bluuebunny/crossref_metadata_2025 huggingface dataset:
Endoscopic Gastrointestinal Anastomosis Using Lumen-apposing Metal Stent (LAMS) for Benign or Malignant Etiologies
Authors: Hakim Seifeldin , Khan Zubair , Shrivastava Ashish , Koroglu Emine , Patil Prithvi , Akyuz Filiz , Akyuz Umit , Ramireddy Srinivas , Badillo Ricardo , DaVee Tomas , Thosani Nirav
Published: October 2020

Background and Aim:

Endoscopic gastrointestinal anastomosis using lumen-apposing metal stents (EGAL) is a new technique that is used as an alternative method to bypass benign or malignant strictures. Endoscopists take advantage of 2 bowel loops that are close to each other and place a stent between the lumen of these 2 bowel loops. The authors performed this systematic review and meta-analysis to evaluate the efficacy and safety of this rising procedure.

Methods:

Electronic database searches were conducted for full eligible articles that were published from the inception to July 2019 using the EGAL procedure to bypass malignant or benign obstruction or to restore bowel integrity after a gastrointestinal altering surgery. The primary outcome of this meta-analysis was to assess efficacy through technical and clinical success. Secondary outcomes were to assess safety through adverse events and to assess the rate of stent maldeployment and the rate of reintervention during the study period.

Results:

Eight studies were eligible, providing data on 269 patients who underwent 271 EGAL procedures. The median age was 65 years (interquartile range: 63 to 66) with 46% male individuals. Out of 269 patients, 203 underwent EGALs because of malignant etiology and 66 underwent EGAL for benign etiology. The median duration of follow-up was 114 days (interquartile range: 78 to 121). Technical success rate was 94.1% [95% confidence interval (CI), 91.4%-96.9%]. Clinical success rate was 91.4% (95% CI, 88.1%-94.7%). Adverse events rate was 8.5% (95% CI, 4.7%-12.3%). Stent maldeployment rate was 9.5% (95% CI, 3.5%-15.4%) of the total performed EGALs and the reintervention rate was 6.0% (95% CI, 2.3%-9.8%).

Conclusion:

EGAL procedure has high efficacy and a relatively safe profile and it can be performed in selected patients. Comparison between EGAL and other conventional therapies is difficult because of the lack of randomized trials.
Proprotein convertase subtilisin/kexin type 9 inhibition as the next statin?
Authors: Rakipovski Günaj , Hovingh G. Kees , Nyberg Michael
Published: October 2020

Purpose of review

Despite the wide use of statins and other LDL-cholesterol (LDL-C)-lowering therapies, atherosclerotic cardiovascular disease remains an important cause of mortality and morbidity. Here, we discuss efficacy, side effects and convenience of current and future therapies inhibiting proprotein convertase subtilisin/kexin type 9 (PCSK9).

Recent findings

Clinical trials with mAbs administered every 2–4 weeks and small interfering RNAs given two to four times per year have consistently demonstrated substantial LDL-C-lowering (40–60%) and improved outcome when added to existing lipid-lowering therapies. Pleiotropic effects of PCSK9 inhibition are somewhat different from those observed with statin treatment as evidenced by reduced levels of triglycerides and lipoprotein(a) with no apparent effect on inflammatory markers in patients treated with PCSK9 inhibitors. Treatment with mAb and small interfering RNA are associated with a high-cost, however, small molecules and vaccines may improve cost and convenience if development of these are successful.

PCSK9 inhibitors are currently considered to be an add-on therapy and whether these drugs will be used as stand-alone and/or as a first choice is dependent on clinical readouts from ongoing and future trials, real-world evidence, convenience and treatment costs.
Digital systems for improving outcomes in patients with primary immune defects
Authors: Rider Nicholas L.
Published: October 2020

Purpose of review

Healthcare has already been impacted by the fourth industrial revolution exemplified by tip of spear technology, such as artificial intelligence and quantum computing. Yet, there is much to be accomplished as systems remain suboptimal, and full interoperability of digital records is not realized. Given the footprint of technology in healthcare, the field of clinical immunology will certainly see improvements related to these tools.

Recent findings

Biomedical informatics spans the gamut of technology in biomedicine. Within this distinct field, advances are being made, which allow for engineering of systems to automate disease detection, create computable phenotypes and improve record portability. Within clinical immunology, technologies are emerging along these lines and are expected to continue.

This review highlights advancements in digital health including learning health systems, electronic phenotyping, artificial intelligence and use of registries. Technological advancements for improving diagnosis and care of patients with primary immunodeficiency diseases is also highlighted.
Current and future regulatory and financial challenges in vascularized composite allotransplantation
Authors: Cooney Carisa M. , Brandacher Gerald
Published: October 2020

Purpose of review

To discuss current and future regulatory and financial issues affecting the field of vascularized composite allotransplantation (VCA).

Recent findings

Vascularized composite allografts are regulated by the US Department of Health and Human Services Organ Procurement and Transplantation Network Final Rule (42 CFR part 121) in the United States and Directive 2010/53/EU of the European Parliament and the Council of 7 July 2010 in the European Union (EU). However, in the United States and most of the EU, VCA is not yet paid for by insurance or third-party payers and many centers depend upon grant funding, philanthropic gifts, and/or supplemental hospital/institutional funding strategies to pay for the transplants and postoperative care.

In the absence of randomized clinical trial data, which is infeasible for studying VCA outcomes, consensus data sets are needed to document these procedures’ value proposition and have them accepted as part of the standard of care. Procedure and immunosuppression protocol variability applied to a small patient cohort necessitates collaborative efforts by field experts to devise creative approaches, such as determining return-on-investment for anatomical subunits, to better understand these transplants’ value and impact on patient quality-of-life.
NK Cell-mediated Neuroblastoma Cell Lysis is Enhanced by IgG From Patients With Pediatric Opsoclonus-Myoclonus Syndrome
Authors: Zar Tahira , Tschernatsch Marlene , Hero Barbara , Lang Bethan , Preissner Klaus T. , Blaes Franz
Published: October 2020

Pediatric opsoclonus-myoclonussyndrome (OMS) is a rare autoimmune disorder of which 50% are associated with neuroblastoma (NB). We investigated whether surface-binding autoantibodies in OMS can enhance natural killer (NK) cell-mediated cytotoxicity in these patients. OMS immunoglobulin G (IgG) bound to NB cell lines and NK cell-mediated cytotoxicity to NB cells was enhanced after preincubation with OMS-IgG, but not IgG from NB without OMS or healthy controls. Activation of NK cells by surface-binding autoantibodies may be an additional mechanism of antitumor immunity in children with NB and OMS.
Recruiting Nurses Via Social Media for Survey Studies
Authors: Bethel Claire , Rainbow Jessica G. , Dudding Katherine M.
Published: October 2020

Background

Nurses are a difficult population to recruit for research. Barriers to recruitment of nurses include survey fatigue, hospital structures and institutional review boards as gatekeepers to accessing participants, and limited generalizability of findings. Social media present innovative opportunities to recruit participants for survey research. However, there is limited information about best practices for recruiting nurses through social media.

Objectives

The aim of this report was to examine the advantages and disadvantages of and determine the best practices for recruiting nurses for survey studies via social media.

Methods

We examined recruitment strategies of three survey studies involving nurse participants. Each study used social exchange theory and leverage-saliency theory to guide recruitment. The studies included were (a) the Travel Nurse Onboarding Study, which recruited participants from a single closed group on Facebook; (b) the Presenteeism and Nursing Study where participants were recruited using association listservs, healthcare organizations, and paid ads and postings on social media; and (c) the Pain and Nursing Study in which participants were recruited through social media, association listservs, and in person at conferences.

Results

Social media offer accessible, low-cost, high-yield approaches to recruitment of nurses for survey studies.

Discussion

Useful strategies for crafting effective recruitment via social media are presented, including how, where, when, and how often to post. The generalizability of social media research is also discussed. Suggestions are provided for researchers using social media as well as guidelines for institutional review boards to address gray areas of social media research. Data integrity protection techniques are proposed to ensure social media survey data are not corrupted by malicious bots. This report outlines best practices for the recruitment of nurses for survey studies using social media.
Mural Intracholecystic Neoplasms Arising in Adenomyomatous Nodules of the Gallbladder
Authors: Rowan Daniel J. , Pehlivanoglu Burcin , Memis Bahar , Bagci Pelin , Erbarut Ipek , Dursun Nevra , Jang Kee-Taek , Sarmiento Juan , Mucientes Francisco , Cheng Jeanette D. , Roa Juan C. , Araya Juan C. , Bellolio Enrique , Losada Hector , Jang Jin-Young , Koshiol Jill , Reid Michelle D. , Basturk Olca , Adsay Volkan
Published: October 2020

Intracholecystic neoplasms (ICNs) (pyloric gland adenomas and intracholecystic papillary neoplasms, collectively also called intracholecystic papillary/tubular neoplasms) form multifocal, extensive proliferations on the gallbladder mucosa and have a high propensity for invasion (>50%). In this study, 19 examples of a poorly characterized phenomenon, mural papillary mucinous lesions that arise in adenomyomatous nodules and form localized ICNs, were analyzed. Two of these were identified in 1750 consecutive cholecystectomies reviewed specifically for this purpose, placing its incidence at 0.1%. Median age was 68 years. Unlike other gallbladder lesions, these were slightly more common in men (female/male=0.8), and 55% had documented cholelithiasis. All were characterized by a compact multilocular, demarcated, cystic lesion with papillary proliferations and mucinous epithelial lining. The lesions’ architecture, distribution, location, and typical size were suggestive of evolution from an underlying adenomyomatous nodule. All had gastric/endocervical-like mucinous epithelium, but 5 also had a focal intestinal-like epithelium. Cytologic atypia was graded as 1 to 3 and defined as 1A: mucinous, without cytoarchitectural atypia (n=3), 1B: mild (n=7), 2: moderate (n=2), and 3: severe atypia (n=7, 3 of which also had invasive carcinoma, 16%). Background gallbladder mucosal involvement was absent in all but 2 cases, both of which had multifocal papillary mucosal nodules. In conclusion, these cases highlight a distinct clinicopathologic entity, that is, mural ICNs arising in adenomyomatous nodules, which, by essentially sparing the “main” mucosa, not displaying “field-effect/defect” phenomenon, and only rarely (16%) showing carcinomatous transformation, are analogous to pancreatic branch duct intraductal papillary mucinous neoplasms.
Regulating Critical Care Ultrasound, It Is All in the Interpretation
Authors: Su Erik , Soni Nilam J. , Blaivas Michael , Bhargava Vidit , Steffen Katherine , Haileselassie Bereketeab
Published: October 2020

Point-of-care ultrasound (POCUS) use is rapidly expanding as a practice in adult and pediatric critical care environments. In January 2020, the Joint Commission endorsed a statement from the Emergency Care Research Institute citing point-of-care ultrasound as a potential hazard to patients for reasons related to training and skill verification, oversight of use, and recordkeeping and accountability mechanisms for clinical use; however, no evidence was presented to support these concerns. Existing data on point-of-care ultrasound practices in pediatric critical care settings verify that point-of-care ultrasound use continues to increase, and contrary to the concerns raised, resources are becoming increasingly available for point-of-care ultrasound use. Many institutions have recognized a successful approach to addressing these concerns that can be achieved through multispecialty collaborations.
Comparison of Regularly Scheduled Ibuprofen Versus “Pro Re Nata” for Ankle Sprains in Children Treated in the Emergency Department
Authors: Lim Rodrick , Sangha Gurinder , Lepore Natasha , Bartlett Katelyn M. , Seabrook Jamie A. , Rieder Michael
Published: October 2020

Objective

We compared pain and degree of disability in patients with acute ankle sprains receiving regular scheduled ibuprofen versus pro re nata (PRN).

Methods

This study is a randomized single-blinded controlled trial of children aged 7 to 17 years presenting with acute ankle sprain to an emergency department. Patients were randomized to receive 10 mg/kg of ibuprofen per dose (maximum 600 mg) every 6 hours regular scheduled versus PRN. Outcome measures included a 100-mm visual analog scale pain and degree of disability at day 4. A sample size of 72 children had a power of 80% to detect a clinically meaningful difference of 20 mm between the regular and PRN group.

Results

We randomly assigned 99 patients to receive regular scheduled (n = 50) or PRN (n = 49) ibuprofen. Pain scores and degree of disability at day 4 showed no significant differences between groups. The rate of reported adverse effects was higher in the regular scheduled group (11.4% vs 9.5%) versus the PRN group.

Conclusions

Our study suggests that there is little benefit from routinely using a regular scheduled ibuprofen regimen for acute pediatric ankle sprains.
Perceived Social Support and Children’s Physiological Responses to Stress: An Examination of the Stress-Buffering Hypothesis
Authors: Chen Lihua , Zilioli Samuele , Jiang Yanping , Wang Xiaolei , Lin Danhua
Published: October 2020

Objective

The current study aimed to examine the stress-buffering effect of children’s perceived social support on their hypothalamic-pituitary-adrenocortical axis and autonomic nervous system reactivity to an acute laboratory stressor.

Methods

A sample of 150 children (aged 9–13 years, mean [standard deviation] age = 10.69 [0.93] years, 74 girls) reported perceived social support, stressful life events, and underwent the Modified Trier Social Stress Test, during which six saliva samples were collected. A two-piece multilevel growth curve model with landmark registration was used to detect trajectory differences in the reactivity and recovery phases of the stress response and account for individual variation in the timing of poststressor peak hormone concentrations.

Results

The interaction between stressful life events and perceived social support significantly predicted poststressor peak cortisol levels (β = 0.0805, SE = 0.0328, p = .015) and cortisol recovery slope (β = −0.0011, SE = 0.0005, p = .040). Children with more life events and low social support exhibited the lowest poststressor peak cortisol levels and the flattest cortisol recovery slope. In contrast, children high in stressful life events and high in social support displayed cortisol response profiles more similar to those of children with low stressful life events. Conversely, there were no statistically significant two-way interactions of stressful life events and perceived social support on salivary α-amylase parameters (i.e., poststressor peak [p = .38], reactivity slope [p = .81], and recovery slope [p = .32]).

Conclusions

These results provide preliminary evidence for the buffering effect of children’s perceived social support on the association between life stress and hypothalamic-pituitary-adrenocortical axis response profiles.
Blood Interleukin-6 Levels Predict Multiple Organ Dysfunction in Critically Ill Patients
Authors: Shimazui Takashi , Nakada Taka-aki , Yazaki Megumi , Mayumi Toshihiko , Takasu Osamu , Matsuda Kenichi , Sasaki Junichi , Otsubo Hiroki , Teshima Yuto , Nabeta Masakazu , Moriguchi Takeshi , Shibusawa Takayuki , Oda Shigeto
Published: October 2020

Background:

Predicting multiple organ dysfunction (MOD) in the late phase of critical illnesses is essential. Cytokines are considered biomarkers that can predict clinical outcomes; however, their predictive value for late-phase MOD is unknown. This study aimed to identify the biomarker with the highest predictive value for late-phase MOD.

Methods:

This observational study prospectively evaluated data on adult patients with systemic inflammatory response syndrome, those who presented to the emergency department or were admitted to intensive care units in five tertiary hospitals (n = 174). Seven blood biomarkers levels (interleukin-6 [IL-6], IL-8, IL-10, tumor-necrosis factor-α, white blood cells, C-reactive protein, and procalcitonin) were measured at three timepoints (days 0, 1, and 2). The area under the receiver operating characteristic curve (AUC) was analyzed to evaluate predictive values for MOD (primary outcome, MOD on day 7 [late-phase]; secondary outcome, MOD on day 3 [early-phase]).

Results:

Of the measured 7 biomarkers, blood IL-6 levels on day 2 had the highest predictive value for MOD on day 7 using single timepoint data (AUC 0.825, 95% confidence interval [CI] 0.754–0.879). Using three timepoint biomarkers, blood IL-6 levels had the highest predictive value of MOD on day 7 (AUC 0.838, 95% CI 0.768–0.890). Blood IL-6 levels using three timepoint biomarkers had also the highest predictive value for MOD on day 3 (AUC 0.836, 95% CI 0.766–0.888).

Conclusion:

Of the measured biomarkers, blood IL-6 levels had the highest predictive value for MOD on days 3 and 7. Blood IL-6 levels predict early- and late-phase MOD in critically ill patients.
Sphingobacterium chungjuense sp. nov., isolated from a freshwater lake
Authors: Song Jaeho , Joung Yochan , Li Shan-Hui , Hwang Juchan , Cho Jang-Cheon
Published: October 2020

A Gram-stain-negative, rod-shaped, aerobic, non-flagellated, chemoheterotrophic bacterium, designated strain IMCC25678T, was isolated from an artificial freshwater reservoir, Chungju Lake, in the Republic of Korea. The 16S rRNA gene sequence analysis indicated that strain IMCC25678T belongs to the genus

Sphingobacterium

with ≤98.7 % sequence similarities to

Sphingobacterium

species. Whole genome sequencing of strain IMCC25678T revealed a 3.9 Mbp genome size with a DNA G+C content of 42.2 mol%. The IMCC25678T genome shared ≤89.7 % average nucleotide identity and ≤21.4 % digital DNA–DNA hybridization values with closely related species of the genus

Sphingobacterium

, indicating that the strain represents a novel species. Summed feature 3 (C16 : 1
 ω6c and/or C16 : 1
 ω7c), iso-C15 : 0 and iso-C17 : 0 3-OH were found to be the predominant cellular fatty acid constituents in the strain. The major respiratory quinone was MK-7. The major polar lipids were phosphatidylethanolamine, one unidentified phosphoglycolipid, one unidentified sphingolipid and three unidentified polar lipids. Based on the phylogenetic and phenotypic characteristics, strain IMCC25678T was considered to represent a novel species within the genus

Sphingobacterium

, for which the name Sphingobacterium chungjuense sp. nov. is proposed. The type strain is IMCC25678T (=KACC 19485T=NBRC 113130T).
Education and income show heterogeneous relationships to lifespan brain and cognitive differences across European and US cohorts
Authors: Walhovd Kristine B. , Fjell Anders M. , Wang Yunpeng , Amlien Inge K. , Mowinckel Athanasia M. , Lindenberger Ulman , Düzel Sandra , Bartrés-Faz David , Ebmeier Klaus P. , Drevon Christian A , Baaré William , Ghisletta Paolo , Johansen Louise Baruël , Kievit Rogier A. , Henson Richard N. , Madsen Kathrine Skak , Nyberg Lars , Harris Jennifer , Solé-Padullés Cristina , Pudas Sara , Sørensen Øystein , Westerhausen René , Zsoldos Enikő , Nawijn Laura , Lyngstad Torkild Hovde , Suri Sana , Penninx Brenda , Røgeberg Ole J. , Brandmaier Andreas M.
Published: October 2020

Socio-economic status (SES) has been proposed to have facilitating and protective effects on brain and cognition. Here we show that relationships between SES, brain volumes and general cognitive ability differ significantly across European and US cohorts (4-97 years, N ≈ 500,000; 54,000 with brain imaging). Education was positively related to intracranial (ICV) and total brain gray matter (GM) volume. Income was related to ICV, but not GM. Relationships varied significantly across samples, and SES was more strongly related to brain and cognition in US than European cohorts. Differences in neuroanatomical volumes explained part of the SES-cognition relationships. SES was more strongly related to ICV than to GM, implying that SES-cognition relations in adulthood are less likely grounded in neuroprotective effects on GM volume in aging. Rather, a relationship may be established early in life. The findings underscore that SES has no uniform association with, or impact on, brain and cognition.
CN-105 in Participants with Acute SupraTentorial IntraCerebral Hemorrhage (CATCH) Trial
Authors: James Michael L. , Troy Jesse , Nowacki Nathaniel , Komisarow Jordan , Swisher Christa B. , Tucker Kristi , Hatton Kevin , Babi Marc A. , Worrall Bradford B. , Andrews Charles , Woo Daniel , Kranz Peter G. , Lascola Christopher , Maughan Maureen , Laskowitz Daniel T. ,   for the CATCH Investigators
Published: October 2020

Background

Endogenous apoliloprotein E mediates neuroinflammatory responses and recovery after brain injury. Exogenously administered apolipoprotein E-mimetic peptides can effectively penetrate the brain and down-regulate acute inflammation. CN-105 is a novel apolipoprotein E-mimetic pentapeptide with excellent preclinical evidence as an acute intracerebral hemorrhage (ICH) therapeutic. TheCN-105 in participants withAcute supraTentorial intraCerebralHemorrhage (CATCH) trial is a first-in-disease-state, multi-center, open-label trial evaluating safety and feasability of CN-105 administration in patients with acute primary supratentorial ICH.

Methods

Eligible patients were age 30-80 years, had confirmed primary supratentorial ICH, and able to intiate CN-105 administration (1.0 mg/kg every 6 hours for 72 hours) within 12 hours of symptom onset.A prioridefined safety endpoints, including hematoma volume, pharmacokinetics, and 30-day neurological outcomes were analyzed. For comparisons, CATCH participants were matched 1:1 with a contemporary ICH cohort through random selection. Hematoma volumes determined from computed tomography images on Days 0, 1, 2, and 5 and ordinal modified Rankin Score at 30 days after ICH were compared.

Results

In 39 participants enrolled across six study sites in the United States, adverse events occurred at expected rate without increase in hematoma expansion or neurological deterioration or significant serum accumulation. CN-105 treatment had an odds ratio (95% confidence interval) of 2.69 (1.31–5.51) for lower 30-day mRS, after adjustment for ICH Score, sex, and race/ethnicity, compared to matched contemporary cohort.

Conclusion

CN-105 administration represents an excellent translational candidate as an actue ICH therapeutic due to its safety, dosing feasibility, favorable pharmacokinetics, and evidence of improved neurological recovery.
Knowledge and practices towards COVID-19 among Palestinians during the COVID-19 outbreak: A second round cross-sectional survey
Authors: Qutob Nouar , Awartani Faisal , Asia Mohammad , Khader Imad Abu
Published: October 2020

Coronavirus disease 2019 (COVID-19) is a highly transmissible illness that spreads rapidly through human-to-human transmission. To assess the knowledge and practices of Palestinians towards COVID-19 after the ease of movement restrictions, we collected data from Palestinian adults between June 15thand June 30th2020. The participants’ pool represented a stratified sample of 1355 adults from Palestinian households across 11 governorates in the West Bank. The questionnaire included 7 demographic questions, 13 questions about participants’ knowledge and awareness of COVID–19, and 4 questions regarding the participants’ safety measures that had been taken in the last three months. Based on the results of this study, we conclude that the majority of participants have a good knowledge about COVID-19, but were not adequately committed to the infection control measures necessary to protect themselves and others. The findings may provide valuable feedback to lawmakers and health administrators to prevent the spread of the epidemic.
Parental acceptance toward behavior guidance techniques for pediatric dental visits: a meta-analysis
Authors: Massignan Carla , Soares Josiane Pezzini , de Souza Pires Maria Marlene , Dick Bruce D. , Porporatti André Luís , De Luca Canto Graziela , Bolan Michele
Published: October 2020

Objective

The systematic review aimed to compare agreement with behavior guidance techniques (BGT) between parents of children with special health care needs (SHCN) and those non-SHCN.

Methods

A structured search of Cochrane Library, Latin American and Caribbean Health Sciences, PubMed, PsycInfo, Scopus, Web of Science, ProQuest Dissertations and Theses Database, Opengrey and Google Scholar was taken up to October 2020. Two authors selected studies independently, extracted the data, assessed the studies’ methodological quality using the Joanna Briggs scale and the Recommendations, Assessment, Development and Evaluation (GRADE).

Results

Forty-eight studies covering the parents’ agreement with BGT were included and 41 were retained for random-effects proportion meta-analysis. The methodological quality assessment varied from low to high. Among the parents of non-SHCN children, the agreement with BGT varied from 84.1% (95% CI: 75.8-90.9; p<0.001; I2 93.3%) for tell-show-do to 25.7% (95% CI: 17.8-34.4; p<0.001; I2 90.4%) for passive protective stabilization, without hand-over-mouth. Among the parents of children with SHCN, the acceptance of BGT varied from 89.1% (95% CI: 56.1-99.7; p<0.001; I2 95.7%) for tell-show-do to 29.1% (95% CI: 11.8-50.0; p=0.001; I2 84.8%) to general anesthesia.

Conclusion

There is very low certainty in evidence that both the parents of children SHCN and non-SHCN were more likely to agree with basic BGT and that they were less likely to agree with the advanced ones.
Local and Distant responses to single pulse electrical stimulation reflect different forms of connectivity
Authors: Crocker Britni , Ostrowski Lauren , Williams Ziv M. , Dougherty Darin D. , Eskandar Emad N. , Widge Alik S. , Chu Catherine J. , Cash Sydney S. , Paulk Angelique C.
Published: October 2020

Background

Measuring connectivity in the human brain can involve innumerable approaches using both noninvasive (fMRI, EEG) and invasive (intracranial EEG or iEEG) recording modalities, including the use of external probing stimuli, such as direct electrical stimulation.

Objective/Hypothesis

To examine how different measures of connectivity correlate with one another, we compared ‘passive’ measures of connectivity during resting state conditions map to the more ‘active’ probing measures of connectivity with single pulse electrical stimulation (SPES).

Methods

We measured the network engagement and spread of the cortico-cortico evoked potential (CCEP) induced by SPES at 53 total sites across the brain, including cortical and subcortical regions, in patients with intractable epilepsy (N=11) who were undergoing intracranial recordings as a part of their clinical care for identifying seizure onset zones. We compared the CCEP network to functional, effective, and structural measures of connectivity during a resting state in each patient. Functional and effective connectivity measures included correlation or Granger causality measures applied to stereoEEG (sEEGs) recordings. Structural connectivity was derived from diffusion tensor imaging (DTI) acquired before intracranial electrode implant and monitoring (N=8).

Results

The CCEP network was most similar to the resting state voltage correlation network in channels near to the stimulation location. In contrast, the distant CCEP network was most similar to the DTI network. Other connectivity measures were not as similar to the CCEP network.

Conclusions

These results demonstrate that different connectivity measures, including those derived from active stimulation-based probing, measure different, complementary aspects of regional interrelationships in the brain.
Pharmacological inhibition of nonsense-mediated RNA decay augments HLA class I-mediated presentation of neoepitopes in MSI CRC
Authors: Becker Jonas P. , Helm Dominic , Rettel Mandy , Stein Frank , Hernandez-Sanchez Alejandro , Urban Katharina , Gebert Johannes , Kloor Matthias , Neu-Yilik Gabriele , von Knebel Doeberitz Magnus , Hentze Matthias W. , Kulozik Andreas E.
Published: October 2020

Microsatellite-unstable (MSI) colorectal cancer is characterized by the accumulation of somatic insertion/deletion (InDel) mutations potentially generating tumor-specific, frameshifted protein sequences. Such mutations typically generate premature translation termination codons targeting the affected mRNAs to degradation by nonsense-mediated RNA decay (NMD), limiting the synthesis and HLA class I-mediated presentation of tumor-specific InDel neoepitopes. We reasoned that the NMD inhibitor 5-azacytidine (5AZA) could serve to increase the expression of NMD-sensitive neoepitopes and analyzed the immunopeptidome of MSI HCT-116 cells using a proteogenomic approach. After immunoprecipitation of HLA:peptide complexes, we identified more than 10,000 HLA class I-presented peptides by LC-MS/MS including five InDel neoepitopes. The InDel neoepitopes were verified on the genomic, transcriptomic, and peptidomic level. Treatment with 5AZA increased the expression of the corresponding frameshift- and premature termination codon-bearing mRNAs and enhanced the presentation of peptides originating from known NMD targets and one of the identified InDel neoepitopes. By analyzing an array of MSI colorectal cancer cell lines and patient samples, we found the underlying frameshift mutation to be highly recurrent and immunization with the corresponding neoepitope induced strong CD8+ T cell responses in an HLA-A*02:01 transgenic mouse model. Our data directly show that peptides originating from frameshifted open reading frames due to InDel mutations in mismatch repair-deficient cells are presented on the cell surface via HLA class I. Moreover, we demonstrate the utility of NMD inhibitor-enhanced HLA class I-mediated presentation of InDel neoepitopes as well as their immunogenicity, uncovering the clinical potential of NMD inhibition in anti-cancer immunotherapy strategies.

One Sentence Summary

Immunopeptidomics identified increased HLA class I-mediated presentation of immunogenic, frameshift-derived neoepitopes following NMD inhibition.
DIMA: Data-driven selection of a suitable imputation algorithm
Authors: Egert Janine , Warscheid Bettina , Kreutz Clemens
Published: October 2020

Motivation

Imputation is a prominent strategy when dealing with missing values (MVs) in proteomics data analysis pipelines. However, the performance of different imputation methods is difficult to assess and varies strongly depending on data characteristics. To overcome this issue, we present the concept of adata-driven selection of a suitable imputation algorithm(DIMA).

Results

The performance and broad applicability of DIMA is demonstrated on 121 quantitative proteomics data sets from the PRIDE database and on simulated data consisting of 5 – 50% MVs with different proportions of missing not at random and missing completely at random values. DIMA reliably suggests a high-performing imputation algorithm which is always among the three best algorithms and results in a root mean square error difference (ΔRMSE) ≤ 10% in 84% of the cases.

Availability and Implementation

Source code is freely available for download atgithub.com/clemenskreutz/OmicsData.
Detecting changes in dynamical structures in synchronous neural oscillations using probabilistic inference
Authors: Yokoyama Hiroshi , Kitajo Keiichi
Published: October 2020

Recent neuroscience studies have suggested that cognitive functions and learning capacity are reflected in the time-evolving dynamics of brain networks. However, an efficient method to detect changes in dynamical brain structures using neural data has yet to be established. To address this issue, we developed a new model-based approach to detect change points in dynamical network structures by combining the model-based network estimation with a phase-coupled oscillator model and sequential Bayesian inference. By giving the model parameter as the prior distribution, applying Bayesian inference allows the extent of temporal changes in dynamic brain networks to be quantified by comparing the prior distribution with posterior distribution using information theoretical criteria. For this, we used the Kullback-Leibler divergence as an index of such changes. To validate our method, we applied it to numerical data and electroencephalography data. As a result, we confirmed that the Kullback-Leibler divergence only increased when changes in dynamical network structures occurred. Our proposed method successfully estimated both directed network couplings and change points of dynamical structures in the numerical and electroencephalography data. These results suggest that our proposed method can reveal the neural basis of dynamic brain networks.
Opening the Pig to Comparative Neuroimaging: A Common Space Approach Contextualizes the Pig and Human Structural Connectome
Authors: Benn R. Austin , Mars Rogier B. , Xu Ting , Yee Jason R. , Rodríguez-Esparragoza Luis , Montesinos Paula , Manzano-Patron J.P , Lopez-Martin Gonzalo , Fuster Valentin , Sanchez-Gonzalez Javier , Duff Eugene P. , Ibañez Borja
Published: October 2020

Neuroimaging’s capability to quickly and rapidly phenotype the cortical organization of the whole brain brings with it the possibility to extend our understanding of cortical organization across the mammalian lineage. However, neuroimaging has thus far generally limited itself to a small number of species, with most animal studies being performed in either rodents or Non-Human Primates. Here we perform a first pass characterization of an animal which has recently seen its stock rise in the neuroscience community with the development of new models of neurological disease; the domestic pig. Characterizing the structural connectome of the pig, we create a white matter atlas, and an anatomical template which we use to build a horizontal translation between the pig and human based on a connectivity blueprint approach. We find that conserved trends of structural connectivity across species enabled spatial prediction of regions of interest between the pig and human, showing the potential horizontal translations have as a tool to assess the translational validity of porcine models of neurological disease. Releasing the anatomical template, white matter atlas, and connectivity blueprints, we hope to ease and promote the acceptance of the pig as an alternative large-animal model by the neuroimaging community.
ACIS, A Novel KepTide™, Binds to ACE-2 Receptor and Inhibits the Infection of SARS-CoV2 Virus in vitro in Primate Kidney Cells: Therapeutic Implications for COVID-19
Authors: Gottschalk Gunnar , Keating James , Kessler Kris , Luan Chi-Hao , Knox Konstance , Roy Avik
Published: October 2020

Coronavirus disease 2019 (COVID-19) is a severe acute respiratory syndrome (SARS) caused by a virus known as SARS-Coronavirus 2 (SARS-CoV2). Without a targeted-medicine, this disease has been causing a massive humanitarian crisis not only in terms of mortality, but also imposing a lasting damage to social life and economic progress of humankind. Therefore, an immediate therapeutic strategy needs to be intervened to mitigate this global crisis. Here, we report a novel KepTide™ (Knock-End Peptide) therapy that nullifies SARS-CoV2 infection. SARS-CoV2 employs its surface glycoprotein “spike” (S-glycoprotein) to interact with angiotensin converting enzyme-2 (ACE-2) receptor for its infection in host cells. Based on our in-silico-based homology modeling study validated with a recent X-ray crystallographic structure (PDB ID:6M0J), we have identified that a conserved motif of S-glycoprotein that intimately engages multiple hydrogen-bond (H-bond) interactions with ACE-2 enzyme. Accordingly, we designed a peptide, termed as ACIS (ACE-2 Inhibitory motif of Spike), that displayed significant affinity towards ACE-2 enzyme as confirmed by biochemical assays such as BLItz and fluorescence polarization assays. Interestingly, more than one biochemical modifications were adopted in ACIS in order to enhance the inhibitory action of ACIS and hence called as KEpTide™. Consequently, a monolayer invasion assay, plaque assay and dual immunofluorescence analysis further revealed that KEpTide™ efficiently mitigated the infection of SARS-CoV2 in vitro in VERO E6 cells. Finally, evaluating the relative abundance of ACIS in lungs and the potential side-effects in vivo in mice, our current study discovers a novel KepTide™ therapy that is safe, stable, and robust to attenuate the infection of SARS-CoV2 virus if administered intranasally.
Rapid Development of Neutralizing and Diagnostic SARS-COV-2 Mouse Monoclonal Antibodies
Authors: Chapman Asheley P. , Tang Xiaoling , Lee Joo R. , Chida Asiya , Mercer Kristina , Wharton Rebekah E. , Kainulainen Markus , Harcourt Jennifer L. , Martines Roosecelis B. , Schroeder Michelle , Zhao Liangjun , Bryksin Anton , Zhou Bin , Bergeron Eric , Bollweg Brigid C. , Tamin Azaibi , Thornburg Natalie , Wentworth David E. , Petway David , Bagarozzi Dennis , Finn M.G. , Goldstein Jason M.
Published: October 2020

The need for high-affinity, SARS-CoV-2-specific monoclonal antibodies (mAbs) is critical in the face of the global COVID-19 pandemic, as such reagents can have important diagnostic, research, and therapeutic applications. Of greatest interest is the ~300 amino acid receptor binding domain (RBD) within the S1 subunit of the spike protein because of its key interaction with the human angiotensin converting enzyme 2 (hACE2) receptor present on many cell types, especially lung epithelial cells. We report here the development and functional characterization of 29 nanomolar-affinity mouse SARS-CoV-2 mAbs created by an accelerated immunization and hybridoma screening process. Differing functions, including binding of diverse protein epitopes, viral neutralization, impact on RBD-hACE2 binding, and immunohistochemical staining of infected lung tissue, were correlated with variable gene usage and sequence.
Transcript-specific determinants of pre-mRNA splicing revealed throughin vivokinetic analyses of the 1stand 2ndchemical steps
Authors: Gildea Michael A. , Dwyer Zachary W. , Pleiss Jeffrey A.
Published: October 2020

Understanding how the spliceosome processes its composite of substrates through the two chemical steps required for mRNA production will be essential to deciphering splicing regulation and mis-regulation. Here we measure thein vivorates of these steps across the genome by coupling metabolic RNA labeling, targeted sequencing, and first order kinetic modeling. We reveal a wide variety of rates by which introns are removed, that splice site sequences are primary determinants of 1ststep rates, and that the 2ndstep is generally faster than the 1ststep. We show that ribosomal protein genes (RPGs) are spliced faster than non-RPGs at each step, and that RPGs share evolutionarily conserved cis-features which facilitate their splicing. A genetic variant defective at the 1ststep shows the expected defect in the 1ststep, but an unexpected change in the 2ndstep which suggests how co-transcriptional splicing functions as an important determinant of splicing rates.
Computational modeling reveals a key role for polarized myeloid cells in controlling osteoclast activity during bone injury repair
Authors: Lo Chen Hao , Baratchart Etienne , Basanta David , Lynch Conor C
Published: October 2020

Bone-forming osteoblasts and -resorbing osteoclasts control bone injury repair, and myeloid-derived cells such as monocytes and macrophages are known to influence their behavior. However, precisely how these multiple cell types coordinate and regulate each other over time to repair injured bone is difficult to dissect using biological approaches. Conversely, mathematical modeling lends itself well to this challenge. Therefore, we generated an ordinary differential equation (ODE) model powered by experimental data (osteoblast, osteoclast, bone volume, pro- and anti-inflammatory myeloid cells) obtained from intra-tibially injured mice. Initial ODE results using only osteoblast/osteoclast populations demonstrated that bone homeostasis could not be recovered after injury, but this issue was resolved upon integration of pro- and anti-inflammatory myeloid population dynamics. Surprisingly, the ODE revealed temporal disconnects between the peak of total bone mineralization/resorption, and osteoblast/osteoclast numbers. Specifically, the model indicated that osteoclast activity must vary greatly (>17-fold) to return the bone volume to baseline after injury and suggest that osteoblast/osteoclast number alone is insufficient to predict bone the trajectory of bone repair. Importantly, the values of osteoclast activity fall within those published previously. These data underscore the value of mathematical modeling approaches to understand and reveal new insights into complex biological processes.
Diazepam attenuates the effects of cocaine on locomotion, 50-kHz ultrasonic vocalizations and phasic dopamine release in the nucleus accumbens of rats
Authors: Sanchez William N. , Pochapski Jose A. , Jessen Leticia F. , Ellenberger Marek , Schwarting Rainer K. , Robinson Donita L. , Andreatini Roberto , Cunha Claudio Da
Published: October 2020

Background and Purpose

Currently, no effective drug exists to treat cocaine use disorders, which affect millions of people worldwide. Benzodiazepines are potential therapeutic candidates, as microdialysis and voltammetry studies have shown that they can decrease dopamine release in the nucleus accumbens of rodents. In addition, we have recently shown that diazepam blocks the increase in dopamine release and the affective marker 50-kHz ultrasonic vocalizations (USV) induced by DL-amphetamine in rats.

Experimental Approach

Here we tested whether administration of 2.5 mg·kg−1diazepam (i.p.) in adult male Wistar rats could block the effects of 20 mg·kg−1cocaine (i.p.) on electrically evoked phasic dopamine release in the nucleus accumbens measured by fast-scan cyclic voltammetry, as well as 50-kHz USV and locomotor activity.

Key Results

Cocaine injection increased evoked dopamine release up to 3-fold within 5 min and the increase was significantly higher than baseline for at least 90 min. The injection of diazepam 15 min later attenuated the cocaine effect by nearly 50% and this attenuation was maintained for at least 30 min. Stimulant drugs, natural rewards and reward predictive cues are known to evoke 50-kHz USV in adult rats. In the present study, cocaine increased the number of 50-kHz USV of the flat, step, trill, and mixed kinds by 12-fold. This effect was at maximum 5 min after cocaine injection, decreased with time and lasted at least 40 min. Diazepam significantly blocked this effect for the entire duration of the session. The distance travelled by control rats during a 40-min session of exploration in an open field was at maximum in the first 5 min and decayed progressively until the end of the session. Cocaine-treated rats travelled significantly longer distances when compared to the control group, while diazepam significantly attenuated cocaine-induced locomotion by up to 50%.

Conclusions and implication

These results suggest that the neurochemical, affective, and stimulant effects of cocaine can be mitigated by diazepam.

What is already known

Diazepam decreases dopamine release in the rodent nucleus accumbens (NAc) and reduces some effects produced by DL-amphetamine.

What this study adds

Diazepam attenuated the increase in phasic dopamine release caused by cocaine.

Diazepam blocked the effect of cocaine on 50-kHz USV and locomotor activity.

Clinical significance

This study demonstrates that diazepam can block specific effects of cocaine that likely contribute to addiction.
Genome diversity and quorum sensing variations in laboratory strains ofPseudomonas aeruginosaPAO1
Authors: Liu Yang , Ahator Stephen Dela , Xu Yinuo , Wang Huishan , Feng Qishun , Zhou Xiaofan , Zhang Lian-Hui
Published: October 2020

ThePseudomonas aeruginosastrain PAO1 has routinely been used as a laboratory model for quorum sensing (QS) studies due to its extensively coordinated regulatory circuits. However, the microevolution ofP. aeruginosalaboratory strains resulting in genetic and phenotypic variations have caused inconsistencies in QS research. To investigate the underlying causes and impact of these variations, we analyzed 5Pseudomonas aeruginosaPAO1 sublines from our laboratory using a combination of phenotypic characterization, high-throughput genome sequencing, and bioinformatic analysis. The major phenotypic variations among the sublines spanned across the levels of QS signals and virulence factors such as pyocyanin and elastase. Furthermore, the sublines exhibited distinct variations in swarming, twitching and biofilm formation. Most of the phenotypic variations were mapped to the effects of mutations in thelasRandmexT, which are key components of the QS circuit. By introducing these mutations in the subline PAO1-E, which is devoid of such mutations, we confirmed their influence on QS, virulence, motility and biofilm formation. The findings further highlight a possible divergent regulatory mechanism between the LasR and MexT in the QS pathways inP. aeruginosa. The results of our study reveal the effects of microevolution on the reproducibility of most research data from QS studies and further highlightmexTas a key component of the QS circuit ofP. aeruginosa.

Importance

Microevolution ofP. aeruginosalaboratory strains results in genotypic and phenotypic variations between strains that have a significant influence on QS research. This work highlights the variations present inP. aeruginosaPAO1 sublines and investigates the impact of the genetic variations on the QS circuit and QS-regulated virulence determinants. Using a combination of NGS and phenotypic analysis, we illustrate the impact of microevolution on the reproducibility of QS, virulence, motility, and biofilm studies among 5 sublines. Additionally, we revealed the significant impact of mutations in key genes such asmexTandlasRon the QS circuit and regulation of virulence. In effect, we show the need for limited propagation and proper handling of laboratory isolates to reduce the microevolution.