after complete resolution of initial double vision and cranial nerve palsies. Transvenous coil embolization through the inferior petrosal sinus was performed in all 4 affected patients. All had follow-up angiography confirming durable closure of their CCF. MRI did not show new mass lesions or abnormal soft tissue enhancement. In all 4 patients, their abducens nerve (VI) palsy remained.

Conclusions:

Delayed CNP can develop despite complete endovascular obliteration of the CCF. The cause of delayed CNP is not yet determined, but may represent fibrosis and ischemia. Long-term follow-up is needed even after complete neurological and radiological recovery is attained in the immediate perioperative period.
Promoting healthy lifestyle considerations during pregnancy in Midwifery clinics in China: a best practice implementation project
Authors: Zhai Jinguo , Hu Xiaoqi , Wen Zhiying , Chen Lihua , Ye Ranran , Zheng Xiaozhu , Xiong Anqi , Barker Timothy H. , McArthur Alexa
Published: August 2020

Objectives:

The aim of this project was to initiate and promote formal and individualized evidence-based education on healthy lifestyle choices during pregnancy for pregnant women.

Introduction:

Evidence suggests that lifestyle choices during pregnancy can have a profound influence on many pregnancy complications and chronic diseases such as preterm birth, diabetes, obesity, fetal growth restriction, breast cancer and hypertensive diseases in both pregnant women and their babies. It is widely accepted that formal, individualized, hospital-directed education about lifestyle choices during pregnancy should commence as early as the first consultation between pregnant women and maternal healthcare workers.

Methods:

The methods of this project were audit and feedback. The approach to data collection used the Joanna Briggs Institute (JBI) Practical Application of Clinical Evidence System and implementation planning utilized the Getting Research into Practice component. A baseline audit of 50 observations of midwife-led education on prenatal lifestyle were conducted and measured against seven best practice audit criteria. Targeted strategies were then implemented to improve compliance to best practice. A follow-up audit was conducted over a 6-month period from June 2019 to November 2019.

Results:

The baseline audit revealed significant deficits between current prenatal education practice and recommended best practice. Zero percent compliance was observed in six out of seven audit criteria, indicating that education provided did not conform to best practice. Total compliance (100%) was observed for one audit criterion at baseline, assessing pregnant women being offered an opportunity to discuss and ask questions regarding the education session or information they had received. Three barriers that prevented midwives from achieving compliance with best practice were identified, and a bundled education strategy was implemented. A follow-up audit indicated 100% compliance of all audit criteria.

Conclusion:

Results demonstrated that formal, individualized, midwife-led prenatal education and provision of relevant evidence-based resources had an immediate positive effect. The project helped to transform care givers’ attitudes toward education regarding lifestyle during pregnancy from a passive routine ‘must do’ task to an active process with focus on healthy lifestyle and engagement of pregnant women. Future strategies such as support from hospital management and social media are planned in conjunction with follow-up clinical audits to ensure sustainability.
Real-time Nowcasting and Forecasting of COVID-19 Dynamics in England: the first wave?
Authors: Birrell Paul , Blake Joshua , van Leeuwen Edwin ,   PHE Joint Modelling Cell, Gent Nick , De Angelis Daniela
Published: August 2020

England has been heavily affected by the SARS-CoV-2 pandemic, with severe ‘lock-down’ mitigation measures now gradually being lifted. The real-time pandemic monitoring presented here has contributed to the evidence informing this pandemic management. Estimates on the 10th May showed lock-down had reduced transmission by 75%, the reproduction number falling from 2.6 to 0.61. This regionally-varying impact was largest in London of 81% (95% CrI: 77%–84%). Reproduction numbers have since slowly increased, and on 19th June the probability that the epidemic is growing was greater than 5% in two regions, South West and London. An estimated 8% of the population had been infected, with a higher proportion in London (17%). The infection-to-fatality ratio is 1.1% (0.9%–1.4%) overall but 17% (14%–22%) among the over-75s. This ongoing work will be key to quantifying any widespread resurgence should accrued immunity and effective contact tracing be insufficient to preclude a second wave.
Joint Investigation of Two-Month Post-Diagnosis IgG Antibody Levels and Psychological Measures for Assessing Longer Term Multi-Faceted Recovery among COVID-19 Cases in Northern Cyprus
Authors: Barin Burc , Yoldascan Banu Elcin , Savaskan Fatma , Ozbalikci Goncagul , Karaderi Tugce , Çakal Hüseyin
Published: September 2020

Following the outbreak of COVID-19, multidisciplinary research focusing on the long-term effects of the COVID-19 infection and the ‘complete longer term recovery’ is still scarce. With regards to long-term consequences, biomarkers of physiological effects as well as the psychological experiences are of significant importance for comprehensively understanding the whole COVID-19 recovery period. The present research surveys the IgG antibody titers and the impact of COVID-19 as a traumatic experience in the aftermath of the active infection period, around two months after diagnosis, in a subset of COVID-19 patients from the first wave of the outbreak in Northern Cyprus. Associations of antibody titers and psychological survey measures with baseline characteristics and disease severity were explored, and correlations among various measures were evaluated. Of the 47 serology tests conducted for presence of IgG antibodies, 39 (83%) were positive. We identified trends demonstrating individuals experiencing severe or critical COVID-19 disease and/or those with comorbidities are more heavily impacted both physiologically and mentally, with higher IgG titers and negative psychological experience compared to those with milder disease and without comorbidities. We also observed that more than half of the COVID-19 cases had negative psychological experiences, being subjected to discrimination and verbal harassment/insult, by family/friends. In summary, as the first study co-evaluating immune response together with mental status, our findings suggest that further multidisciplinary research in larger sample populations as well as community intervention plans are needed to holistically address the physiological and psychological effects of COVID-19 among the cases in the long-term.
Inheritance of a common androgen synthesis variant allele is associated with female COVID susceptibility in UK Biobank
Authors: McManus Jeffrey M. , Sabharwal Navin , Bazeley Peter , Sharifi Nima
Published: September 2020

Context

A sex discordance in COVID exists, with males disproportionately affected. Although sex steroids may play a role in this discordance, no definitive genetic data exist to support androgen-mediated immune suppression for viral susceptibility, nor for adrenally produced androgens.

Objective

The common adrenal-permissive missense-encoding variant HSD3B1(1245C) that enables androgen synthesis from adrenal precursors and that has been linked to suppression of inflammation in severe asthma was investigated in COVID susceptibility and outcomes reported in the UK Biobank.

Methods

The UK Biobank is a long-term study with detailed medical information and health outcomes for over 500,000 genotyped individuals. We obtained COVID test results, inpatient hospital records, and death records and tested for associations between COVID susceptibility or outcomes and HSD3B1(1245A/C) genotype. The outcomes were identification as a COVID case among all subjects, COVID positivity among COVID-tested subjects, and mortality among subjects identified as COVID cases.

Results

Adrenal-permissive HSD3B1(1245C) genotype was associated with identification as a COVID case (odds ratio 1.11 per C allele, p = 0.00054) and COVID test positivity (OR 1.10, p = 0.0036) in older (≥ 70 years of age) women. In women identified as COVID cases, there was a positive linear relationship between age and 1245C allele frequency (p < 0.0001). No associations were found between genotype and mortality.

Conclusion

Our study suggests that a common androgen synthesis variant regulates immune susceptibility to COVID infection in women, with increasingly strong effects as women age.
Continuous digital collection of patient-reported outcomes during inpatient treatment for affective disorders – implementation and feasibility
Authors: Richter Maike , Storck Michael , Blitz Rogério , Goltermann Janik , Seipp Juliana , Dannlowski Udo , Baune Bernhard T. , Dugas Martin , Opel Nils
Published: September 2020

Multivariate predictive models have revealed promising results for the individual prediction of treatment response, relapse risk as well as for the differential diagnosis in affective disorders. Yet, in order to translate personalized predictive modelling from the research context to psychiatric clinical routine, standardized collection of information of sufficient detail and temporal resolution in day-to-day clinical care is needed, based on which machine learning algorithms can be trained. Digital collection of patient-reported outcomes (PROs) is a time- and cost-efficient approach to gain such data throughout the treatment course. However, it remains unclear whether patients with severe affective disorders are willing and able to participate in such efforts, whether the feasibility of such systems might vary depending on individual patient characteristics and if digitally acquired patient-reported outcomes are of sufficient diagnostic validity. To address these questions, we implemented a system for continuous digital collection of patient-reported outcomes via tablet computers throughout inpatient treatment for affective disorders at the Department of Psychiatry at the University of Münster. 364 affective disorder patients were approached, 66.5% of which could be recruited to participate in the study. An average of four assessments were completed during the treatment course, none of the participants dropped out of the study prematurely. 89.3% of participants did not require additional support during data entry. Need of support with tablet handling and slower data entry pace was predicted by older age, whereas depression severity at baseline did not influence these measures. Patient-reported outcomes of depression severity showed high agreement with standardized external assessments by a clinical interviewer. Our results indicate that continuous digital collection of patient-reported outcomes is a feasible, accessible and valid method for longitudinal data collection in psychiatric routine, which will eventually facilitate the identification of individual risk and resilience factors for affective disorders and pave the way towards personalized psychiatric care.
Learning Distance-Dependent Motif Interactions: An Explicitly Interpretable Neural Model of Genomic Events
Authors: Quinn Thomas P. , Nguyen Dang , Nguyen Phuoc , Gupta Sunil , Venkatesh Svetha
Published: August 2020

In many biological studies, prediction is used primarily to validate the model; the real quest is to understand the underlying phenomenon. Therefore, interpretable deep models for biological studies are required. Here, we propose theHyper-parameter eXplainable MotifPairframework (HyperXPair) to model biological motifs and their distance-dependent context through explicitly interpretable parameters. This makesHyperXPairmore than a decision-support tool; it is also a hypothesis-generating tool designed to advance knowledge in the field. We demonstrate the utility of our model by learning distance-dependent motif interactions for two biological problems: transcription initiation and RNA splicing.
Systematic review and meta-analysis of the prevalence of common respiratory viruses in children < 2 years with bronchiolitis reveal a weak role played by the SARS-CoV-2
Authors: Kenmoe Sebastien , Kengne-Nde Cyprien , Ebogo-Belobo Jean Thierry , Mbaga Donatien Serge , Modiyinji Abdou Fatawou , Njouom Richard
Published: September 2020

Introduction The advent of genome amplification assays has allowed description of new respiratory viruses and to reconsider the role played by certain respiratory viruses in bronchiolitis. This systematic review and meta-analysis was initiated to clarify the prevalence of respiratory viruses in children with bronchiolitis in the coronavirus disease 2019 pandemic context.

Methods

We performed an electronic search through Pubmed and Global Index Medicus databases. We included observational studies reporting the detection rate of common respiratory viruses in children with bronchiolitis using molecular assays. Data was extracted and the quality of the included articles was assessed. We conducted sensitivity, subgroups, publication bias, and heterogeneity analyses using a random effect model.

Results

The final meta-analysis included 51 studies. Human respiratory syncytial virus (HRSV) was largely the most commonly detected virus 59.2%; 95% CI [54.7; 63.6]). The second predominant virus was Rhinovirus (RV) 19.3%; 95% CI [16.7; 22.0]) followed by Human bocavirus (HBoV) 8.2%; 95% CI [5.7; 11.2]). Other reported viruses included Human Adenovirus (HAdV) 6.1%; 95% CI [4.4; 8.0]), Human Metapneumovirus (HMPV) 5.4%; 95% CI [4.4; 6.4]), Human Parainfluenzavirus (HPIV) 5.4%; 95% CI [3.8; 7.3]), Influenza 3.2%; 95% CI [2.2; 4.3], mild Human Coronavirus (HCoV) 2.9%; 95% CI [2.0; 4.0]), and Enterovirus (EV) 2.9%; 95% CI [1.6; 4.5]). HRSV was the predominant virus involved in multiple detection and most codetections were HRSV + RV 7.1%, 95% CI [4.6; 9.9]) and HRSV + HBoV 4.5%, 95% CI [2.4; 7.3]).

Conclusions

The present study has shown that HRSV is the main cause of bronchiolitis in children, we also have Rhinovirus, and Bocavirus which also play a significant role. No study has reported the presence of Severe Acute Respiratory Syndrome Coronavirus-2 in children with bronchiolitis to date.
A Continuous Time Representation of smFRET for the Extraction of Rapid Kinetics
Authors: Kilic Zeliha , Sgouralis Ioannis , Heo Wooseok , Ishii Kunihiko , Tahara Tahei , Pressé Steve
Published: August 2020

Our goal is to learn kinetic rates from single molecule FRET (smFRET) data even if these exceed the data acquisition rate. To achieve this, we develop a variant of our recently proposedhidden Markov jump process(HMJP) with which we learn transition kinetics from parallel measurements in donor and acceptor channels. Our HMJP generalizes the hidden Markov model (HMM) paradigm in two critical ways: (1) it deals with physical smFRET systems as they switch between conformational states incontinuous time; (2) it estimates the transition rates between conformational states directly without having recourse to transition probabilities or assuming slow dynamics (as is necessary of the HMM). Our continuous time treatment learns transition kinetics and photon emission rates for dynamical regimes inaccessible to the HMM which treats system kinetics in discrete time. We validate the robustness of our framework on simulated data and demonstrate its performance on experimental data from FRET labeled Holliday junctions.
Blocking the Rac1-TRPC5 pathway protects human podocytes
Authors: Zhou Yiming , Kim Choah , Pablo Juan Lorenzo B. , Zhang Fan , Jung Ji Yong , Xiao Li , Bazua Silvana , Emani Maheswarareddy , Hopkins Corey , Weins Astrid , Greka Anna
Published: August 2020

Podocyte injury and the appearance of proteinuria are key features of several progressive kidney diseases. Genetic deletion or selective inhibition of TRPC5 channels with small-molecule inhibitors protects podocytes in rodent models of disease, but less is known about the human relevance and translatability of TRPC5 inhibition. Here, we investigate the effect of TRPC5 inhibition in puromycin aminonucleoside (PAN)-treated human iPSC-derived podocytes and kidney organoids. We first established that systemic administration of the TRPC5-specific blocker AC1903 was sufficient to protect podocyte cytoskeletal proteins and suppress proteinuria in PAN-induced nephrosis in rats, an established model of podocyte injury and progressive kidney disease. PAN treatment also triggered the Rac1-TRPC5 injury pathway in human iPSC-derived podocytes and kidney organoids. TRPC5 current was recorded in human iPSC-derived podocytes, and was blocked by AC1903. The TRPC5 blocker also reversed the effects of PAN-induced injury in human podocytes in both 2D and 3D culture systems. Taken together, these results revealed the relevance of the TRPC5-Rac1 pathway in human kidney tissue highlighting the potential of this therapeutic strategy for patients.
Hyaluronan Synthesis Inhibition Impairs Antigen Presentation and Delays Transplantation Rejection
Authors: Marshall Payton L. , Nagy Nadine , Kaber Gernot , Barlow Graham L. , Ramesh Amrit , Xie Bryan J. , Linde Miles H. , Haddock Naomi L. , Lester Colin A. , Tran Quynh-Lam , de Vries Christiaan , Malkovskiy Andrey , Gurevich Irina , Martinez Hunter A. , Kuipers Hedwich F. , Yadava Koshika , Zhang Xiangyue , Evanko Stephen P. , Gebe John A. , Wang Xi , Vernon Robert B. , Hargil Aviv , de la Motte Carol , Wight Thomas N. , Engleman Edgar G. , Krams Sheri M. , Meyer Everett , Bollyky Paul L.
Published: August 2020

A coat of pericellular hyaluronan surrounds mature dendritic cells (DC) and contributes to cell-cell interactions. We asked whether 4-methylumbelliferone (4MU), an oral inhibitor of HA synthesis, could inhibit antigen presentation. We find that 4MU treatment reduces pericellular hyaluronan, destabilizes interactions between DC and T-cells, and prevents T-cell proliferationin vitroandin vivo. These effects were observed only when 4MU was added prior to initial antigen presentation but not later, consistent with 4MU-mediated inhibition ofde novoantigenic responses. Building on these findings, we find that 4MU delays rejection of allogeneic pancreatic islet transplant and allogeneic cardiac transplants in mice and suppresses allogeneic T-cell activation in human mixed lymphocyte reactions. We conclude that 4MU, an approved drug, may have benefit as an adjunctive agent to delay transplantation rejection.
Snord67 promotes lymph node metastasis and regulates U6-mediated alternative splicing in breast cancer
Authors: Chao Yvonne L. , Zhu Yinzhou , Wiedner Hannah J. , Tsai Yi-Hsuan , Wilkinson Lily , Porrello Alessandro , Van Swearingen Amanda E.D. , Carey Lisa A. , Giudice Jimena , Holley Christopher L. , Pecot Chad V.
Published: August 2020

Small nucleolar RNAs (snoRNAs) have long been considered “housekeeping genes”, important for ribosomal biogenesis and protein synthesis. However, there is increasing evidence that this largely ignored class of non-coding RNAs (ncRNAs) also have wide-ranging, non-canonical functions in diseases, including cancer. SnoRNAs have been shown to have both oncogenic and tumor suppressor roles, yet whether snoRNAs regulate metastasis is unknown. Here we show that expression of certain snoRNAs are enriched in lymph node (LN) metastases in a micro-surgical, immune-competent mouse model of breast cancer. We identify the snoRNA Snord67 as a key regulator of LN metastasis. Knockout of Snord67 resulted in significantly decreased LN tumor growth and subsequent development of distant metastases. This was associated with loss of targeted 2’-O-methylation on the small nuclear RNA U6, a component of the spliceosome. RNA sequencing revealed distinct alternative splicing patterns in Snord67 knockout cells. Using rapid autopsy breast cancer cases, we found that matched human primary tumor and LN metastases revealed similar alternatively spliced genes, including several that are known to contribute to cancer. These results demonstrate that Snord67 is critical for growth of LN metastases and subsequent spread to distant metastases, and suggest that snoRNA-guided modifications of the spliceosome represent a previously unappreciated, yet targetable pathway in cancer.
A simplified cell-based assay to identify coronavirus 3CL protease inhibitors
Authors: Resnick Samuel J. , Iketani Sho , Hong Seo Jung , Zask Arie , Liu Hengrui , Kim Sungsoo , Melore Schuyler , Nair Manoj S. , Huang Yaoxing , Tay Nicholas E.S. , Rovis Tomislav , Yang Hee Won , Stockwell Brent R. , Ho David D. , Chavez Alejandro
Published: August 2020

We describe a mammalian cell-based assay capable of identifying coronavirus 3CL protease (3CLpro) inhibitors without requiring the use of live virus. By enabling the facile testing of compounds across a range of coronavirus 3CLpro enzymes, including the one from SARS-CoV-2, we are able to quickly identify compounds with broad or narrow spectra of activity. We further demonstrate the utility of our approach by performing a curated compound screen along with structure-activity profiling of a series of small molecules to identify compounds with antiviral activity. Throughout these studies, we observed concordance between data emerging from this assay and from live virus assays. By democratizing the testing of 3CL inhibitors to enable screening in the majority of laboratories rather than the few with extensive biosafety infrastructure, we hope to expedite the search for coronavirus 3CL protease inhibitors, to address the current epidemic and future ones that will inevitably arise.
Epigenetic inheritance and the evolution of infectious diseases
Authors: McLeod David V. , Wild Geoff , Úbeda Francisco
Published: August 2020

Genes with identical DNA sequences may show differential expression because of epigenetic marks. These marks in pathogens are key to their virulence and are being evaluated as targets for medical treatment. Where epigenetic marks were created in response to past conditions (epigenetically inherited), they represent a form of memory, the impact of which has not been considered in the evolution of infectious diseases. We fill this gap by exploring the evolution of virulence in pathogens that inherit epigenetic information on the sex of their previous host. We show that memories of past hosts can also provide clues about the sex of present and future hosts when women and men differ in their immunity to infection and/or their interactions with the sexes. These biological and social differences between the sexes are pervasive in humans. We show that natural selection can favour the evolution of greater virulence in infections originating from one sex. Furthermore, natural selection can favour the evolution of greater virulence in infections across sexes (or within sexes). Our results explain certain patterns of virulence in diseases like measles, chickenpox and polio that have puzzled medical researchers for decades. In particular, they address why girls infected by boys (or boys infected by girls) are more likely to die from the infection than girls infected by girls (or boys infected by boys). We propose epigenetic therapies to treat infections by tampering with the memories of infecting pathogens. Counterintuitively, we predict that successful therapies should target pathogen’s genes that inhibit virulence, rather than those enhancing virulence. Our findings imply that pathogens can carry memories of past environments other than sex (e.g. those related to socioeconomic status) that may condition their virulence and could signify an important new direction in personalised medicine.
Previously unrecorded distribution of marine sediments derived yeast isolates revealed by DNA barcoding
Authors: PrasannaKumar Chinnamani , Velmurugan Shanmugam , Subramanian Kumaran , Pugazhvendan S. R. , Nagaraj D. Senthil , Khan K. Feroz , Sadiappan Balamurugan , Manokaran Seerangan , Hemalatha Kaveripakam Raman , Aruni Wilson , Sivamaruthi Bhagavathi Sundaram , Chaiyasut Chaiyavat
Published: August 2020

For the yeast population and diversity, marine habitats are the least explored niches and the lack of validated database is considered to be a drawback for yeast research. The aim of the present study is to create a comprehensive DNA barcode library for marine derived yeast species isolated from organic burial hotspots such as coastal sediment in mangrove and continental shelf ecosystems. As we enriched, isolated and ITS gene sequenced 1017 marine derived yeast isolates belonging to 157 marine species in 55 genera, 28 families, 14 orders, 8 classes of 2 Phyla (viz., Ascomycota and Basidiomycota) of which 13 yeast species were first time barcoded. We witnessed yeast species of both terrestrial and marine endemic origin in the barcode datasets. Due to the large volume of sequencing trace files, the variable length of extracted sequences, and the lack of reference sequences in public databases, difficulties were faced in taxonomic sequence validation. The length of the majority of the sequences (99.42%) were more than or equal to 600 base pairs. BLAST analysis revealed that 13 yeast species were barcoded for the first time. The genus, Candida was the speciose genera isolated in this study. K2P intra-species distance analysis performed for selective groups yielded an average of 0.33%, well below the previously proposed yeast barcode gap. ITS gene NJ-tree based identification conducted for selective species in Ascomycota and Basidomycota, precisely clustered the same species into one group, indicating the efficacy of ITS gene in yeast species delineation. Besides isolating some of the common marine yeast species such as Candida oceani, Bandonia marina and Yarrowia lipolytica, we found approximately 60% of the yeast species isolates were previously unrecorded from the marine environment (example; Cystobasidiopsis lactophilus, Slooffia cresolica, Udeniozyma ferulica, Colacogloea falcatus and Pichia guilliermondii), of which 16.5% were recognised as potential human pathogens (example; Candida orthopsilosis, C. rugosa, Debaryomyces fabryi and Yamadazyma triangularis). Apart from releasing the barcode data in GenBank, provisions were made to access the entire dataset along with meta-data in the Barcode of life database (http://dx.doi.org/10.5883/DS-MYIC). This research constitutes the largest dataset to date for collecting marine yeast isolates and their barcodes. As meta- and environmental barcoding analysis were expanding its scope including environmental assessment and monitoring, the datasets such as ours will be more useful.
Synthesis and structures of three isoxazole-containing Schiff bases
Authors: Mason Helen E. , Howard Judith A. K. , Sparkes Hazel A.
Published: August 2020

The synthesis and structures of three isoxazole-containing Schiff bases are reported, namely, (E)-2-{[(isoxazol-3-yl)imino]methyl}phenol, C10H8N2O2, (E)-2-{[(5-methylisoxazol-3-yl)imino]methyl}phenol, C11H10N2O2, and (E)-2,4-di-tert-butyl-6-{[(isoxazol-3-yl)imino]methyl}phenol, C18H24N2O2. All three structures contain an intramolecular O—H...N hydrogen bond, alongside weaker intermolecular C—H...N and C—H...O contacts. The C—O(H) and imine C=N bond lengths were consistent with structures existing in the enol rather than the keto form. Despite having dihedral angles <25°, none of the compounds were observed to be strongly thermochromic, unlike their anil counterparts; however, all three compounds showed a visible colour change upon irradiation with UV light.