bluuebunny/crossref_metadata_2025 huggingface dataset:
Responding to the Pandemic: Challenges With Public Health Surveillance Systems and Development of a COVID-19 National Surveillance Case Definition to Support Case-Based Morbidity Surveillance During the Early Response
Authors: Hamilton Janet J. , Turner Kathryn , Lichtenstein Cone Meredith
Published: November 2020

Responding to introductions of diseases and conditions of unknown etiology is a critical public health function. In late December 2019, investigation of a cluster of pneumonia cases of unknown origin in Wuhan, China, resulted in the identification of a novel coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Multiple public health surveillance actions were rapidly implemented to detect introduction of the virus into the United States and track its spread including establishment of a national surveillance case definition and addition of the disease, coronavirus disease 2019, to the list of nationally notifiable conditions. Challenges in conducting effective case-based surveillance and the public health data supply chain and infrastructure are discussed.
Bilateral Complete Cleft Lip Repair: A Step-by-Step Video Series
Authors: Denadai Rafael , Pai Betty C. J. , Sato Nobuhiro , Lonic Daniel , Chou Pang-Yun , Lo Lun-Jou
Published: November 2020

Surgeons-in-training learning how to perform cleft surgery should not only acquire a broad repertoire of technical details but also master the proper execution of techniques based on the modern principles of bilateral cleft lip repair with synchronous reconstruction of cleft nose deformity. This article describes a bilateral complete cleft lip repair by adopting these principles, plus a modified composition of mucosal flaps for the nasal floor and intraoral linings, including the prolabial mucosal flap, C-flap mucosal flap, inferior turbinate mucosal flap, and lateral nasal mucosal flap. The accompanying four-part video series presents the step-by-step approach for design and execution of this alternative technique.
Cost-Effectiveness of Treatments after Closed Extraarticular Distal Radius Fractures in Older Adults from the WRIST Clinical Trial
Authors: Yoon Alfred P. , Shauver Melissa J. , Hutton David W. , Chung Kevin C. ,   For the WRIST Group
Published: November 2020

Background:

This study performs an economic analysis of volar locking plate, external fixation, percutaneous pinning, or casting in elderly patients with closed distal radius fractures.

Methods:

This is a secondary analysis of the Wrist and Radius Injury Surgical Trial, a randomized, multicenter, international clinical trial with a parallel nonoperative casted group of patients older than 60 years with surgically indicated, extraarticular closed distal radius fractures. Thirty-Six-Item Short-Form Health Survey–converted utilities and total costs from Medicare were used to calculate quality-adjusted life-years and incremental cost-effectiveness ratio.

Results:

Casted patients were self-selected and older (p < 0.001) than the randomized surgical cohorts, but otherwise similar in sociodemographic characteristics. Quality-adjusted life-years for percutaneous pinning were highest at 9.17 and external fixation lowest at 8.81. Total costs expended were $16,354 for volar locking plates, $16,012 for external fixation, $11,329 for percutaneous pinning, and $6837 for casting. The incremental cost-effectiveness ratios for volar locking plates and external fixation were dominated by percutaneous pinning and casting. The ratio for percutaneous pinning compared to casting was $28,717. Probabilistic sensitivity analysis revealed a 10, 5, 53, and 32 percent chance of volar locking plate, external fixation, percutaneous pinning, and casting, respectively, being cost-effective at the willingness-to-pay threshold of $100,000 per quality-adjusted life-year.

Conclusions:

Casting is the most cost-effective treatment modality in the elderly with closed extraarticular distal radius fractures and should be considered before surgery. In unstable closed fractures, percutaneous pinning, which is the most cost-effective surgical intervention, may be considered before volar locking plates or external fixation.
99mTc-PSMA SPECT/CT Versus 68Ga-PSMA PET/CT in the Evaluation of Metastatic Prostate Cancer
Authors: Fallahi Babak , Khademi Niloufar , Karamzade-Ziarati Najme , Fard-Esfahani Armaghan , Emami-Ardekani Alireza , Farzanefar Saeed , Eftekhari Mohammad , Beiki Davood
Published: November 2020

Background

99mTc–prostate-specific membrane antigen (PSMA) SPECT/CT is less expensive and readily available modality compared with 68Ga-PSMA PET/CT for imaging prostate cancer (PC). The aim of this study is to compare the value of these 2 modalities in patients confirmed or suspicious to have metastatic prostate cancer.

Patients and Methods

Twenty-two patients with the mean age of 66.6 ± 10.1 years were studied using 99mTc-PSMA SPECT/CT and 68Ga-PSMA PET/CT, with less than 7 days interval between the 2 imaging procedures. Whole-body PET/CT was done 60 minutes after IV injection of 185 MBq (5 mCi) of 68Ga-PSMA. 99mTc-PSMA SPECT/CT was performed 3 hours after IV injection of 555 to 740 MBq (15–20 mCi) of 99mTc-PSMA. The images of each modality were interpreted independently, and the results were compared according to patient-based as well as region-based analyses.

Results

In patient-based evaluation, both 99mTc-PSMA SPECT/CT and 68Ga-PSMA PET/CT scans were positive in 95.45% (21/22). In region-based evaluation, 68Ga-PSMA PET/CT detected 53 regions (median of 2 regions per patient; range, 0–5), whereas 43 (median of 2 regions per patient; range, 0–5) were detected by 99mTc-PSMA SPECT/CT. Most of these differences could be explained by lower detection rate of 99mTc-PSMA SPECT/CT in prostate bed (n = 6). PET/CT detected more involved regions than SPECT/CT (P = 0.007), whereas similar frequency of extraprostatic lesions were diagnosed in both modalities (P = 0.102). Significant correlation was also demonstrated between serum prostate-specific antigen level and imaging parameters of disease extension detected by 2 modalities.

Conclusions

99mTc-PSMA SPECT/CT could be a potential substitute for 68Ga-PSMA PET/CT in high-risk patients, except when evaluation of prostate bed is of major concern.
Usual and Rare Abdominal Location of Giant Cell Arteritis Diagnosed and Follow-up With 18F-FDG PET/CT
Authors: Bonnefoy Pierre-Benoît , Goutte Julie , Jacquet-Francillon Nicolas , Habouzit Vincent , Prevot Nathalie
Published: November 2020

Giant cell arteritis is not an uncommon disease, and its extension is furthermore finely assessed with new-generation PET/CT system. 18F-FDG PET/CT is increasingly used in case of large-vessel vasculitis for optimal diagnosis, activity monitoring (even when treated with interleukin 6 receptor inhibitor), and evaluation damage progression. We reported the case of a 61-year-old woman with common giant cell arteritis pattern on 18F-FDG PET/CT (aorta and large arteries) and uptakes in all aorta branches, mainly impressive and uncommon in the abdomen. After 2 years of therapeutic optimization including IV tocilizumab and monitoring with 18F-FDG PET/CT, a complete metabolical response was assessed.
Gastrointestinal Stromal Tumor Incidentally Detected on 18F-Fluciclovine PET/CT
Authors: Raghavan Kesav , Flavell Robert R. , Westphalen Antonio C. , Behr Spencer C.
Published: November 2020

We present a case of metastatic gastrointestinal stromal tumor incidentally detected on 18F-fluciclovine PET/CT. A 68-year-old man with history of intermediate-risk prostate cancer (Gleason score 4 + 3 = 7; pT2cN0M0) previously treated with retropubic radical prostatectomy, adjuvant whole pelvis radiation, and androgen deprivation therapy (leuprolide) presented with slowly rising serum prostate-specific antigen over 3 years, concerning for recurrent prostate cancer. To identify potential sites of recurrent disease, an 18F-fluciclovine PET/CT was obtained. Multiple tracer-avid mesenteric masses and enlarged lymph nodes were found throughout the abdomen and pelvis, later biopsy-proven to reflect metastatic gastrointestinal stromal tumor.
Restoration of Ramus Height in Child Patients With Extracapsular Condylar Fractures: Is This Mission Almost Impossible to Accomplish?
Authors: Zhou Hai-Hua , Lv Kun , Yang Rong-Tao , Li Zhi , Li Zu-Bing
Published: November 2020

Objective:

This study aimed to assess whether ramus height is restored in children with extracapsular condylar fractures treated by conservative or surgery procedures.

Methods:

The sample consisted of 35 children (collected consecutively) less than 12 years old who presented with extracapsular condylar fractures and treated within an 8-year period (June 2011 to April 2019). Data on the age, gender, date of injury, mechanism of trauma, location and pattern of mandibular condylar fracture, associated injuries and treatment methods were recorded and analyzed. Ramus height restoration is the main evaluation indicator during the follow-up period.

Results:

Within the 8-year record retrieval, the 35 children sustained 41 extracapsular condylar fractures. For the sample size, 10 (24.4%) and 31 (75.6%) had condylar neck and base fractures, respectively. Deviation and green-stick fracture were the predominant types in condylar neck and base fractures, accounting for more than 3 quarters (31, 75.6%). The majority (33, 80.5%) of patients were treated with nonsurgical treatment, and 8 (19.5%) were treated by open reduction and internal fixation (ORIF). During the follow-up period (1–1419 days, average time of 110.6 days), only 1 patient (with bilateral extracapsular condylar fractures) had their ramus height restored (follow-up period, 256 days). Most members of the ORIF group (5 of 8, 62.5%) postoperatively showed bended ramus (deviated angularly/fragment angulation).

Conclusion:

Conservative treatment could hardly restore the ramus height of children with extracapsular condylar fractures. Anatomically or totally restoring the ramus height is difficult even with the surgical treatment of ORIF; however, surgical treatment of ORIF can substantially restore the ramus height for dislocated fractures or seriously displaced fractures.
The Upper Buccal Musculomucosal Flap for Nasal Lining and Columellar Defect Reconstruction
Authors: Yen Cheng-I , Chang Chun-Shin , Chen Hung-Chang , Yang Shih-Yi , Chang Shu-Yin , Yang Jui-Yung , Chuang Shiow-Shuh , Hsiao Yen-Chang
Published: November 2020

Restoring the nasal lining is a great challenge in the reconstruction of nasal defects. In this series, the authors present our experience in using the upper buccal musculomucosal (UBMM) flap for the reconstruction of full thickness columellar or nasal lining defects. Ten patients who underwent UBMM flap reconstruction of columellar or nasal lining defects, with or without composite grafting, were identified between December of 2014 and February of 2017. The records were retrospectively reviewed to determine the demographics, nasal deformity etiology, surgical technique, complications, flap survival rate and duration of follow-up. Of these ten patients, three were men, and seven were women; the average age was 48.1 years (range, 34–66 years). Four patients underwent bilateral UBMM flaps, and 6 patients underwent unilateral UBMM flap reconstruction. All of the donor sites were closed without complications, except for one small granuloma that occurred 8 months later. Of the total 14 flaps, 7 healed well, 6 healed well after minimal debridement in the clinic, and one failed and was replaced with a contralateral UBMM flap. The average follow-up time was 20.1 months (range, 8–38 months). All patients had satisfactory aesthetic and functional outcomes. Due to the limited availability of healthy local tissue for nasal lining reconstruction after multiple surgeries, the UBMM flap serves as an applicable choice to restore columellar or nasal lining defects, with minimal donor site morbidity and no visible external scarring.
Septal Reconstruction With Folded Porous Polythylene Implants: An Alternative Technique for the Correction of Severe Saddle Nose Deformities in Asian Populations
Authors: Min Peiru , Wang Zhuwei , Zhang Zheng , Zhang Yixin , Pu Zheming
Published: November 2020

Background:

Congenital or secondary deficiency in septal cartilage leads to an unpleasant cosmetic appearance and compromised function as well. Rhinoplasty maneuvers such as spreader graft and septal extension graft with autologous tissue have been exhibited to correct the deformities. However, the relatively severe donor site morbidity stands as a main concern for both surgeons and patients.

Methods:

From January of 2014 to April of 2018, 52 patients presenting septal deformities underwent rhinoplasty with our modified technique. A piece of Medpor (8438) was tailored, folded and then placed as a combination of spreader and septal extension graft. The surgical outcomes were evaluated both objectively and subjectively.

Results:

All the patients were followed up for 12 to 24 months postoperatively. The ratio of tip projection and the nasal length exhibited significant improvement in all our patients. Nasal obstruction subjectively mended among the 24 patients who had airway obstruction complaint preoperatively. Only 2 patients had severe adverse events and the implants were removed instantly.

Conclusions:

With our modified technique, Medpor proved to be an effective and reliable material for the reconstruction of septal cartilage, which provides us an alternative way to achieve extended spreader and septal extension graft with one single implant in the correction of saddle nose.

Level of Evidence: Level IV, therapeutic study.
Intravascular Papillary Endothelial Hyperplasia as a Cause of Reversible Vision Loss
Authors: Liu Catherine , Daigle Patrick , Munoz David G. , Nijhawan Navdeep
Published: November 2020

Intravascular papillary endothelial hyperplasia (IPEH) is a benign vascular lesion that is formally diagnosed on histopathology. IPEH seldom presents in periocular tissues and is even less commonly seen deep within the orbit. As with cavernous hemangioma, this lesion tends to distort surrounding structures and can cause a significant mass effect in the orbit. The authors present an unusual case of orbital IPEH that resulted in severe proptosis and progressive vision loss from optic nerve compression. In toto surgical excision of the lesion resulted in significant recovery of vision loss and resolution of symptoms associated with proptosis. To the best of our knowledge, this case is the first to illustrate the potential for visual recovery after surgery in a patient with compressive optic neuropathy from orbital IPEH.
The Hematopoietic Stem/Progenitor Cell Response to Hemorrhage, Injury, and Sepsis: A Review of Pathophysiology
Authors: Kelly Lauren S. , Darden Dijoia B. , Fenner Brittany P. , Efron Philip A. , Mohr Alicia M.
Published: November 2020

Hematopoietic stem/progenitor cells (HSPC) have both unique and common responses following hemorrhage, injury, and sepsis. HSPCs from different lineages have a distinctive response to these “stress” signals. Inflammation, via the production of inflammatory factors, including cytokines, hormones, and interferons, has been demonstrated to impact the differentiation and function of HSPCs. In response to injury, hemorrhagic shock, and sepsis, cellular phenotypic changes and altered function occur, demonstrating the rapid response and potential adaptability of bone marrow hematopoietic cells. In this review, we summarize the pathophysiology of emergency myelopoiesis and the role of myeloid-derived suppressor cells, impaired erythropoiesis, as well as the mobilization of HSPCs from the bone marrow. Finally, we discuss potential therapeutic options to optimize HSPC function after severe trauma or infection.
Telemedicine for neuro-ophthalmology: challenges and opportunities
Authors: Liu Yin Allison , Ko Melissa W. , Moss Heather E.
Published: November 2020

Purpose of review

Telemedicine for neuro-ophthalmology (tele-neuro-ophthalmology) has the potential to increase access to neuro-ophthalmic care by improving efficiency and decreasing the need for long-distance travel for patients. Requirements for decreased person-to-person contacts during the COVID-19 pandemic accelerated adoption of tele-neuro-ophthalmology. This review highlights the challenges and opportunities with tele-neuro-ophthalmology.

Recent findings

Tele-neuro-ophthalmology programs can be used for triage, diagnostic consultation, and long-term treatment monitoring. Formats include telephone appointments, interprofessional collaborations, remote data interpretation, online asynchronous patient communication, and video visits. Barriers to long-term implementation of tele-neuro-ophthalmology arise from data quality, patient engagement, workflow integration, state and federal regulations, and reimbursement. General neurologists may collaborate with local eye care providers for ophthalmic examination, imaging, and testing to facilitate efficient and effective tele-neuro-ophthalmology consultation.

Tele-neuro-ophthalmology has tremendous potential to improve patient access to high-quality cost-effective neuro-ophthalmic care. However, many factors may impact its long-term sustainability.
Vision loss and hallucinations: perspectives from neurology and ophthalmology
Authors: Hamedani Ali G.
Published: November 2020

Purpose of review

The aim of this article is to summarize the evidence for visual impairment as a risk factor for visual hallucinations in neurologic disease and recent advances in our understanding of the central visual pathways that mediate this association.

Recent findings

Recent studies have described the prevalence Charles Bonnet syndrome and questioned its lack of association with cognitive impairment, used advanced neuroimaging to show that disinhibition of the occipital lobe is involved in the pathogenesis of visual hallucinations in Parkinson's disease, and demonstrated that visual impairment because of eye disease is a consistent risk factor for visual hallucinations across a number of different neurodegenerative disease populations.

Through connections between the primary visual cortex and other brain structures, visual function is closely tied to visual hallucinations. Given that the vast majority of vision loss is caused by ophthalmic disease, much of which is preventable or treatable, the detection and treatment of vision loss in at-risk populations may reduce the burden and consequences of visual hallucinations in older adults.
Identification of a novel lineage of Crimean–Congo haemorrhagic fever virus in dromedary camels, United Arab Emirates
Authors: Khalafalla Abdelmalik I. , Li Yan , Uehara Anna , Hussein Nasareldien A. , Zhang Jing , Tao Ying , Bergeron Eric , Ibrahim Ibrahim H. , Al Hosani Mohamed A. , Yusof Mohd F. , Alhammadi Zulaikha M. , Alyammahi Saeed M. , Gasim Esmat F. , Ishag Hassan Z. A. , Hosani Farida A. l. , Gerber Susan I. , Almuhairi Salama S. , Tong Suxiang
Published: November 2020

Crimean–Congo haemorrhagic fever virus (CCHFV) is a tick-borne virus causing Crimean–Congo haemorrhagic fever (CCHF), a disease reported to have a high fatality rate in numerous countries. The virus is geographically widespread due to its vector, and numerous wild and domestic animals can develop asymptomatic infection. Serological and limited molecular evidence of CCHFV has previously been reported in Camelus dromedarius (the dromedary, or one-humped camel) in the United Arab Emirates (UAE). In this study, 238 camel samples were screened for CCHFV RNA where 16 camel samples were positive for CCHFV by RT-PCR. Analysis of full-length CCHFV genome sequences revealed a novel lineage in camels from the UAE, and potential reassortment of the M segment of the genome.
A Survey of Provider Satisfaction of a New, Flexible Extended-Length Pharyngeal Airway to Relieve Upper Airway Obstruction During Deep Sedation
Authors: McMurray Roxanne , Gordan Leah
Published: November 2020

Background

Maintaining an open airway in a spontaneously-breathing patient under deep sedation, or deep monitored anaesthesia care, can be challenging. Specifically, current oral airways are not long enough to displace obstruction caused by redundant pharyngeal tissue, prompting external maneuvers by anesthetists that can impact patient outcomes and facility operational efficiency. As procedures increase at outpatient surgical centers, there is a need for an anesthesia provider-validated airway device that can sufficiently open an obstructed airway and maintain airway patency.

Methods

This prospective, multi-center user-experience survey evaluated anesthesia provider experience of a new airway device for adult patients with airway obstruction during deep sedation. The novel external airway has a longer flexible tubing allowing for displacement of pharyngeal tissue, smaller diameter to allow placement alongside an endoscopy bite block, and is manufactured with softer material to allow ease of insertion and patient comfort.

Results

Fifty-four anaesthetists at 15 hospital systems reported their experience of airway use in 86 cases. The novel airway device was 95% successful in establishing and maintaining a patent airway (n=68). Survey responses indicated that the airway was easy to place (93%), allowed for a “hands-off approach” (98%), and would improve airway management practice and patient outcomes (86%).

Conclusions

This pilot study demonstrated that the novel external airway is an effective and satisfactory method for anaesthesia providers to alleviate airway obstruction during deep sedation. Additional studies will be initiated to confirm efficacy and cost-effectiveness in patient populations and clinical environments that will most benefit from the new airway device.
Protein phosphatase 2A, complement component 4, and APOE genotype linked to Alzheimer’s disease using a systems biology approach
Authors: Jun Gyungah R. , You Yang , Zhu Congcong , Meng Gaoyuan , Chung Jaeyoon , Panitch Rebecca , Hu Junming , Xia Weiming ,   The Alzheimer’s Disease Genetics Consortium, Bennett David A. , Foroud Tatiana M. , Wang Li-San , Haines Jonathan L. , Mayeux Richard , Pericak-Vance Margaret A. , Schellenberg Gerard D. , Au Rhoda , Lunetta Kathryn L. , Ikezu Tsuneya , Stein Thor D. , Farrer Lindsay A.
Published: November 2020

Background

Recent reports suggest that the rare apolipoprotein E (APOE) Christchurch mutation and ε2 allele protect against Alzheimer’s disease (AD) pathology by reducing the burden of tau pathology. However, the mechanism(s) underlying the ε2 protective effect linking to tau is largely unknown.

Methods

The role of the ε2 allele in Alzheimer’s disease (AD) was investigated a genome-wide association study (GWAS) for AD among 2,120 ε2 carriers from the Alzheimer Disease Genetics Consortium (ADGC), and then prioritized by gene network analysis, differential gene expression analysis at tissue- and cell-levels as well as methylation profiling of CpG sites, in prefrontal cortex tissue from 761 brains of the Religious Orders Study and Memory and Aging Project (ROSMAP) and the Framingham Heart Study (FHS), Boston University Alzheimer’s Disease Center (BUADC). The levels of two catalytic subunit proteins from protein phosphatase 2A (PPP2CA and PPP2CB) were validated in prefrontal cortex area of 193 of the FHS/BUADC brains. The findings from human autopsied brains were further validated by a co-culture experiment of human isogenic APOE induced pluripotent stem cell (iPSC) derived neurons and astrocytes.

Results

Of the significantly associated loci with AD among APOE ε2 carriers (P<10−6), PPP2CB (P=1.1×10−7) was the key node in the APOE ε2-related gene network and contained the most significant CpG site (P=7.3×10−4) located 2,814 base pair upstream of the top-ranked GWAS variant. Among APOE ε3/ε4 subjects, the level of Aβ42 was negatively correlated with protein levels of PPP2CA (P=9.9×10−3) and PPP2CB (P=2.4×10−3), and PPP2CA level was correlated with the level of pTau231 level (P=5.3×10−3). Significant correlations were also observed for PPP2CB with complement 4B (C4B) protein levels (P=3.3×10−7) and PPP2CA with cross reactive protein (CRP) levels (P=6.4×10−4). C1q level was not associated with Aβ42, pTau231, PPP2CB, or C4B levels. We confirmed the significant correlation of PPP2CB expression with pTau231/tTau ratio (P=0.01) and C4A/B (P=2.0×10−4) expression observed in brain tissue in a co-culture experiment of iPSC derived neurons and astrocytes.

Conclusion

We demonstrated for the first time a molecular link between a tau phosphatase and the classical complement pathway, especially C4, and AD-related tau pathology.
Largest GWAS (N=1,126,563) of Alzheimer’s Disease Implicates Microglia and Immune Cells
Authors: Wightman Douglas P , Jansen Iris E , Savage Jeanne E. , Shadrin Alexey A , Bahrami Shahram , Rongve Arvid , Børte Sigrid , Winsvold Bendik S , Drange Ole Kristian , Martinsen Amy E , Skogholt Anne Heidi , Willer Cristen , Bråthen Geir , Bosnes Ingunn , Nielsen Jonas Bille , Fritsche Lars , Thomas Laurent F. , Pedersen Linda M , Gabrielsen Maiken E , Johnsen Marianne Bakke , Meisingset Tore Wergeland , Zhou Wei , Proitsi Petra , Hodges Angela , Dobson Richard , Velayudhan Latha ,   23andMe Research Team, Sealock Julia M , Davis Lea K , Pedersen Nancy L. , Reynolds Chandra A. , Karlsson Ida K. , Magnusson Sigurdur , Stefansson Hreinn , Thordardottir Steinunn , Jonsson Palmi V. , Snaedal Jon , Zettergren Anna , Skoog Ingmar , Kern Silke , Waern Margda , Zetterberg Henrik , Blennow Kaj , Stordal Eystein , Hveem Kristian , Zwart John-Anker , Athanasiu Lavinia , Saltvedt Ingvild , Sando Sigrid B , Ulstein Ingun , Djurovic Srdjan , Fladby Tormod , Aarsland Dag , Selbæk Geir , Ripke Stephan , Stefansson Kari , Andreassen Ole A. , Posthuma Danielle
Published: November 2020

Late-onset Alzheimer’s disease is a prevalent age-related polygenic disease that accounts for 50-70% of dementia cases1. Late-onset Alzheimer’s disease is caused by a combination of many genetic variants with small effect sizes and environmental influences. Currently, only a fraction of the genetic variants underlying Alzheimer’s disease have been identified2,3. Here we show that increased sample sizes allowed for identification of seven novel genetic loci contributing to Alzheimer’s disease. We highlighted eight potentially causal genes where gene expression changes are likely to explain the association. Human microglia were found as the only cell type where the gene expression pattern was significantly associated with the Alzheimer’s disease association signal. Gene set analysis identified four independent pathways for associated variants to influence disease pathology. Our results support the importance of microglia, amyloid and tau aggregation, and immune response in Alzheimer’s disease. We anticipate that through collaboration the results from this study can be included in larger meta-analyses of Alzheimer’s disease to identify further genetic variants which contribute to Alzheimer’s pathology. Furthermore, the increased understanding of the mechanisms that mediate the effect of genetic variants on disease progression will help identify potential pathways and gene-sets as targets for drug development.
The Time Course of Clinical Oxygenator Failure Due to Clot Formation
Authors: Demarest Caitlin T. , Shoemaker Samantha J. , Salna Michael P. , Chicotka Scott R. , Fung Kenmond , Bacchetta Matthew D. , Antaki James F. , Cook Keith E.
Published: November 2020

Background

Long-term use of extracorporeal membrane oxygenation (ECMO) remains limited because of poor biocompatibility, which often leads to clot formation and device failure. Despite this common pathway to failure, there are no published studies on the rate of clot formation and resulting performance deficits in current oxygenators.

Methods

ECMO cases with either Maquet’s CardioHelp (CH, n=28) or Quadrox (Qx, n=14) oxygenators were evaluated over a three-month period. Data was collected prospectively and included patient characteristics and hematological data. The inlet-outlet oxygen content difference (ΔCO2) and blood flow resistance were calculated as measures of device function, and device failure due to clot formation was defined as a resistance increase greater than 1 mmHg/(L/min)/day for more than one day.

Results

There were no statistically significant differences in patient age, total days on ECMO, platelet count (PLT) prior to ECMO, activated partial thromboplastin time during ECMO, initial resistance, and device blood flow rate. During ECMO, the Qx group had a significantly greater change in PLT (Qx: - 34±10%; CH: 7±15%), rapidity to failure due to clot formation, and a greater decline in ΔCO2 (all p<0.05). Clot burden was focused at the center of the CH oxygenator, farthest from all inlets, whereas Qx devices developed a more diffuse clot pattern.

Conclusions

Qx oxygenators clot earlier than CH oxygenators with a correlated drop in ΔCO2 and greater PLT reduction. These differences are likely due to the distributed, four-inlet CH design vs. the single inlet Qx design and differences in pump-induced platelet activation.
Sensitivity Analysis on Predictive Capability of SIRD Model for Coronavirus Disease (COVID-19)
Authors: Sedaghat Ahmad , Alkhatib Fadi , Oloomi Seyed Amir Abbas , Malayer Mahdi Ashtian , Mosavi Amir
Published: November 2020

SIR model is one of the simplest methods used in prediction of endemic/pandemic outbreaks. We examined SIRD model for development of COVID-19 in Kuwait which was started on 24 February 2020 by 5 patients in Kuwait. This paper investigates sensitivity of SIRD model for development of COVID-19 in Kuwait based on duration of progressed days of data. For Kuwait, we have fitted SIRD model to COVID-19 data for 20, 40, 60, 80, 100, and 116 days of data and assessed sensitivity of the model with number of days of data. The parameters of SIRD model are obtained using an optimization algorithm (lsqcurvefit) in MATLAB. The total population of 50,000 is equally applied for all Kuwait time intervals. Results of SIRD model indicates that after 40 days the peak infectious day can be adequately predicted; althogh, error percentage from sensetivity analysis indicates that different exposed population sizes are not correctly predicted. SIRD type models are too simple to robustly capture all features of COVID-19 and more precise methods are needed to tackle nonlinear dynamics of a pandemic.
Sensitive quantitative detection of SARS-CoV-2 in clinical samples using digital warm-start CRISPR assay
Authors: Ding Xiong , Yin Kun , Li Ziyue , Sfeir Maroun M. , Liu Changchun
Published: November 2020

Quantifying severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in clinical samples is crucial for assessing the infectivity of coronavirus disease 2019 and the efficacy of antiviral drugs. Here, we describe a digital warm-start CRISPR (WS-CRISPR) assay for sensitive quantitative detection of SARS-CoV-2 in clinical samples. The WS-CRISPR assay combines low-temperature reverse transcription dual-priming mediated isothermal amplification (RT-DAMP) and CRISPR-Cas12a-based detection in one-pot, attributed to the mediation role by pyrophosphatase and phosphorothioated primers. The WS-CRISPR assay is initiated at above 50 °C and overcomes undesired premature target amplification at room temperature, enabling accurate digital nucleic acid quantification. By targeting SARS-CoV-2’s nucleoprotein gene, digital WS-CRISPR assay is able to detect down to 5 copies/μl SARS-CoV-2 RNA in the chip within 90 minutes. It is clinically validated by quantitatively determining 32 clinical swab samples and three clinical saliva samples, showing 100% agreement with RT-PCR results. Moreover, the digital WS-CRISPR assay has been demonstrated to directly detect SARS-CoV-2 in heat-treated saliva samples without RNA extraction, showing high tolerance to inhibitors. Thus, the digital WS-CRISPR method, as a sensitive and reliable CRISPR assay, facilitates accurate SARS-CoV-2 detection toward digitized quantification.
N439K variant in spike protein may alter the infection efficiency and antigenicity of SARS-CoV-2 based on molecular dynamics simulation
Authors: Zhou Wenyang , Xu Chang , Wang Pingping , Luo Meng , Xu Zhaochun , Cheng Rui , Jin Xiyun , Guo Yu , Xue Guangfu , Juan Liran , Nie Huan , Jiang Qinghua
Published: November 2020

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), causing an outbreak of coronavirus disease 2019 (COVID-19), has been undergoing various mutations. The analysis of the structural and energetic effects of mutations on protein-protein interactions between the receptor binding domain (RBD) of SARS-CoV-2 and angiotensin converting enzyme 2 (ACE2) or neutralizing monoclonal antibodies will be beneficial for epidemic surveillance, diagnosis, and optimization of neutralizing agents. According to the molecular dynamics simulation, a key mutation N439K in the SARS-CoV-2 RBD region created a new salt bridge which resulted in greater electrostatic complementarity. Furthermore, the N439K-mutated RBD bound hACE2 with a higher affinity than wild-type, which may lead to more infectious. In addition, the N439K-mutated RBD was markedly resistant to the SARS-CoV-2 neutralizing antibody REGN10987, which may lead to the failure of neutralization. These findings would offer guidance on the development of neutralizing antibodies and the prevention of COVID-19.
Interactions of anti-COVID-19 drug candidates with multispecific ABC and OATP drug transporters
Authors: Telbisz Ágnes , Ambrus Csilla , Mózner Orsolya , Szabó Edit , Várady György , Bakos Éva , Sarkadi Balázs , Özvegy-Laczka Csilla
Published: November 2020

In the COVID-19 epidemic, several repurposed drugs have been proposed to alleviate the major health effects of the disease. These drugs are often applied together with analgesics or non-steroid anti-inflammatory compounds, and co-morbid patients may also be treated with anticancer, cholesterol-lowering or antidiabetic agents. Since drug ADME-tox properties may be significantly affected by multispecific transporters, here we examined the interactions of the repurposed drugs with the key human multidrug transporters, present in the major tissue barriers and strongly affecting pharmacokinetics. Our in vitro studies, using a variety of model systems, explored the interactions of the antimalarial agents chloroquine and hydroxychloroquine, the antihelmintic ivermectin, and the proposed antiviral compounds, ritonavir, lopinavir, favipiravir and remdesivir with the ABCB1/Pgp, ABCG2/BCRP and ABCC1/MRP1 exporters, as well as the OATP2B1 and OATP1A2 uptake transporters. The results presented here show numerous pharmacologically relevant transporter interactions and may provide a warning for the potential toxicities of these repurposed drugs, especially in drug combinations at the clinic.
Metabolic profile discriminates and predictsArabidopsissusceptibility to virus under field conditions
Authors: Rubio Bernadette , Fernandez Olivier , Cosson Patrick , Berton Thierry , Caballero Mélodie , Roux Fabrice , Bergelson Joy , Gibon Yves , Schurdi-Levraud Valérie
Published: November 2020

As obligatory parasites, plant viruses alter host cellular metabolism. There is a lack of information on the variability of virus-induced metabolic responses among genetically diverse plants in a natural context with daily changing conditions. To decipher the metabolic landscape of plant-virus interactions in a natural setting, one hundred and thirty-two and twenty-six accessions ofArabidopsis thalianawere inoculated withTurnip mosaic virus(TuMV), in two field experiments over 2 years. The accessions were phenotyped for viral accumulation, above-ground biomass, targeted and untargeted metabolic profiles. The accessions revealed quantitative response to the virus, from susceptibility to resistance. Susceptible accessions accumulate primary and secondary metabolites upon infection, at the cost of hindered growth. Orthogonal Partial Least Squares-Discriminant Analysis (OPLS-DA) revealed that the primary metabolites sucrose, glucose and glutamate discriminate susceptible and resistant accessions. Twenty-one metabolic signatures were found to significantly accumulate in resistant accessions whereas they maintained their growth at the same level as mock-inoculated plants without biomass penalty.

Metabolic content was demonstrated to discriminate and to be highly predictive of the susceptibility of inoculatedArabidopsis. The PLS coefficient estimated in the training data set reveals, after cross-validation, a correlation of 0.61 between predicted and true viral accumulation. This study is the first to describe the metabolic landscape of plant-virus interactions in a natural setting and its predictive link to susceptibility. It reveals that, in this undomesticated species and in ecologically realistic conditions, growth and resistance are in a permanent conversation and provides new insights on plant-virus interactions.
Challenges for targeting SARS-CoV-2 proteases as a therapeutic strategy for COVID-19
Authors: Steuten Kas , Kim Heeyoung , Widen John C. , Babin Brett M. , Onguka Ouma , Lovell Scott , Bolgi Oguz , Cerikan Berati , Cortese Mirko , Muir Ryan K. , Bennett John M. , Geiss-Friedlander Ruth , Peters Christoph , Bartenschlager Ralf , Bogyo Matthew
Published: November 2020

Two proteases produced by the SARS-CoV-2 virus, Mproand PLpro, are essential for viral replication and have become the focus of drug development programs for treatment of COVID-19. We screened a highly focused library of compounds containing covalent warheads designed to target cysteine proteases to identify new lead scaffolds for both Mproand PLproproteases. These efforts identified a small number of hits for the Mproprotease and no viable hits for the PLproprotease. Of the Mprohits identified as inhibitors of the purified recombinant protease, only two compounds inhibited viral infectivity in cellular infection assays. However, we observed a substantial drop in antiviral potency upon expression of TMPRSS2, a transmembrane serine protease that acts in an alternative viral entry pathway to the lysosomal cathepsins. This loss of potency is explained by the fact that our lead Mproinhibitors are also potent inhibitors of host cell cysteine cathepsins. To determine if this is a general property of Mproinhibitors, we evaluated several recently reported compounds and found that they are also effective inhibitors of purified human cathepsin L and B and showed similar loss in activity in cells expressing TMPRSS2. Our results highlight the challenges of targeting Mproand PLproproteases and demonstrate the need to carefully assess selectivity of SARS-CoV-2 protease inhibitors to prevent clinical advancement of compounds that function through inhibition of a redundant viral entry pathway.
Association of renal function with diabetic retinopathy and macular edema among patients with type 2 diabetes mellitus
Authors: Wang Lanhua , Jin Ling , Wang Wei , Gong Xia , Li Yuting , Li Wangting , Meng Jie , Liang Xiaoling , Huang Wenyong , Liu Yizhi
Published: November 2020

Purpose

To investigate the associations between renal function and the presence of diabetic retinopathy (DR) in diabetic patients.

Methods

A total of 1877 diabetic participants aged 30 to 80 years were consecutively recruited from October 2017 to April 2019. All participants underwent blood and urine analyses and standardized 7-field fundus imaging. The presence of DR, vision-threatening DR (VTDR) and DME was graded based on the fundus photographs. Renal function was defined as normal, mildly impaired or chronic kidney disease (CKD) based on different estimated glomerular filtration rates (GFRs).

Results

Unlike a normal GFR, CKD was significantly associated with any DR (OR=1.89, P=0.017) and VTDR (OR=2.76, P=0.009), and mildly impaired renal function was associated with only any DR (OR=1.39, P=0.031). The analysis of the effect of microalbuminuria on relationship between GFR and DR showed that the GFR was associated with any DR only in the presence of microalbuminuria, while the GFR was an independent risk factor for VTDR regardless of microalbuminuria status (all P<0.05). The risks of any DR (OR=1.74 for quartile 2 and 3.09 for quartile 4) and VTDR (OR=3.27 for quartile 2 and 6.41 for quartile 4) increased gradually as the microalbuminuria quartile increased (all P<0.05). The third (OR=2.99, P=0.029) and fourth microalbuminuria quartiles (OR=4.74, P=0.002) were independent DME risk factors.

Conclusions

There was a strong association between GFR and VTDR, whereas the association of GFR and any DR was significant only under the premise of microalbuminuria. High microalbuminuria was significantly associated with DR and DME.
Stable neutralizing antibody levels six months after mild and severe COVID-19 episode
Authors: Pradenas Edwards , Trinité Benjamin , Urrea Víctor , Marfil Silvia , Ávila-Nieto Carlos , de la Concepción María Luisa Rodríguez , Tarrés-Freixas Ferran , Pérez-Yanes Silvia , Rovirosa Carla , Ainsua-Enrich Erola , Rodon Jordi , Vergara-Alert Júlia , Segalés Joaquim , Guallar Victor , Valencia Alfonso , Izquierdo-Useros Nuria , Paredes Roger , Mateu Lourdes , Chamorro Anna , Massanella Marta , Carrillo Jorge , Clotet Bonaventura , Blanco Julià
Published: November 2020

Understanding mid-term kinetics of immunity to SARS-CoV-2 is the cornerstone for public health control of the pandemic and vaccine development. However, current evidence is rather based on limited measurements, thus losing sight of the temporal pattern of these changes1–6. In this longitudinal analysis, conducted on a prospective cohort of COVID-19 patients followed up to 242 days, we found that individuals with mild or asymptomatic infection experienced an insignificant decay in neutralizing activity that persisted six months after symptom onset or diagnosis. Hospitalized individuals showed higher neutralizing titers, which decreased following a two-phase pattern, with an initial rapid decline that significantly slowed after day 80. Despite this initial decay, neutralizing activity at six months remained higher among hospitalized individuals. The slow decline in neutralizing activity at mid-term contrasted with the steep slope of antibody titers change, reinforcing the hypothesis that the quality of immune response evolves over the post-convalescent stage4,5.
Peptide Ancestry Informative Markers in Uterine Neoplasms from Women of European, African and Asian Ancestry
Authors: Bateman Nicholas W. , Tarney Christopher M. , Abulez Tamara S. , Hood Brian L. , Conrads Kelly A. , Zhou Ming , Soltis Anthony R. , Teng Pang-ing , Jackson Amanda , Tian Chunqiao , Dalgard Clifton L. , Wilkerson Matthew D. , Kessler Michael D. , Goecker Zachary , Loffredo Jeremy , Shriver Craig D , Hu Hai , Cote Michele , Parker Glendon J. , Segars James , Al-Hendy Ayman , Risinger John R. , Darcy Kathleen M. , Casablanca Yovanni , Maxwell G. Larry , Conrads Thomas P. , O’Connor Timothy D.
Published: November 2020

Characterization of ancestry-linked peptide variants in disease-relevant patient tissues represents a foundational step to connect patient ancestry with molecular disease pathogenesis. Nonsynonymous single nucleotide polymorphisms (SNPs) encoding missense substitutions within tryptic peptides exhibiting high allele frequencies in European, African, and East Asian populations, termed peptide ancestry informative markers (pAIMs), were prioritized from 1000 genomes.In silicoanalysis shows that as few as 20 pAIMs can determine ancestry proportions similarly to >260K SNPs (R2=0.9905). Multiplexed proteomic analysis of >100 human endometrial cancer cell lines and uterine leiomyoma tissues resulted in the quantitation of 62 pAIMs that correlate with self-described race and genotype-confirmed patient ancestry. Candidates include a D451E substitution in GC vitamin D-binding protein previously associated with altered vitamin D levels in African and European populations. These efforts describe a generalized set of markers for proteoancestry assessment that will further support studies investigating the impact of ancestry on the human proteome and how this relates to the pathogenesis of uterine neoplasms.
Different RNA profiles in plasma derived small and large extracellular vesicles of Neurodegenerative diseases patients
Authors: Sproviero Daisy , Gagliardi Stella , Zucca Susanna , Arigoni Maddalena , Giannini Marta , Garofalo Maria , Olivero Martina , Dell’Orco Michela , Pansarasa Orietta , Bernuzzi Stefano , Avenali Micol , Ramusino Matteo Cotta , Diamanti Luca , Minafra Brigida , Perini Giulia , Zangaglia Roberta , Costa Alfredo , Ceroni Mauro , Perrone-Bizzozero Nora I. , Calogero Raffaele A. , Cereda Cristina
Published: November 2020

Background

Identifying robust biomarkers is essential for early diagnosis of neurodegenerative diseases (NDs). Large (LEVs) and small extracellular vesicles (SEVs) are extracellular vesicles (EVs) of different sizes and biological functions transported in blood and they may be valid biomarkers for NDs. The aim of our study was to investigate common and different mRNA/miRNA signatures in plasma derived LEVs and SEVs of Alzheimer’s Disease (AD), Parkinson’s disease (PD), Amyotrophic Lateral Sclerosis (ALS) and Fronto-Temporal Dementia (FTD) patients.

Methods

LEVs and SEVs were isolated from plasma of patients and healthy volunteers (CTR) by filtration and ultracentrifugation and RNA was extracted. Whole transcriptome and miRNA libraries were carried out by Next Generation Sequencing (NGS).

Results

We detected different deregulated RNAs in LEVs and SEVs from patients with the same disease. MiRNAs resulted to be the most interesting subpopulation of transcripts transported by plasma derived SEVs since they appeared to discriminate all NDs disease from CTRs and they can provide a signature for each NDs. Common enriched pathways for SEVs were mainly linked to ubiquitin mediated proteolysis and Toll-like receptor signaling pathways and for LEVs to neurotrophin signaling and Glycosphingolipid biosynthesis pathway.

Conclusion

LEVs and SEVs are involved in different pathways and this might give a specificity to their role in the spreading/protection of the disease. The study of common and different RNAs transported by LEVs and SEVs can be of great interest for biomarker discovery and for pathogenesis studies in neurodegeneration.
Antagonistic fungal enterotoxins intersect at multiple levels with host innate immune defences
Authors: Zhang Xing , Harding Benjamin , Aggad Dina , Courtine Damien , Chen Jia-Xuan , Pujol Nathalie , Ewbank Jonathan J.
Published: November 2020

Animals and plants need to defend themselves from pathogen attack. Their defences drive innovation in virulence mechanisms, leading to never-ending cycles of co-evolution in both hosts and pathogens. A full understanding of host immunity therefore requires examination of pathogen virulence strategies. Here, we take advantage of the well-studied innate immune system ofCaenorhabditis elegansto dissect the action of two virulence factors from its natural fungal pathogenDrechmeria coniospora. We show that these two enterotoxins have strikingly different effects when expressed individually in the nematode epidermis. One is able to interfere with diverse aspects of host cell biology, altering vesicle trafficking and preventing the key STAT-like transcription factor STA-2 from activating defensive antimicrobial peptide gene expression. The second, potentially as a consequence of a host surveillance mechanism, increases STA-2 levels in the nucleus, modifies the nucleolus, and causes increased defence gene expression. Our results highlight the remarkably complex and potentially antagonistic mechanisms that come into play in the interaction between co-evolved hosts and pathogens.