bluuebunny/crossref_metadata_2025 huggingface dataset:
“Sharing Hope and Healing”: A Culturally Tailored Social Media Campaign to Promote Living Kidney Donation and Transplantation Among Native Americans
Authors: Britt Rebecca K. , Britt Brian C. , Anderson Jenn , Fahrenwald Nancy , Harming Shana
Published: December 2020

In this article, the authors discuss a community-based participatory research (CBPR)–driven and culturally tailored social media campaign to promote living kidney donation and transplantation (LKDT) serving Native American communities, who are disproportionately burdened by kidney failure. The effort represents a collaboration among researchers, tribal leaders and community members, medical centers, and other stakeholders to facilitate health promotion related to LKDT among the broader Native American community. Campaign objectives were collaboratively established by the researchers and stakeholders, and the campaign approach and materials were likewise developed in consultation with the community. The results indicated that the use of success stories about LKDT within campaign materials was a statistically significant predictors of heightened campaign engagement (p = .003, β = .223). Recommendations are offered for partnering with tribal communities and other stakeholders, as well as for building tailored health promotion strategies.
Targeting laryngeal cancer cells with 5-fluorouracil and curcumin using mesoporous silica nanoparticles
Authors: Wang Ding , Yu Dan , Liu Xueshibojie , Wang Qian , Chen Xuyang , Hu Xindan , Wang Qiong , Jin Chunshun , Wen Lianji , Zhang Ling
Published: December 2020

Objective:

To explore the inhibitory and synergistic effects of 5-fluorouracil and curcumin on Hep-2 laryngeal cancer cells and clarify the effect of mesoporous silica nanoparticles as drug carriers.

Methods:

The inhibitory effects of 5-fluorouracil and curcumin on Hep-2 cells were detected using the CCK-8 assay. CompuSyn was used to calculate the synergistic effect of the 2 drugs. Flow cytometry was used to detect apoptosis and cell cycle arrest induced by 5-fluorouracil and curcumin. The drugs were loaded into mesoporous nanoparticles. Western blotting was used to detect the expression of related proteins after treatment. The growth of subcutaneous tumors in BALB/c nude after the intraperitoneal injection with drug-loaded mesoporous silica nanoparticles was recorded.

Results:

5-Fluorouracil and curcumin synergistically induced apoptosis and cell cycle arrest in Hep-2 cells. Mesoporous silica nanoparticles as drug carriers enhanced the therapeutic effects of 5-fluorouracil and curcumin.

Conclusions:

Mesoporous silica nanoparticles are expected to be effective drug carriers that enhance the synergistic effects of 5-fluorouracil and curcumin on laryngeal cancer.
The Potential Role of CERS1 in Autophagy Through PI3K/AKT Signaling Pathway in Hypophysoma
Authors: Wang Jingtao , Zhang Jimin , Ma Dongzhou , Li Xiushan
Published: December 2020

To explore the role and mechanism of CERS1 in hypophysoma and investigate whether CERS1 overexpression can change the autophagy process of hypophysoma, and then to explore whether CERS1’s effect was regulated by the PI3K/AKT signaling pathway. Western blot and RT-PCR were used to analyze the expression or mRNA level of CERS1 at different tissues or cell lines. Afterwards, the occurrence and development of hypophysoma in vivo and in vitro, respectively, was observed by using CERS1 overexpression by lentivirus. Finally, MK-2206 and LY294002 were applied to discuss whether the role of CERS1 was regulated by the PI3K/AKT signaling pathway. Results show that the CERS1 expression and mRNA level in tumor or AtT-20 cells were decreased. CERS1 over-expressed by lentivirus could inhibit hypophysoma development in vivo and in vitro by reducing tumor volume and weight, weakening tumor proliferation and invasion, and enhancing apoptosis. In addition, shCERS1 could reverse the process. The above results indicate that CERS1 is possibly able to enhance autophagy in hypophysoma through the PI3K/AKT signaling pathway.
Ten-Year Experience of Stereotactic Body Radiotherapy at a Single Institution: Impact of Technological Development on the Outcome of Patients With Early Lung Cancer
Authors: Koiwai Keiichiro , Endo Yuuki , Mizuhata Kai , Ina Hironobu , Fukazawa Ayumu , Ozawa Takesumi , Fujinaga Yasunari
Published: December 2020

Purpose:

Advanced radiotherapeutic techniques and apparatus have been developed and widely applied in stereotactic body radiation therapy for early-stage non-small cell lung cancer, but their clinical benefits have not necessarily been confirmed. This study was performed to review our 10-year experience with therapy for the disease and to evaluate whether the advanced radiotherapeutic system implemented in our hospital 5 years after we began the therapy improved the clinical outcomes of patients.

Materials and Methods:

Patients who underwent the therapy at our hospital between April 2008 and March 2018 were retrospectively reviewed. They were divided into 2 groups treated with the conventional system or the advanced system, and the characteristics and clinical outcomes were compared between the groups. The same analyses were also performed in propensity-matched patients from the 2 groups.

Results:

Among the 73 patients eligible for this study, 42 were treated with the conventional system and 31 with the advanced system. All were treated as planned, and severe adverse events were rare. The local progression-free survival rate in the advanced system group was significantly higher than in the conventional system group (P = 0.025). In the propensity-matched patients, both the local progression-free survival rate and the overall survival rate were significantly higher compared in the advanced system group than the conventional system group (P = 0.089 and 0.080, respectively).

Conclusion:

The advanced system improved the outcomes of patients with the disease, suggesting that technological development has had a strong impact on clinical outcomes.
Mental Health, Sexual Orientation, and Perceived Social Network Support in Relation to Hazardous Alcohol Consumption Among Active Duty Military Men
Authors: Blair Cheríe S. , Dunlap Shannon , Tzen Michael , Castro Carl A. , Goldbach Jeremy T. , Holloway Ian W.
Published: December 2020

Knowledge surrounding perceived network support and alcohol consumption among active duty U.S. military personnel is limited, particularly among sexual minorities.

We sought to determine the correlates of hazardous alcohol consumption and whether perceived network support moderated the relationship between sexual orientation and Alcohol Use Identification Test (AUDIT-C) score.

The sample comprised cisgender men currently serving in the U.S. military ( N = 292). Participants were recruited through respondent-driven sampling and completed an online survey. Logistic regression analysis evaluated associations between positive AUDIT-C with sociodemographic characteristics (including sexual orientation), military service, mental health, and perceived social network support. Interaction analysis assessed the moderating effect of perceived network support on sexual orientation and AUDIT-C.

Among study participants, 52.7% (154/292) had positive AUDIT-C, while 65.4% (191/292) self-identified as heterosexual/straight and 34.6% (101/292) identified as gay or bisexual. In adjusted analysis, positive AUDIT-C was associated with increased post-traumatic stress disorder symptomatology (adjusted odds ratio [adjOR] 1.03; 95% CI [1.00, 1.06]; p = .019) and high perceived network support (adjOR 1.85; 95% CI [1.04, 3.29]; p = .036), while mental health service utilization had reduced odds of positive AUDIT-C (adjOR 0.40; 95% CI [0.20, 0.78]; p = .007). In interaction analysis, high perceived network support was associated with increased odds of positive AUDIT-C among sexual minority men (adjOR 3.09; 95% CI [1.21, 7.93]; p = .019) but not heterosexual men (adjOR 1.38; 95% CI [0.68, 2.81]; p = .37).

Hazardous alcohol use was prevalent among all men in our sample. Perceived social network support may influence hazardous alcohol consumption, particularly among sexual minority servicemen. These findings suggest the potential role of tailored social network-based interventions to decrease hazardous alcohol use among military personnel.
Nutrition Strategies for Reducing Risk of Burnout Among Physicians and Health Care Professionals
Authors: Esquivel Monica Kazlausky
Published: December 2020

Under typical circumstances, up to half of physicians, 31% of nurses who provide direct patient care, and 37% of nurses working in nursing homes experience burnout, and these rates are likely exacerbated following the Coronavirus disease 2019 pandemic. Diet is a mediating and modifiable factor with regard to burnout risk. Chronic stress, such as the stress experienced by individuals suffering from burnout, has been shown to influence the amounts and types of foods individuals eat, contributing both to excessive eating and undereating and the development of chronic diseases. Dietary strategies to mitigate burnout for physicians and health care professionals should be developed based on existing evidence related to nutrition and mental health, incorporate effective behavior change theory, and include systems-level change to promote healthy eating among health care professionals. Evidence supports the application of the Mediterranean diet, cognitive behavioral theory, and mindful eating interventions. Policy and systems approaches should support the availability of healthy foods at employer-sponsored events and eating outlets, worksite wellness, and nutrition education in medical training curriculum.
Use of distal protection filter device for rescue mechanical thrombectomy for symptomatic free-floating thrombus of the cervical internal carotid artery
Authors: Denezpi Taryn M , Green Ross S , Carlson Andrew P
Published: December 2020

Background

Intraluminal free floating thrombus (FFT) of the cervical internal carotid artery (ICA) is a potentially high-risk lesion for recurrent ischemic strokes, with no single optimal treatment established.

Objective

To describe a novel interventional technique for mechanical thrombectomy of intraluminal free floating thrombus using a distal protection filter device and aspiration.

Methods

We identified two cases where anticoagulation was contraindicated in patients with intraluminal FFT and minimal underlying stenosis. In both cases, a distal protection device was used to extract the thrombus under proximal flow arrest and aspiration.

Results

Mechanical thrombectomy was successful in both cases, one with “en bloc” removal of the thrombus and one with piecemeal removal. Neither case showed any residual angiographic stenosis or atherosclerotic disease.

Conclusion

Mechanical thrombectomy using a distal protection device is a novel and technically feasible approach for select cases of cervical intraluminal thrombus. This may represent a therapeutic option in select cases with high risk of anticoagulation and in the unusual subset of younger patients with minimal atherosclerotidc disease.
Asymptomatic thrombosis of extrahepatic portal vein aneurysm necessitating hybrid operative repair
Authors: Gorolay Vineet , Nguyen Daniel , Samra Jaswinder , Neale Michael
Published: December 2020

Background

Congenital portal vein aneurysm is a rare vascular anomaly with poorly understood natural history. Whereas asymptomatic aneurysms are often managed conservatively, surgery has been used in symptomatic cases complicated by thrombosis or rupture. Surgical experience in management of portal aneurysms is restricted to case studies with limited comparative data and inconsistent reporting of outcomes. A hybrid open and endovascular approach has rarely been described in the literature.

Methods

We present a case of an extrahepatic portal aneurysm which demonstrated changes on surveillance imaging concerning for early asymptomatic thrombosis. Acute thrombus was identified at the time of open aneurysm repair. We review the limited literature regarding management of portal vein aneurysms in non-cirrhotic patients.

Results

Our case was complicated by intrahepatic thrombo-embolism, which necessitated hybrid thrombectomy and anticoagulant therapy. The patient remains asymptomatic at three-year follow-up with no recurrent aneurysm or thrombosis on surveillance Doppler and CT imaging.

Conclusions

Altered hemodynamic appearances on Doppler ultrasound and contrast-enhanced CT may warn of impending thrombosis in portal vein aneurysms. Hybrid open and endovascular surgical repair ensures vessel patency and a durable surgical result.
Surface replacing arthroplasty of the proximal interphalangeal joint using the CapFlex-PIP implant: a prospective study with 5-year outcomes
Authors: Reischenböck Vanessa , Marks Miriam , Herren Daniel B. , Schindele Stephan
Published: December 2020

The purpose of this prospective study was to evaluate the 5-year outcomes in patients after proximal interphalangeal joint arthroplasty using the surface replacing implant, CapFlex-PIP. Ninety-two prosthesis were implanted and 65 patients with 68 implants were available for follow-up. The brief Michigan Hand Outcomes Questionnaire score improved significantly from 45 (SD 15) before surgery to 71 (SD 17) at 5 years. On the numeric rating scale, pain during activities decreased significantly from 6.4 (SD 1.9) to 1.8 (SD 1.9). Range of motion of the joints increased significantly from 45° (SD 21) to 54° (SD 24). An axis deviation of more than 5° was found in 65% of the joints before surgery, but only in 25% at 5 years. Soft tissue reoperations were performed on eight patients. Four out of 92 implants underwent revision for stiffness or implant loosening. In three implants, the distal component migrated without needing revision. Overall, the CapFlex-PIP implant demonstrates favourable medium-term results in surface replacing arthroplasty of the proximal interphalangeal joint.

Level of evidence: IV
Glycemic Metrics Derived From Intermittently Scanned Continuous Glucose Monitoring
Authors: Hansen Klavs Würgler , Bibby Bo Martin
Published: December 2020

Background:

Glucose data from intermittently scanned continuous glucose monitoring (isCGM) is a combination of scanned and imported glucose values. The present knowledge of glycemic metrics originate mostly from glucose data from real-time CGM sampled every five minutes with a lack of information derived from isCGM.

Methods:

Glucose data obtained with isCGM and hemoglobin A1c (HbA1c) were obtained from 169 patients with type 1 diabetes. Sixty-one patients had two observations with an interval of more than three months.

Results:

The best regression line of HbA1c against mean glucose was observed from 60 days prior to HbA1c measurement as compared to 14, 30, and 90 days. The difference between HbA1c and estimated HbA1c (=glucose management indicator [GMI]) first observed correlated with the second observation (R2 0.61, P < .001). Time in range (TIR, glucose between 3.9 and 10 mmol/L) was significantly related to GMI (R2 0.87, P < .001). A TIR of 70% corresponded to a GMI of 6.8% (95% confidence interval, 6.3-7.4). The fraction of patients with the optimal combination of TIR >70% and time below range (TBR) <4% was 3.6%. The fraction of patients with TBR>4% was four times higher for those with high glycemic variability (coefficient of variation [CV] >36%) than for those with lower CV.

Conclusion:

The individual difference between HbA1c and GMI was reproducible. High glycemic variability was related to increased TBR. A combination of TIR and TBR is suggested as a new composite quality indicator.
Providing Compassionate Care: The Role of Medical Students and Videoconference Technology in the COVID-19 Pandemic
Authors: Suresh Deepika , Flatley Kevin , McDonough Margaret , Cochran-Caggiano Nicholas , Inglis Peter , Fordyce Samuel , Schachter Allison , Acosta Ernesto , Wales Danielle , Jacob Jackcy
Published: December 2020

Patient and family communication is a well-known factor associated with improved patient outcomes. During the COVID-19 pandemic, visitation restrictions meant communication with patients and their families became a challenge, particularly with intubated patients in the intensive care unit. As the hospital filled with COVID-19 patients, medical students and physicians at Albany Medical Center identified the urgent need for a better communication method with families. In response, the COVID-19 Compassion Coalition (CCC) was formed. The CCC’s goal was to decrease the distress felt by families unable to visit their hospitalized loved ones. They developed a streamlined process for videoconferencing between patients on COVID-19 units and their families by using tablets. Having medical students take responsibility for this process allowed nurses and physicians to focus on patient care. Incorporating videoconferencing technology can allow physicians and nurses to better connect with families, especially during unprecedented times like a pandemic.
Reclaiming the city one plot at a time? DIY garden projects, radical democracy, and the politics of spatial appropriation
Authors: Bach Claire E , McClintock Nathan
Published: December 2020

Unsanctioned guerrilla gardens, long a feature of North American cities, are frequently planted as radical challenge to conventional urban land use. Over the past decade, a number of community-led garden projects – projets citoyens – have appeared on sidewalks and in vacant lots, and alleys of Montreal, Quebec’s inner-core neighborhoods under the banner of “appropriating” or “reclaiming” urban space. In this article, we examine the rise of these DIY (do-it-yourself) garden projects and the extent to which they have been institutionalized via municipal agencies and NGOs. We find the distinction between institutionalized and guerrilla projects to be quite blurry, and ask whether such spaces – and the social relations forged within and between them – are able to effectively challenge hegemonic abstract space (as conceived by Lefebvre) and contribute to a radical democratic urban politics (as conceived by Rancière). We conclude that the power of these projects to transform capitalist urban space and challenge the dominant socio-spatial order is limited. We argue, however, that their transformative potential lies instead in their functioning as spaces of political subject formation, where participants collaboratively articulate counter-hegemonic imaginaries and master the skills of collective autogestion – albeit only for a small and relatively homogenous group of Montrealers. Critical attention to absent and silenced voices and self-reflexive awareness of historical and contemporary processes of exclusion and displacement are crucial in order for these projects to become truly radical democratic spaces.
A cost–benefit analysis of implementing urban heat island adaptation measures in small- and medium-sized cities in Austria
Authors: Johnson Daniel , See Linda , Oswald Sandro M , Prokop Gundula , Krisztin Tamás
Published: December 2020

Urban heat islands are an increasing concern even in small- to medium-sized cities, although these areas are still understudied especially in terms of the economic feasibility of adaptation options. This paper uses adaptation scenarios produced by an urban climate model as inputs to a social cost–benefit analysis in three small- to medium-sized cities in Austria: Mödling, Klagenfurt, and Salzburg. The adaptation scenarios, which consider measures such as increasing the reflectivity of different sealed surfaces (referred to as the White City scenario) as well as greening measures (i.e. the Green City scenario), show decreases in the number of hot days (Tmax ≥30°C) when implemented. Benefits include reductions in heat-related mortality, which are modeled based on trends of daily mortality and climate data, reduced morbidity, productivity loss, and numerous urban ecosystem services. The results demonstrate favorable benefit–cost ratios of a combination of measures (White and Green City) of 1.27, 1.36, and 2.68 for Mödling, Klagenfurt, and Salzburg, respectively, indicating positive economic grounds for supporting policies in line with the adaptation scenarios. Furthermore, results of the Green City vs. White City showed higher benefits for the combined and Green City scenarios despite higher costs for each of the cities.
Commoning the Established Order of Property: Reclaiming Fishing Commons in Mumbai
Authors: Kamath Lalitha , Dubey Gopal
Published: December 2020

This article narrates how a fisherfolk community comprising original inhabitants of Mumbai has been spatially squeezed and choked by surrounding urban developments, compelling them to turn away from their customary livelihoods and ways of living. The community resists this through a political project of indigenous reclaiming. The project is material in nature—focused on reclaiming alienated lands—but also imaginative—reasserting a newly imagined, albeit contested, identity as a fishing community founded on repurposing its fishing commons and reconfiguring the dominant notion of property as private. Using the lens of boundaries allows us to understand the closures and opportunities presented by these complex urban transformations. Overall, the fishers’ reclamation is directed at redefining, contesting, blurring and ‘commoning’ the established ordering boundary of private property that erases their customary claims—their remembered boundary spans not just the village settlement but also the land–sea commons—and is seen as unjust.
Hypermanganesemia-Induced Cerebral Toxicity Mimicking an Acute Ischemic Stroke: A Case Report and Review of Overlapping Pathologies
Authors: Reinert Justin P. , Garner Michael , Forbes Laramie
Published: December 2020

Objective: To review and consider risk factors associated with the accumulation of and toxicity from manganese in patients receiving total parenteral nutrition (TPN). Case Summary: A 66-year-old female presented to the emergency department with right facial and arm weakness that initiated 1 hour prior to admission. Past medical history includes oral cancer with chronic aspiration and gastroparesis secondary to chemotherapy, TPN for 9 months, and a previous episode of right facial and arm parasthesias due to hypertensive emergency 4 years prior. The patient was assigned a National Institutes of Health Stroke Scale score of 6, cleared of an intracranial hemorrhage on imaging, and was administered tPA (tissue plasminogen activator) for an acute ischemic stroke after managing her hypertension to <185/110 mm Hg. Resolution of symptoms occurred within 24 hours. A magnetic resonance imaging of the patient’s brain 24-hours post-tPA indicated an increased signal density in the globus pallidus, which in turn is linked with encephalopathy and has been described as a marker for hypermanganesemia. Discussion: Manganese is an essential trace element with a critical role in numerous physiologic functions. Though readily obtained from dietary sources and rarely causing issue, manganese provided to patients via TPN may result in toxicities. Though the presentation of neurotoxicities associated with TPN-delivered manganese has been previously documented, the clinical presentation of toxicity has never mimicked an acute ischemic stroke. Conclusion: Though an evaluation of overlapping pathologies is warranted, this patient’s clinical presentation of manganese toxicity mimicked an acute ischemic stroke and resulted in the administration of a fibrinolytic. A more comprehensive appreciation of the implications of trace elements is demanded of clinicians.
Pharmacological Management of Steroid-Induced Psychosis: A Review of Patient Cases
Authors: Huynh Grace , Reinert Justin P.
Published: December 2020

Objective: To review the efficacy and safety of medications used in the management of steroid-induced psychosis. Data Sources: A comprehensive literature search was conducted using PubMed, MEDLINE, ProQuest, and Scopus between May and October 2020 using the following search terminology: “steroid-induced psychosis” OR “corticosteroid-induced psychosis.” Study Selection and Data Extraction: Definitive cases, as defined by the Diagnostic and Statistical Manual of Mental Disorders, 5th edition, were included in this review. Geriatric patients >65 years of age, those with a confounding neurological condition such as a traumatic brain or spinal cord injury, or those with active malignancy were excluded. Data Synthesis: A total of 13 patient cases were included in this review, representing 8 male patients and 5 female patients. The mean age at symptom presentation was 42.5 years. Six patients presented with delusions, 5 presented with hallucinations, and 2 presented with both manifestations; 12 patients were managed with an antipsychotic, with haloperidol being the most commonly prescribed, followed by risperidone. One patient was managed with lithium and clonazepam alone. All patients returned to their psychological baseline upon the discontinuation or decreased dose of steroids in combination with Pharmacological intervention, though the time to resolution of symptoms varied significantly. No notable adverse drug events associated with treatments were reported. Conclusions: Steroid-induced psychosis is a serious adverse effect of corticosteroid therapy; however, management strategies that combine a dose reduction or elimination of steroids, in combination with an antipsychotic medication, are effective in resolving this syndrome.
EQSIM—A multidisciplinary framework for fault-to-structure earthquake simulations on exascale computers part I: Computational models and workflow
Authors: McCallen David , Petersson Anders , Rodgers Arthur , Pitarka Arben , Miah Mamun , Petrone Floriana , Sjogreen Bjorn , Abrahamson Norman , Tang Houjun
Published: December 2020

Computational simulations have become central to the seismic analysis and design of major infrastructure over the past several decades. Most major structures are now “proof tested” virtually through representative simulations of earthquake-induced response. More recently, with the advancement of high-performance computing (HPC) platforms and the associated massively parallel computational ecosystems, simulation is beginning to play a role in increased understanding and prediction of ground motions for earthquake hazard assessments. However, the computational requirements for regional-scale geophysics-based ground motion simulations are extreme, which has restricted the frequency resolution of direct simulations and limited the ability to perform the large number of simulations required to numerically explore the problem parametric space. In this article, recent developments toward an integrated, multidisciplinary earth science-engineering computational framework for the regional-scale simulation of both ground motions and resulting structural response are described with a particular emphasis on advancing simulations to frequencies relevant to engineered systems. This multidisciplinary computational development is being carried out as part of the US Department of Energy (DOE) Exascale Computing Project with the goal of achieving a computational framework poised to exploit emerging DOE exaflop computer platforms scheduled for the 2022–2023 timeframe.
Glucocorticoid-induced eosinopenia results from CXCR4-dependent bone marrow migration
Authors: Hong So Gun , Sato Noriko , Legrand Fanny , Gadkari Manasi , Makiya Michelle , Stokes Kindra , Howe Katherine N. , Yu Shiqin Judy , Linde Nathaniel Seth , Clevenger Randall R. , Hunt Timothy , Hu Zonghui , Choyke Peter L. , Dunbar Cynthia E. , Klion Amy D. , Franco Luis M.
Published: December 2020

Glucocorticoids are considered first-line therapy in a variety of eosinophilic disorders. They lead to a transient, profound decrease in circulating human eosinophils within hours of administration. The phenomenon of glucocorticoid-induced eosinopenia has been the basis for the use of glucocorticoids in eosinophilic disorders, and it has intrigued clinicians for 7 decades, yet its mechanism remains unexplained. To investigate, we first studied the response of circulating eosinophils to in vivo glucocorticoid administration in 3 species and found that the response in rhesus macaques, but not in mice, closely resembled that in humans. We then developed an isolation technique to purify rhesus macaque eosinophils from peripheral blood and performed live tracking of zirconium-89-oxine–labeled eosinophils by serial positron emission tomography/computed tomography imaging, before and after administration of glucocorticoids. Glucocorticoids induced rapid bone marrow homing of eosinophils. The kinetics of glucocorticoid-induced eosinopenia and bone marrow migration were consistent with those of the induction of the glucocorticoid-responsive chemokine receptor CXCR4, and selective blockade of CXCR4 reduced or eliminated the early glucocorticoid-induced reduction in blood eosinophils. Our results indicate that glucocorticoid-induced eosinopenia results from CXCR4-dependent migration of eosinophils to the bone marrow. These findings provide insight into the mechanism of action of glucocorticoids in eosinophilic disorders, with implications for the study of glucocorticoid resistance and the development of more targeted therapies. The human study was registered at ClinicalTrials.gov as #NCT02798523.
Local blood coagulation drives cancer cell arrest and brain metastasis in a mouse model
Authors: Feinauer Manuel J. , Schneider Stefan W. , Berghoff Anna S. , Robador Jose Ramon , Tehranian Cedric , Karreman Matthia A. , Venkataramani Varun , Solecki Gergely , Grosch Julia Katharina , Gunkel Katharina , Kovalchuk Bogdana , Mayer Frank Thomas , Fischer Manuel , Breckwoldt Michael O. , Brune Maik , Schwab Yannick , Wick Wolfgang , Bauer Alexander T. , Winkler Frank
Published: December 2020

Clinically relevant brain metastases (BMs) frequently form in cancer patients, with limited options for effective treatment. Circulating cancer cells must first permanently arrest in brain microvessels to colonize the brain, but the critical factors in this process are not well understood. Here, in vivo multiphoton laser-scanning microscopy of the entire brain metastatic cascade allowed unprecedented insights into how blood clot formation and von Willebrand factor (VWF) deposition determine the arrest of circulating cancer cells and subsequent brain colonization in mice. Clot formation in brain microvessels occurred frequently (>95%) and specifically at intravascularly arrested cancer cells, allowing their long-term arrest. An extensive clot embedded ∼20% of brain-arrested cancer cells, and those were more likely to successfully extravasate and form a macrometastasis. Mechanistically, the generation of tissue factor-mediated thrombin by cancer cells accounted for local activation of plasmatic coagulation in the brain. Thrombin inhibition by treatment with low molecular weight heparin or dabigatran and an anti-VWF antibody prevented clot formation, cancer cell arrest, extravasation, and the formation of brain macrometastases. In contrast, tumor cells were not able to directly activate platelets, and antiplatelet treatments did reduce platelet dispositions at intravascular cancer cells but did not reduce overall formation of BMs. In conclusion, our data show that plasmatic coagulation is activated early by intravascular tumor cells in the brain with subsequent clot formation, which led us to discover a novel and specific mechanism that is crucial for brain colonization. Direct or indirect thrombin and VWF inhibitors emerge as promising drug candidates for trials on prevention of BMs.
Eculizumab discontinuation in children and adults with atypical hemolytic-uremic syndrome: a prospective multicenter study
Authors: Fakhouri Fadi , Fila Marc , Hummel Aurélie , Ribes David , Sellier-Leclerc Anne-Laure , Ville Simon , Pouteil-Noble Claire , Coindre Jean-Philippe , Le Quintrec Moglie , Rondeau Eric , Boyer Olivia , Provôt François , Djeddi Djamal , Hanf William , Delmas Yahsou , Louillet Ferielle , Lahoche Annie , Favre Guillaume , Châtelet Valérie , Launay Emma Allain , Presne Claire , Zaloszyc Ariane , Caillard Sophie , Bally Stéphane , Raimbourg Quentin , Tricot Leïla , Mousson Christiane , Le Thuaut Aurélie , Loirat Chantal , Frémeaux-Bacchi Véronique
Published: December 2020

The optimal duration of eculizumab treatment in patients with atypical hemolytic uremic syndrome (aHUS) remains poorly defined. We conducted a prospective national multicenter open-label study to assess eculizumab discontinuation in children and adults with aHUS. Fifty-five patients (including 19 children) discontinued eculizumab (mean treatment duration, 16.5 months). Twenty-eight patients (51%) had rare variants in complement genes, mostly in MCP (n = 12; 22%), CFH (n = 6; 11%), and CFI (n = 6; 10%). At eculizumab discontinuation, 17 (30%) and 4 patients (7%) had stage 3 and 4 chronic kidney disease, respectively. During follow-up, 13 patients (23%; 6 children and 7 adults) experienced aHUS relapse. In multivariable analysis, female sex and presence of a rare variant in a complement gene were associated with an increased risk of aHUS relapse, whereas requirement for dialysis during a previous episode of acute aHUS was not. In addition, increased sC5b-9 plasma level at eculizumab discontinuation was associated with a higher risk of aHUS relapse in all patients and in the subset of carriers with a complement gene rare variant, both by log-rank test and in multivariable analysis. Of the 13 relapsing patients, all of whom restarted eculizumab, 11 regained their baseline renal function and 2 had a worsening of their preexisting chronic kidney disease, including 1 patient who progressed to end-stage renal disease. A strategy of eculizumab discontinuation in aHUS patients based on complement genetics is reasonable and safe. It improves the management and quality of life of a sizeable proportion of aHUS patients while reducing the cost of treatment. This trial was registered at www.clinicaltrials.gov as #NCT02574403.
Identification of novel alternative splicing biomarkers for breast cancer with LC/MS/MS and RNA-Seq
Authors: Zhang Fan , Deng Chris K. , Wang Mu , Deng Bin , Barber Robert , Huang Gang
Published: December 2020

Background

Alternative splicing isoforms have been reported as a new and robust class of diagnostic biomarkers. Over 95% of human genes are estimated to be alternatively spliced as a powerful means of producing functionally diverse proteins from a single gene. The emergence of next-generation sequencing technologies, especially RNA-seq, provides novel insights into large-scale detection and analysis of alternative splicing at the transcriptional level. Advances in Proteomic Technologies such as liquid chromatography coupled tandem mass spectrometry (LC–MS/MS), have shown tremendous power for the parallel characterization of large amount of proteins in biological samples. Although poor correspondence has been generally found from previous qualitative comparative analysis between proteomics and microarray data, significantly higher degrees of correlation have been observed at the level of exon. Combining protein and RNA data by searching LC–MS/MS data against a customized protein database from RNA-Seq may produce a subset of alternatively spliced protein isoform candidates that have higher confidence.

Results

We developed a bioinformatics workflow to discover alternative splicing biomarkers from LC–MS/MS using RNA-Seq. First, we retrieved high confident, novel alternative splicing biomarkers from the breast cancer RNA-Seq database. Then, we translated these sequences into in silico Isoform Junction Peptides, and created a customized alternative splicing database for MS searching. Lastly, we ran the Open Mass spectrometry Search Algorithm against the customized alternative splicing database with breast cancer plasma proteome. Twenty six alternative splicing biomarker peptides with one single intron event and one exon skipping event were identified. Further interpretation of biological pathways with our Integrated Pathway Analysis Database showed that these 26 peptides are associated with Cancer, Signaling, Metabolism, Regulation, Immune System and Hemostasis pathways, which are consistent with the 256 alternative splicing biomarkers from the RNA-Seq.

Conclusions

This paper presents a bioinformatics workflow for using RNA-seq data to discover novel alternative splicing biomarkers from the breast cancer proteome. As a complement to synthetic alternative splicing database technique for alternative splicing identification, this method combines the advantages of two platforms: mass spectrometry and next generation sequencing and can help identify potentially highly sample-specific alternative splicing isoform biomarkers at early-stage of cancer.
Increased usability, algorithmic improvements and incorporation of data mining for structure calculation of proteins with REDCRAFT software package
Authors: Cole Casey , Parks Caleb , Rachele Julian , Valafar Homayoun
Published: December 2020

Background

Traditional approaches to elucidation of protein structures by Nuclear Magnetic Resonance spectroscopy (NMR) rely on distance restraints also known as Nuclear Overhauser effects (NOEs). The use of NOEs as the primary source of structure determination by NMR spectroscopy is time consuming and expensive. Residual Dipolar Couplings (RDCs) have become an alternate approach for structure calculation by NMR spectroscopy. In previous works, the software package REDCRAFT has been presented as a means of harnessing the information containing in RDCs for structure calculation of proteins. However, to meet its full potential, several improvements to REDCRAFT must be made.

Results

In this work, we present improvements to REDCRAFT that include increased usability, better interoperability, and a more robust core algorithm. We have demonstrated the impact of the improved core algorithm in the successful folding of the protein 1A1Z with as high as ±4 Hz of added error. The REDCRAFT computed structure from the highly corrupted data exhibited less than 1.0 Å with respect to the X-ray structure. We have also demonstrated the interoperability of REDCRAFT in a few instances including with PDBMine to reduce the amount of required data in successful folding of proteins to unprecedented levels. Here we have demonstrated the successful folding of the protein 1D3Z (to within 2.4 Å of the X-ray structure) using only N-H RDCs from one alignment medium.

Conclusions

The additional GUI features of REDCRAFT combined with the NEF compliance have significantly increased the flexibility and usability of this software package. The improvements of the core algorithm have substantially improved the robustness of REDCRAFT in utilizing less experimental data both in quality and quantity.
Physiological and transcriptomic analyses reveal the roles of secondary metabolism in the adaptive responses of Stylosanthes to manganese toxicity
Authors: Jia Yidan , Li Xinyong , Liu Qin , Hu Xuan , Li Jifu , Dong Rongshu , Liu Pandao , Liu Guodao , Luo Lijuan , Chen Zhijian
Published: December 2020

Background

As a heavy metal, manganese (Mn) can be toxic to plants. Stylo (Stylosanthes) is an important tropical legume that exhibits tolerance to high levels of Mn. However, little is known about the adaptive responses of stylo to Mn toxicity. Thus, this study integrated both physiological and transcriptomic analyses of stylo subjected to Mn toxicity.

Results

Results showed that excess Mn treatments increased malondialdehyde (MDA) levels in leaves of stylo, resulting in the reduction of leaf chlorophyll concentrations and plant dry weight. In contrast, the activities of enzymes, such as peroxidase (POD), phenylalanine ammonia-lyase (PAL) and polyphenol oxidase (PPO), were significantly increased in stylo leaves upon treatment with increasing Mn levels, particularly Mn levels greater than 400 μM. Transcriptome analysis revealed 2471 up-regulated and 1623 down-regulated genes in stylo leaves subjected to Mn toxicity. Among them, a set of excess Mn up-regulated genes, such as genes encoding PAL, cinnamyl-alcohol dehydrogenases (CADs), chalcone isomerase (CHI), chalcone synthase (CHS) and flavonol synthase (FLS), were enriched in secondary metabolic processes based on gene ontology (GO) analysis. Numerous genes associated with transcription factors (TFs), such as genes belonging to the C2H2 zinc finger transcription factor, WRKY and MYB families, were also regulated by Mn in stylo leaves. Furthermore, the C2H2 and MYB transcription factors were predicted to be involved in the transcriptional regulation of genes that participate in secondary metabolism in stylo during Mn exposure. Interestingly, the activation of secondary metabolism-related genes probably resulted in increased levels of secondary metabolites, including total phenols, flavonoids, tannins and anthocyanidins.

Conclusions

Taken together, this study reveals the roles of secondary metabolism in the adaptive responses of stylo to Mn toxicity, which is probably regulated by specific transcription factors.
Time series prediction of under-five mortality rates for Nigeria: comparative analysis of artificial neural networks, Holt-Winters exponential smoothing and autoregressive integrated moving average models
Authors: Adeyinka Daniel Adedayo , Muhajarine Nazeem
Published: December 2020

Background

Accurate forecasting model for under-five mortality rate (U5MR) is essential for policy actions and planning. While studies have used traditional time series modeling techniques (e.g., autoregressive integrated moving average (ARIMA) and Holt-Winters smoothing exponential methods), their appropriateness to predict noisy and non-linear data (such as childhood mortality) has been debated. The objective of this study was to model long-term U5MR with group method of data handling (GMDH)-type artificial neural network (ANN), and compare the forecasts with the commonly used conventional statistical methods—ARIMA regression and Holt-Winters exponential smoothing models.

Methods

The historical dataset of annual U5MR in Nigeria from 1964 to 2017 was obtained from the official website of World Bank. The optimal models for each forecasting methods were used for forecasting mortality rates to 2030 (ending of Sustainable Development Goal era). The predictive performances of the three methods were evaluated, based on root mean squared errors (RMSE), root mean absolute error (RMAE) and modified Nash-Sutcliffe efficiency (NSE) coefficient. Statistically significant differences in loss function between forecasts of GMDH-type ANN model compared to each of the ARIMA and Holt-Winters models were assessed with Diebold-Mariano (DM) test and Deming regression.

Results

The modified NSE coefficient was slightly lower for Holt-Winters methods (96.7%), compared to GMDH-type ANN (99.8%) and ARIMA (99.6%). The RMSE of GMDH-type ANN (0.09) was lower than ARIMA (0.23) and Holt-Winters (2.87). Similarly, RMAE was lowest for GMDH-type ANN (0.25), compared with ARIMA (0.41) and Holt-Winters (1.20). From the DM test, the mean absolute error (MAE) was significantly lower for GMDH-type ANN, compared with ARIMA (difference = 0.11,p-value = 0.0003), and Holt-Winters model (difference = 0.62, p-value< 0.001). Based on the intercepts from Deming regression, the predictions from GMDH-type ANN were more accurate (β0 = 0.004 ± standard error: 0.06; 95% confidence interval: − 0.113 to 0.122).

Conclusions

GMDH-type neural network performed better in predicting and forecasting of under-five mortality rates for Nigeria, compared to the ARIMA and Holt-Winters models. Therefore, GMDH-type ANN might be more suitable for data with non-linear or unknown distribution, such as childhood mortality. GMDH-type ANN increases forecasting accuracy of childhood mortalities in order to inform policy actions in Nigeria.
Risk factors for a positive SARS-CoV-2 PCR in patients with common cold symptoms in a primary care setting – a retrospective analysis based on a joint documentation standard
Authors: Just Johannes , Puth Marie-Therese , Regenold Felix , Weckbecker Klaus , Bleckwenn Markus
Published: December 2020

Background

Combating the COVID-19 pandemic is a major challenge for health systems, citizens and policy makers worldwide. Early detection of affected patients within the large and heterogeneous group of patients with common cold symptoms is an important element of this effort, but often hindered by limited testing resources, false-negative test results and the lack of pathognomonic symptoms in COVID-19. Therefore, we aimed to identify anamnestic items with an increased/decreased odds ratio for a positive SARS-CoV-2 PCR (CovPCR) result in a primary care setting.

Methods

We performed a multi-center cross-sectional cohort study on predictive clinical characteristics for a positive CovPCR over a period of 4 weeks in primary care patients in Germany.

Results

In total, 374 patients in 14 primary care centers received CovPCR and were included in this analysis. The median age was 44.0 (IQR: 31.0–59.0) and a fraction of 10.7% (n = 40) tested positive for COVID-19. Patients who reported anosmia had a higher odds ratio (OR: 4.54; 95%-CI: 1.51–13.67) for a positive test result while patients with a sore throat had a lower OR (OR: 0.33; 95%-CI: 0.11–0.97). Furthermore, patients who had a first grade contact with an infected persons and showed symptoms themselves also had an increased OR for positive testing (OR: 5.16; 95% CI: 1.72–15.51). This correlation was also present when they themselves were still asymptomatic (OR: 12.55; 95% CI: 3.97–39.67).

Conclusions

Several anamnestic criteria may be helpful to assess pre-test probability of COVID-19 in patients with common cold symptoms.
Mortality is not increased with Diabetes in hospitalised very old adults: a multi-site review
Authors: Smerdely Peter
Published: December 2020

Background

Few data exist regarding hospital outcomes in people with diabetes aged beyond 75 years. This study aimed to explore the association of diabetes with hospital outcome in the very old patient.

Methods

A retrospective review was conducted of all presentations of patients aged 65 years or more admitted to three Sydney teaching hospitals over 6 years (2012–2018), exploring primarily the outcomes of in-hospital mortality, and secondarily the outcomes of length of stay, the development of hospital-acquired adverse events and unplanned re-admission to hospital within 28 days of discharge. Demographic and outcome data, the presence of diabetes and comorbidities were determined from ICD10 coding within the hospital’s electronic medical record. Logistic and negative binomial regression models were used to assess the association of diabetes with outcome.

Results

A total of 139,130 separations (mean age 80 years, range 65 to 107 years; 51% female) were included, with 49% having documented comorbidities and 26.1% a diagnosis of diabetes.

When compared to people without diabetes, diabetes was not associated with increased odds of mortality (OR: 0.89 SE (0.02), p < 0.001). Further, because of a significant interaction with age, diabetes was associated with decreased odds of mortality beyond 80 years of age. While people with diabetes overall had longer lengths of stay (10.2 days SD (13.4) v 9.4 days SD (12.3), p < 0.001), increasing age was associated with shorter lengths of stay in people aged more than 90 years. Diabetes was associated with increased odds of hospital-acquired adverse events (OR: 1.09 SE (0.02), p < 0.001) and but not 28-day re-admission (OR: 0.88 SE (0.18), p = 0.523).

Conclusion

Diabetes has not been shown to have a negative impact on mortality or length of stay in hospitalised very old adults from data derived from hospital administrative records. This may allow a more measured application of diabetic guidelines in the very old hospitalised patient.