bluuebunny/crossref_metadata_2025 huggingface dataset:
A Novel Technique With Ileal Mesentery to Reconstruct the Pelvic Peritoneum After Pelvic Dissection With End Colostomy for Rectal Cancer
Authors: Luo Wenjun , Lu Tingting , Xu Zhengwen , Qian Chuan , Li Fugen , Xiao Yanling , Jia Yingdong , Zhang Bo
Published: June 2022

See video on DCR YouTube Channel at https://youtu.be/lvF_lE7sROA

BACKGROUND:

After abdominoperineal resection, low anterior resection, and end colostomy for lower rectal cancer, it is necessary to reconstruct the pelvic peritoneum to avoid small bowel obstruction, perineal hernia, and radiation enteritis in patients for whom postoperative radiotherapy is planned. However, pelvic peritoneal closure is technically difficult in patients who lack enough peritoneum to cover the defect or have received neoadjuvant radiation and have a rigid pelvis.

IMPACT OF INNOVATION:

The impact of this innovation is to reconstruct the pelvic peritoneum with the distal ileal mesentery laparoscopically.

TECHNOLOGY, MATERIALS AND METHODS:

After removal of the tumor, the distal ileal mesentery was selected to completely cover the defect. Subsequently, suturing of the ileal mesentery to the posterior wall of the urinary bladder and all sides of the pelvic cavity was performed. Finally, the patients were returned to the headfirst supine position to ensure that there was no small bowel falling into the pelvic dead space.

PRELIMINARY RESULTS:

All surgical procedures were successfully performed laparoscopically from January 2019 to April 2021. No perineal complications or intestinal obstructions occurred during the follow-up period.

CONCLUSIONS AND FUTURE DIRECTIONS:

This novel technique was found to be safe and effective. Moreover, it provided an economical method for the reconstruction of the pelvic peritoneum using autologous material, which could preserve the small intestine in the abdomen to avoid related complications. Additional larger series of patients with longer follow-up are needed to validate the safety and feasibility of this method.
Ethical Challenges in Staffing: The Importance of Building Moral Muscle
Authors: Lesandrini Jason , Reis David
Published: June 2022

Addressing ethics issues in healthcare is essential to living out an organization's mission, vision, and values. In addition to exacerbating existing ethical dilemmas, the COVID-19 pandemic raised many new and complex questions for leaders and their organizations. Ethical issues related to the workforce require a deliberate and comprehensive consideration of values. The case study scenarios presented here demonstrate examples of common ethical staffing challenges that healthcare leaders have faced, notably the allocation of care providers among COVID-19 patients and the balancing of care quality with staff and patient safety. With access to expert resources and a decision-making framework, leaders can build the moral muscle to meet these challenges and reach ethically justifiable resolutions. These staffing issues highlight the need for increased access to ethics resources for organizational leaders, including moral development support and assistance from experts to resolve complex ethical matters.
Cyclodialysis Cleft After Secondary Intraocular Lens Placement With Yamane Technique
Authors: Yee Claudine , Joye Ashlin S. , Nanji Afshan A. , Chamberlain Winston D.
Published: June 2022

Purpose:

The purpose of this study was to report a rare case of cyclodialysis cleft after secondary intraocular lens (IOL) placement using the Yamane flanged intrascleral haptic fixation technique.

Methods:

This study is an observational case report.

Results:

A 74-year-old man with an ocular history of spontaneously dislocated IOL and subsequent anterior chamber IOL (ACIOL) placement presented with monocular diplopia secondary to ACIOL subluxation. The patient underwent explantation of the subluxed ACIOL and placement of a scleral-fixated IOL using the Yamane technique. The postoperative course was complicated by persistent hypotony, prompting ultrasound biomicroscopy, which revealed a cyclodialysis cleft adjacent to one of the externalized IOL haptics. The haptic was discovered in the involved supraciliary space while performing direct cyclopexy. The cyclodialysis cleft closed with return to physiologic intraocular pressure.

Conclusions:

Cyclodialysis cleft formation is a possible complication of scleral IOL fixation and should be suspected in cases of prolonged postoperative hypotony. Extended longitudinal tracking of the needle and haptic through the supraciliary space may be one mechanism for cyclodialysis cleft formation in the Yamane technique.
A 10-Year Review of the Management of Ocular Mucous Membrane Pemphigoid: A Private Practice Experience
Authors: Johnson Kasey B. , Rosenbaum James T. , Yarter Jason T. , Broadbent Talmage , Michels Kevin S.
Published: June 2022

Purpose:

Ocular mucous membrane pemphigoid (OcMMP) is a rare and potentially blinding condition for which consensus treatment guidelines do not exist. The purpose of this study was to assess the effectiveness and safety of various immunomodulatory agents in the treatment of OcMMP in a private practice setting.

Methods:

We conducted a 10-year retrospective chart review of patients managed with OcMMP (n = 22). The median age at diagnosis was 73 (range: 35–91) years, and 59% (13/22) of patients were female. Visual acuity, Foster stage, and adverse effects (AEs) were documented. Treatment outcomes for each treatment episode were qualified at 3 months as complete response (CR), response (R), or failure (F). After 3 months, CR was then further subqualified as sustained CR, reactivation after initial CR, or AE after initial CR. The Fisher exact test P values were calculated for each outcome in comparison with mycophenolate.

Results:

Twenty patients were treated with an immunomodulatory agent for a total of 55 treatment episodes. In comparison to dapsone, mycophenolate was more likely to achieve sustained CR (50% vs. 0%, P = 0.022) and R (100% vs. 50%, P = 0.007), and less likely to fail (0% vs. 50%, P = 0.007). Dapsone was also more likely to be discontinued because of AEs than mycophenolate (40% vs. 6%, P = 0.041).

Conclusions:

Mycophenolate is a superior first-line agent to dapsone in the treatment of OcMMP. Although not statistically significant, mycophenolate trends toward superiority over methotrexate as well. Mycophenolate is very effective when used in combination with rituximab. Azathioprine remains a reasonable second-line agent.
Deep Anterior Lamellar Keratoplasty and Penetrating Keratoplasty for Keratoconus: A Claims-Based Analysis
Authors: Mgboji Glory E. , Varadaraj Varshini , Thanitcul Chanon , Canner Joseph K. , Woreta Fasika A. , Soiberman Uri S. , Srikumaran Divya
Published: June 2022

Purpose:

The purpose of this study was to report 1) demographic and clinical characteristics for US patients with keratoconus undergoing deep anterior lamellar keratoplasty (DALK) or penetrating keratoplasty (PK) and 2) complication rates for the 2 procedures.

Methods:

We performed a retrospective review of 2010 to 2018 health records for patients with keratoconus age younger than 65 years using the IBM MarketScan Database. A multivariable model adjusting for potential confounders was used to determine factors associated with receiving DALK over PK. Rates of complications 90 days and 1 year postoperatively were calculated. For select complications only (repeat keratoplasty, glaucoma surgery, and cataract surgery), Kaplan–Meier survival curves were additionally constructed over a period of up to 7 years.

Results:

A total of 1114 patients with keratoconus (mean age: 40.5 ± 12.6 years) were included in the analysis. Hundred nineteen received DALK, and 995 received PK. Regional differences exist, with patients in the north central United States having greater odds of receiving DALK than northeastern patients (OR = 5.08, 95% confidence interval, 2.37–10.90). Rates of endophthalmitis, choroidal hemorrhage, infectious keratitis, graft failure, graft rejection, postoperative cataract, glaucoma, or retinal surgery were all low at 90 days and 1 year. Complication rates for DALK and PK were both low beyond 1 year for repeat keratoplasty, cataract, and glaucoma surgery.

Conclusions:

There are regional differences between DALK and PK utilization rates. In addition, DALK and PK complication rates in this nationally representative sample are low at 1 year and beyond, but further studies are needed to assess whether longer-term complications differ by procedure type.
An Outcomes Study of Proximal Interphalangeal Joint Silicone Implant Arthroplasty Using the Volar Approach
Authors: Riggs Jeanne M. , Burns Patricia B. , Chung Kevin C.
Published: June 2022

Background:

Arthroplasty is performed at the proximal interphalangeal joint for the management of disabling osteoarthritis. This prospective cohort study evaluated outcomes of the silicone implant for the proximal interphalangeal joint using the volar approach. The authors hypothesize that the volar approach without extensor mechanism disruption will provide improved motion and maintain joint extension.

Methods:

Consecutive candidates for proximal interphalangeal joint silicone implant arthroplasty using the volar approach were evaluated. The Michigan Hand Outcomes Questionnaire and functional measurements, including grip/pinch strength and arc of motion, were administered preoperatively and at 6 weeks and 3, 6, and 12 months postoperatively.

Results:

Twenty-eight patients (35 joints) were included in the study. Eighteen patients (24 joints) were followed to 1 year postoperatively, with an entire cohort average of 10-month follow-up. Nineteen patients were white women, and the mean age was 64 years. The authors’ hypothesis was supported by the results showing a mean gain in arc of motion of 7 degrees and a mean 5-degree extension lag improvement at 1 year. The mean postoperative arc of motion was 53 degrees with a 10-degree average extension lag. The median Michigan Hand Outcomes Questionnaire pain score improved from 70 (60 to 80) to 28 (5 to 45); scores also improved for each of the questionnaire domains. Median grip strength was unchanged.

Conclusions:

The volar approach to proximal interphalangeal joint arthroplasty is technically challenging but facilitates early aggressive rehabilitation. This is critical for providing improved flexion, especially in the ulnar digits without worsening extension lag.

CLINICAL QUESTION/LEVEL OF EVIDENCE:

Therapeutic, IV.
ACTIVATION OF THE MITOCHONDRIAL ANTIVIRAL SIGNALING PROTEIN (MAVS) FOLLOWING LIVER ISCHEMIA/REPERFUSION AND ITS EFFECT ON INFLAMMATION AND INJURY
Authors: Ailenberg Menachem , Kapus Andras , Leung Chung Ho , Szaszi Katalin , Williams Philip , diCiano-Oliveira Caterina , Marshall John C. , Rotstein Ori D.
Published: June 2022

Resuscitation of trauma patients after hemorrhagic shock causes global I/R, which may contribute to organ dysfunction. Oxidative stress resulting from I/R is known to induce signaling pathways leading to the production of inflammatory molecules culminating in organ dysfunction/injury. Our recent work demonstrated that oxidative stress was able to induce activation of the mitochondrial antiviral signaling protein (MAVS), a protein known to be involved in antiviral immunity, in an in vitro model. We therefore hypothesized that the MAVS pathway might be involved in I/R-induced inflammation and injury. The present studies show that MAVS is activated in vivo by liver I/R and in vitro in RAW 264.7 cells by hypoxia/reoxygenation (H/R). We utilized both in vivo (liver I/R in MAVS knockout mice) and in vitro (MAVS siRNA in RAW 264.7 cells followed by H/R) models to study the role of MAVS activation on downstream events. In vivo, we demonstrated augmented injury and inflammation in MAVS knockout mice compared with wild-type animals; as shown by increased hepatocellular injury, induction of hepatocyte apoptosis augmented plasma TNF-α levels. Further, in vitro silencing of MAVS by specific siRNA in RAW 264.7 and exposure of the cells to H/R caused activation of mitophagy. This may represent a compensatory response to increased liver inflammation. We conclude that activation of MAVS by hypoxia/reoxygenation dampens inflammation, potentially suggesting a novel target for intervention.
Combined oropharyngeal/nares and nasopharyngeal swab sampling remain effective for molecular detection of SARS-CoV-2 Omicron variant
Authors: Patriquin Glenn , LeBlanc Jason J. , Gillis Holly A. , McCracken Gregory R. , Pettipas Janice J. , Hatchette Todd F.
Published: June 2022

The world has experienced several waves of SARS-CoV-2 variants of concern (VoCs) throughout the COVID-19 pandemic since the first cases in December 2019. The Omicron VoC has increased transmission, compared to its predecessors, and can present with sore throat and other cold-like symptoms. Given the predominance of throat symptoms, and previous work demonstrating better sensitivity using antigen-based rapid detection tests when a throat swab is included in the standard nasal sampling, this quality improvement project sought to ensure ongoing suitability of both combined oropharyngeal/nares (OPN) and nasopharyngeal (NP) swab sampling used throughout the pandemic. Consenting participants meeting Public Health testing criteria (mostly symptomatic or a close contact of a known case) were enrolled, and paired NP and OPN swabs were subjected to nucleic acid amplification testing (NAAT). Comparing paired specimens from 392 participants sensitivity of NP swabs was 89.1 % (95 % CI, 78.8–94.9), and that of OPN was 98.4 % (95 % CI: 90.9->99.9) (P-value 0.052). This project demonstrated that both NP and combined OPN swabs detected the Omicron variant with similar sensitivity by NAAT, supporting the continued use of either swab collection for SARS-CoV-2 molecular detection.
Evaluation of Blood-Based Exosomes as Biomarkers for Aging-Related TDP-43 pathology
Authors: Winston Charisse N. , Sukreet Sonal , Lynch Haley , Lee Virginia M.-Y. , Wilcock Donna M. , Nelson Peter T. , Rissman Robert A.
Published: June 2022

INTRODUCTION

Limbic predominant age related TDP-43 encephalopathy (LATE) is a recently characterized brain disease that mimics Alzheimer’s disease (AD) clinically. To date, LATE is difficult to diagnose antemortem using clinical information or biomarkers. Recent studies suggest concentrations of exosomal protein cargo derived from neuronal and glial cells may serve as useful diagnostic biomarkers for AD and other neurodegenerative diseases.

METHODS

TDP-43 was evaluated in neuronal (NDE), astrocyte (ADE), and microglial derived exosomes (MDE). Exosome preparations were isolated from the plasma of research subjects with autopsy-confirmed diagnoses, including many with LATE. Quantified TDP-43 concentrations were compared to cohort that included healthy controls, mild cognitively impairment (MCI), and AD dementia with diagnoses other than LATE.

RESULTS

TDP-43 was significantly elevated in plasma ADEs derived from autopsy confirmed LATE-NC subjects, with or without comorbid AD pathology. Measurable levels of TDP-43 were also detected in exosome depleted plasma; however, TDP-43 levels were not significantly different between persons with and without eventual autopsy confirmed LATE-NC. No correlation was observed between exosomal TDP-43 levels with cognition-based variables, sex, and APOE carrier status.

DISCUSSION

Blood-based exosomes, specifically measuring TDP-43 accumulation in ADEs, may serve as a powerful diagnostic tool to rapidly identify subjects who are currently living with LATE-NC.
Spatial learning overshadows learning novel odors and sounds in both a predatory and a frugivorous bat
Authors: Dixon M. May , Carter Gerald , Ryan Michael J. , Page Rachel A.
Published: June 2022

Abstract

To be efficient while foraging, animals should be selective about attending to and remembering the cues of food that best predict future meals. One hypothesis is that animals with different foraging strategies should vary in their reliance on spatial and feature cues. Animals that store food or feed on spatially stable food, like fruit or flowers, should be predisposed to learning a meal’s location, whereas predators that hunt mobile prey should instead be biased towards learning feature cues such as color or sound. Previous studies suggest that nectar- and fruit-feeding bats should rely relatively more on spatial cues, whereas predatory bats should rely more on feature cues, yet no experiment has compared these two foraging strategies under the same conditions. To test this hypothesis, we compared learning in the frugivorous bat, Artibeus jamaicensis, and the predatory bat, Lophostoma silvicolum, which hunts katydids using acoustic cues. We trained bats to find food paired with a unique odor, sound, and location. We then dissociated these cues to assess which cue each bat had learned. Rather than finding that the frugivore and predator are on opposite ends of a continuum in their relative reliance on spatial and feature cues, we found that both species learned spatial cues with no evidence that either learned the sounds or odors. We discuss interpretations of these results in the context of past work on use of spatial cues versus feature cues. Compared to feature cues, spatial cues may be fundamentally more rich, salient, or memorable.

Lay Summary

When animals learn how to obtain food, they could attend to many possible cues—such as the associated smells, sights, sounds, or locations of the food. It has been hypothesized that natural selection has shaped animals to pay particular attention to the types of cues that are most useful for finding their typical food. In bats, this would predict that predatory species that hunt mobile, noisy insects by sound should be biased towards learning a food-associated sound, whereas bats that eat stationary and silent fruit should be biased towards learning a food’s location. We gave predatory and fruit-eating bats the opportunity to simultaneously learn food-rewarded odors, sounds, or locations.

Regardless of their diets, both species of bats learned locations rather than the odors or sounds associated with food. Spatial cues may be particularly rich or salient, and when they are reliable, animals may use them for learning over other cues regardless of their typical food.
NcPath: A novel tool for visualization and enrichment analysis of human non-coding RNA and KEGG signaling pathways
Authors: Li Zutan , Chen Yuanyuan , Zhang Yuan , Fang Jingya , Xu Zhihui , Zhang Hao , Mao Minfang , Zhang Liangyun , Pian Cong
Published: June 2022

Noncoding RNAs play important roles in transcriptional processes and participate in the regulation of various biological functions, in particular miRNAs and lncRNAs. Despite their importance for several biological functions, the existing signaling pathway databases do not include information on miRNA and lncRNA. Here, we redesigned a novel pathway database named NcPath by integrating and visualizing a total of 178,308 human experimentally-validated miRNA-target interactions (MTIs), 36,537 experimentally-verified lncRNA target interactions (LTIs), and 4,879 experimentally-validated human ceRNA networks across 222 KEGG pathways (including 27 sub-categories). To expand the application potential of the redesigned NcPath database, we identified 553,523 reliable lncRNA-PCG interaction pairs by integrating co-expression relations, ceRNA relations, co-TF-binding interactions, co-Histone-modification interactions, cis-regulation relations and lncPro Tool predictions between lncRNAs and protein-coding genes. In addition, to determine the pathways in which miRNA/lncRNA targets are involved, we performed a KEGG enrichment analysis using an hypergeometric test. The NcPath database also provides information on MTIs/LTIs/ceRNA networks, PubMed IDs, gene annotations and the experimental verification method used. In summary, the NcPath database will serve as an important and continually updated platform that provides annotation and visualization of the pathways on which noncoding RNAs (miRNA and lncRNA) are involved, and provide support to multimodal noncoding RNAs enrichment analysis. The NcPath database is freely accessible at http://ncpath.pianlab.cn/.
Metabolomic profiles of human glioma inform patient survival
Authors: Scott Andrew J. , Correa Luis O. , Sun Yilun , Ravikumar Visweswaran , Andren Anthony C. , Zhang Li , Srinivasan Sudharsan , Jairath Neil , Verbal Kait , Muraszko Karin , Sagher Oren , Carty Shannon A. , Hervey-Jumper Shawn , Orringer Daniel , Kim Michelle M. , Junck Larry , Umemura Yoshie , Leung Denise , Venneti Sriram , Camelo-Piragua Sandra , Lawrence Theodore S. , Ippolito Joseph E. , Al-Holou Wajd N. , Chinnaiyan Prakash , Heth Jason , Rao Arvind , Lyssiotis Costas A. , Wahl Daniel R.
Published: June 2022

Aims

Targeting tumor metabolism may improve the outcomes for patients with glioblastoma (GBM). To further preclinical efforts targeting metabolism in GBM, we tested the hypothesis that brain tumors can be stratified into distinct metabolic groups with different patient outcomes. Therefore, to determine if tumor metabolites relate to patient survival, we profiled the metabolomes of human gliomas and correlated metabolic information with clinical data.

Results

We found that isocitrate dehydrogenase-wildtype (IDHwt) GBMs are metabolically distinguishable from IDH mutated (IDHmut) astrocytomas and oligodendrogliomas. Survival of patients with IDHmut gliomas was expectedly more favorable than those with IDHwt GBM, and metabolic signatures can stratify IDHwt GBMs subtypes with varying prognoses. Patients whose GBMs were enriched in amino acids had improved survival while those whose tumors were enriched for nucleobases and carbohydrates fared more poorly. These findings were recapitulated in validation cohorts using both metabolomic and transcriptomic data.

Innovation

Our results suggest the existence of metabolic subtypes of GBM with differing prognoses and further support the concept that metabolism may drive the aggressiveness of human gliomas.

Conclusions

Our data show that metabolic signatures of human gliomas can inform patient survival. These findings may be used clinically to tailor novel metabolically targeted agents for GBM patients with different metabolic phenotypes.
Pronounced state-level variation in prescription cannabinoids to Medicaid patients
Authors: Liu Edward Y. , McCall Kenneth L. , Piper Brian J.
Published: June 2022

Dronabinol is approved for chemotherapy induced nausea as well as vomiting and HIV-induced anorexia, while cannabidiol is primarily approved for childhood epileptic disorders Lennox-Gastaut and Dravet syndrome. The use pattern for these prescription cannabinoids in the US is unknown. This study analyzed Medicaid claims for dronabinol and cannabidiol prescriptions from 2016-2020. Dronabinol prescriptions decreased by 25.3% from 2016 to 2020 while cannabidiol prescriptions increased by 16,272.99 % from 2018 to 2020. The spending on these drugs parallels that on their prescription trend with a 66.3% decrease in reimbursement for dronabinol ($5.7 million in 2020), whereas that of cannabidiol increased by +26,582.0% ($233.3 million in 2020). Dronabinol prescriptions in Connecticut were 136.4 times larger than New Mexico and 17 states had zero prescriptions. Idaho prescriptions, when corrected for number of enrollees, were 15.4-fold higher than Washington DC. Prescribing of dronabinol and cannabidiol did not differ significantly based on the whether the state had an active medical marijuana program. The prescriptions of pharmaceutical grade tetrahydrocannabinol were decreasing while cannabidiol was increasing. This study also identified pronounced state level variation in cannabinoid prescribing to Medicaid patients. Further research to identify the origins of these disparities is needed.
Improved Version of ChETA Promotes Aggression in the Medial Amygdala
Authors: Hu Rongfeng K. , Chen Patrick B. , Berndt André , Anderson David J. , Hong Weizhe
Published: June 2022

The development of optogenetic tools has significantly advanced our understanding of neural circuits and behavior. The medial amygdala, posterior dorsal subdivision (MeApd) is part of a distributed network controlling social behaviors such as mating and aggression. Previous work showed that activation of GABAergic neurons in mouse MeApd using channelrodopsin-2 (ChR2H134R) promoted aggression. In a recent study, Baleisyte et al. (2022) confirmed these findings using the same reagents (i.e. ChR2H134R), but also reported that a different ChR2 variant with faster kinetics—ChETA—inhibited rather than promoted aggression when high laser power, long duration photostimulation conditions were used. As ChETA is known to have a substantially lower photocurrent than ChR2 and other opsins, an improved version of ChETA (i.e. ChR2E123T/T159C; ChETATC) was subsequently developed. ChETATC has larger photocurrents than the original ChETA while maintaining fast kinetics and low plateau depolarization. Here we show that activating MeApd GABAergic neurons using the improved ChETATC promotes aggression, similar to ChR2H134R, suggesting that the results obtained using the original ChETA are not due to a difference in channel kinetics. Furthermore, we found that ChETATC is capable of driving a rapid onset of aggression within 200-300 milliseconds of stimulation, suggesting that this effect reflects direct activation of MeApd GABAergic neurons. We conclude that the different behavioral phenotypes observed using the original ChETA vs. ChETATC and ChR2 likely reflects the weaker photocurrents in ChETA vs. other opsins, and/or the long duration/high power photostimulation conditions used with ChETA. Consistent with this conclusion, the results obtained using ChR2 or ChETATC are complementary to findings from loss-of-functions experiments using optogenetic inhibition, chemogenetic inhibition, and neuronal ablation. These data support a positive-acting role of MeApd Vgat+ neurons in aggression. Our findings, in conjunction with studies of Berndt et al. (2011), suggest that the improved ChETATC should be used when faster kinetics than ChR2 offers are required.
A uniquely stable trimeric model of SARS-CoV-2 spike transmembrane domain
Authors: Aliper E.T. , Krylov N.A. , Nolde D.E. , Polyansky A.A. , Efremov R.G.
Published: June 2022

The spike (S) protein of SARS-CoV-2 effectuates membrane fusion and virus entry into target cells. Its transmembrane domain (TMD) represents a homotrimer of α-helices anchoring the spike in the viral envelope. Although S-protein models available to date include the TMD, its precise configuration was given brief consideration. Understanding viral fusion entails realistic TMD models, while no reliable approaches towards predicting the 3D structure of transmembrane (TM) trimers exist. Here, we propose a comprehensive computational framework to model the spike TMD (S-TMD) based solely on its primary structure. First, we performed amino acid sequence pattern matching and compared molecular hydrophobicity potential (MHP) distribution on the helix surface against TM homotrimers with known 3D structures and thus selected the TMD of the tumour necrosis factor receptor 1 (TNFR-1) for subsequent template-based modelling. We then iteratively built an all-atom homotrimer model of S-TMD based on “dynamic MHP portraits” and residue variability motifs. In this model each helix possessed two overlapping interfaces interacting with either of the remaining helices, which include conservative residues I1216, F1220, I1227, M1229, and M1233. Finally, the stability of this and several alternative models (including a recent NMR structure) and a set of mutant forms was tested in all-atom molecular dynamics (MD) simulations in a POPC bilayer mimicking the viral envelope membrane. Unlike other configurations, our model trimer remained extraordinarily tightly packed over a microsecond-range MD and retained its stability when palmitoylated in accordance with experimental data. Palmitoylation had no significant impact on the TMD conformation nor the way in which the lipid bilayer was perturbed in the presence of the trimer. Overall, the resulting model of S-TMD conforms to known basic principles of TM helix packing and will be further used to explore the complex machinery of membrane fusion from a broader perspective beyond the TMD.
Continuous Indexing of Fibrosis (CIF): Improving the Assessment and Classification of MPN Patients
Authors: Ryou Hosuk , Sirinukunwattana Korsuk , Aberdeen Alan , Grindstaff Gillian , Stolz Bernadette , Byrne Helen , Harrington Heather A. , Sousos Nikolaos , Godfrey Anna L. , Harrison Claire N. , Psaila Bethan , Mead Adam J. , Rees Gabrielle , Turner Gareth D.H. , Rittscher Jens , Royston Daniel
Published: June 2022

The detection and grading of fibrosis in myeloproliferative neoplasms (MPN) is an important component of disease classification, prognostication and disease monitoring. However, current fibrosis grading systems are only semi-quantitative and fail to capture sample heterogeneity. To improve the detection, quantitation and representation of reticulin fibrosis, we developed a machine learning (ML) approach using bone marrow trephine (BMT) samples (n = 107) from patients diagnosed with MPN or a reactive / nonneoplastic marrow. The resulting Continuous Indexing of Fibrosis (CIF) enhances the detection and monitoring of fibrosis within BMTs, and aids the discrimination of MPN subtypes. When combined with megakaryocyte feature analysis, CIF discriminates between the frequently challenging differential diagnosis of essential thrombocythemia (ET) and pre-fibrotic myelofibrosis (pre-PMF) with high predictive accuracy [area under the curve = 0.94]. CIF also shows significant promise in the identification of MPN patients at risk of disease progression; analysis of samples from 35 patients diagnosed with ET and enrolled in the Primary Thrombocythemia-1 (PT-1) trial identified features predictive of post-ET myelofibrosis (area under the curve = 0.77). In addition to these clinical applications, automated analysis of fibrosis has clear potential to further refine disease classification boundaries and inform future studies of the micro-environmental factors driving disease initiation and progression in MPN and other stem cell disorders. The image analysis methods used to generate CIF can be readily integrated with those of other key morphological features in MPNs, including megakaryocyte morphology, that lie beyond the scope of conventional histological assessment.

Key Points

Machine learning enables an objective and quantitative description of reticulin fibrosis within the bone marrow of patients with myeloproliferative neoplasms (MPN),

Automated analysis and Continuous Indexing of Fibrosis (CIF) captures heterogeneity within MPN samples and has utility in refined classification and disease monitoring

Quantitative fibrosis assessment combined with topological data analysis may help to predict patients at increased risk of progression to post-ET myelofibrosis, and assist in the discrimination of ET and pre-fibrotic PMF (pre-PMF)
The State of Household Handwashing by Mothers and Associated Risk Factors in Nepal: A Systematic Review
Authors: Dhital Shalik Ram , Chojenta Catherine , Bagade Tanmay , Loxton Deborah
Published: June 2022

Approximately 53% of households do not use soap and water for handwashing. Mothers oversee their hygiene and are ideally placed to teach their children about handwashing with soap. This paper aims to determine the rates of household handwashing with soap by mothers in Nepal and explore the factors associated with the uptake of handwashing. A systematic literature search using PubMed/Medline, Embase, PsycINFO, CINAHL, and Grey literature was searched. Eligible articles were extracted and recorded then descriptive analysis was performed. The quality assessment of the article was done using STROBE guidelines. We screened 187 articles from database searching and 16 from additional grey literature. A total of 120 full-textt articles and records were retrieved to evaluate for inclusion in the review. We identified seven articles that met the criteria for inclusion. The included studies contained 32,010 participants from articles. Current handwashing rates by mothers were varied, ranging from 5% to 67%. The potential risk factors for a lack of handwashing were lack of knowledge, lack of handwashing facilities, and absence of regularities. The hygiene advocacy, provision of soap and water, family encouragement and support, the establishment of a handwashing strategy, and mothers’ participation in decision making are key possible solutions.
Transcriptomics Meta-Analysis Predicts Two Robust Human Biomarkers for Severe Infection with SARS-CoV-2
Authors: Clancy Jeffrey , Hoffmann Curtis S. , Pickett Brett E.
Published: June 2022

Defining the human factors associated with severe vs mild SARS-CoV-2 infection has become of increasing interest. Mining large numbers of public gene expression datasets is an effective way to identify genes that contribute to a given phenotype. Combining RNA-sequencing data with the associated clinical metadata describing disease severity can enable earlier identification of patients who are at higher risk of developing severe COVID-19 disease. We consequently identified 358 public RNA-seq human transcriptome samples from the Gene Expression Omnibus database that had disease severity metadata. We then subjected these samples to a robust RNA-seq data processing workflow to quantify gene expression in each patient. This process involved using Salmon to map the reads to the reference transcriptomes, edgeR to calculate significant differential expression levels, and gene ontology enrichment using Camera. We then applied a machine learning algorithm to the read counts data to identify features that best differentiated samples based on COVID-19 severity phenotype. Ultimately, we produced a ranked list of genes based on their Gini importance values that includes GIMAP7 and S1PR2, which are associated with immunity and inflammation (respectively). Our results show that these two genes can potentially predict people with severe COVID-19 at up to ∼90% accuracy. We expect that our findings can help contribute to the development of improved prognostics for severe COVID-19.
COVID-19 and per capitagreen tea consumption: update
Authors: Storozhuk Maksim
Published: June 2022

Purpose

In spite of the development of numerous vaccines for the prevention of COVID-19 and approvement of several drugs for its treatment, there is still a great need in effective and inexpensive therapy of this disease. Pharmacological evidence suggesting the therapeutic potential of green tea catechins in amelioration/treatment of COVID19 is growing rapidly, however, there are only a few epidemiological studies addressing this possibility. The aim of this study was to provide update regarding ecological study assessing this issue as of January 2021.

Methods

The methodological approach used in this report is similar to that described previously. Briefly, information about COVID-19 morbidity (defined as a total number of cases per million population) and mortality (defined as a total number of deaths per million population) for a specific date was directly obtained from Worldometers info. Coronavirus. Analysis was restricted to 134 countries or territories with at least 3 million population. Twenty-one of these countries/territories, with estimatedper/capitagreen tea consumption above 150 g (annually), were considered as a group with the high consumption. Countries/territories with the estimatedper/capitagreen tea consumption below 150 g (N=82) were considered as the group with low the consumption.

Results

Pronounced differences in COVID-19 morbidity and mortality between groups of countries with high and low green tea consumption were found as of February 20, 2022. These differences were still observed in a subset of countries with HDI above 0.55. Moreover, in this restricted subset of countries, weak but statistically significant correlations between COVID-19 morbidity (or mortality) and per/capita green tea consumption were observed in a multiple regression model accounting for: population density, percentage of population aged above 65, and percentage of urban population.

Conclusion

The obtained results provide additional, though indirect, support of the idea that green tea catechins can be useful for treatment/amelioration of COVID-19. These results are in line with emerging evidence from other studies, including pharmacological. Nevertheless, further research is necessary to directly validate or reject this idea.
MTaxi : A comparative tool for taxon identification of ultra low coverage ancient genomes
Authors: Atağ Gözde , Vural Kıvılcım Başak , Kaptan Damla , Özkan Mustafa , Koptekin Dilek , Sağlıcan Ekin , Doğramacı Sevcan , Köz Mevlüt , Yılmaz Ardan , Söylev Arda , Togan İnci , Somel Mehmet , Özer Füsun
Published: June 2022

A major challenge in zooarchaeology is to morphologically distinguish closely related species’ remains, especially using small bone fragments. Shotgun sequencing aDNA from archeological remains and comparative alignment to the candidate species’ reference genomes will only apply when reference nuclear genomes of comparable quality are available, and may still fail when coverages are low. Here, we propose an alternative method, MTaxi, that uses highly accessible mitochondrial DNA (mtDNA) to distinguish between pairs of closely related species from ancient DNA sequences. MTaxi utilises mtDNA transversion-type substitutions between pairs of candidate species, assigns reads to either species, and performs a binomial test to determine the sample taxon. We tested MTaxi on sheep/goat and horse/donkey data, between which zooarchaeological classification can be challenging in ways that epitomise our case. The method performed efficiently on simulated ancient genomes down to 0.5x mitochondrial coverage for both sheep/goat and horse/donkey, with no false positives. Trials on n=18 ancient sheep/goat samples and n=10 horse/donkey samples of known species identity with mtDNA coverages 0.1x - 12x also yielded 100% accuracy. Overall, MTaxi provides a straightforward approach to classify closely related species that are compelling to distinguish through zooarchaeological methods using low coverage aDNA data, especially when similar quality reference genomes are unavailable. MTaxi is freely available athttps://github.com/goztag/MTaxi.
Long-term Antibody Release Polycaprolactone (PCL) Capsule and the Release Kinetics In Natural and Accelerated Degradation
Authors: Thomas Waterkotte , He Xingyu , Wanasathop Apipa , Li Kevin , Park Yoonjee
Published: June 2022

Although therapy using monoclonal antibodies (mAbs) has been steadily successful over the last 20 years, the means of delivery of mAbs has not been optimized, especially for long-term delivery. Frequent injections or infusions have been current standard of care. In this study, we have developed a long-term antibody biodegradable implant using a porous polycaprolactone (PCL) capsule. It released Bevacizumab (Bev) slowly for 8 months to date. The Bev release kinetics fit a drug release model with experimental data of the diffusion coefficient and partition coefficient through the polymer capsule. Since screening drug release profiles for the long-term (> 6 months) is time consuming, an accelerated degradation method was used after validating characteristics of the PCL capsule in natural and accelerated degradation conditions. The correlation of time period between the natural and the accelerated degradation was determined. Overall, the study suggests mAbs can be released from a porous PCL capsule without an effect of the polymer degradation over the long period (~ 6 months) and the long-term release kinetics can be determined by the accelerated degradation within 14 days.
Short superficial white matter and aging: a longitudinal multi-site study of 1,293 subjects and 2,711 sessions
Authors: Schilling Kurt G , Archer Derek B , Yeh Fang-Cheng , Rheault Francois , Cai Leon Y , Shafer Andrea , Resnick Susan M , Hohman Timothy , Jefferson Angela , Anderson Adam W , Kang Hakmook , Landman Bennett A
Published: June 2022

It is estimated that short association fibers, or 'U-shaped' fibers running immediately beneath the cortex, may make up as much as 60% of the total white matter volume. However, these have been understudied relative to the long-range association, projection, and commissural fibers of the brain. This is largely because of limitations of diffusion MRI fiber tractography, which is the primary methodology used to non-invasively study the white matter connections. Inspired by recent anatomical considerations and methodological improvements in U-fiber tractography, we aim to characterize changes in these fiber systems in cognitively normal aging, which provide insight into the biological foundation of age-related cognitive changes, and a better understanding of how age-related pathology differs from healthy aging. To do this, we used three large, longitudinal and cross-sectional datasets (N = 1293 subjects, 2711 sessions) to quantify microstructural features and length/volume features of several U-fiber systems. We find that axial, radial, and mean diffusivities show positive associations with age, while fractional anisotropy has negative associations with age in superficial white matter throughout the entire brain. These associations were most pronounced in the frontal, temporal, and temporoparietal regions. Moreover, measures of U-fiber volume and length decrease with age in a heterogenous manner across the brain, with prominent effects observed for pre- and post-central gyri. These features, and their variations with age, provide the background for characterizing normal aging, and, in combination with larger association pathways and gray matter microstructural features, may provide insight into fundamental mechanisms associated with aging and cognition.
Automated detection of extracellular action potentials from single neurons
Authors: Cheng Zhuowei , Guzman Elmer , van der Molen Tjitse , Sharf Tal , Hansma Paul K. , Kosik Kenneth S , Petzold Linda , Tovar Kenneth R
Published: June 2022

Multi-electrode arrays (MEAs) non-invasively record extracellular action potentials (eAPs, also known as spikes) from hundreds of neurons simultaneously. However, because extracellular electrodes sample from the local electrical field, each electrode can detect eAPs from multiple nearby neurons. Interpreting spike trains at individual electrodes of high-density arrays requires spike sorting, a computational process which groups eAPs from single ’units’ based on assumptions of how spike waveforms correlate with different neuronal sources. Additionally, when experimental conditions result in changes to eAP waveforms, spike sorting routines may have difficulty correlating eAPs from multiple neurons at single electrodes before and after such waveform changes. We present here a novel, empirical method for unambiguously isolating eAPs from individual, uniquely identifiable neurons, based on automated multi- point detection of action potential propagation. This method is insensitive to changes in eAP waveform morphology because it makes no assumptions about the relationship between spike waveform and neuronal source. Our algorithm for automated detection of action potential propagation produces a ’fingerprint’ that uniquely identifies those spikes from each neuron. By unambiguously isolating eAPs from multiple neurons in each recording, on a range of platforms and experimental preparations, our method now enables high-content screening with contemporary MEAs. We outline the limitations and strengths of propagation-based isolation of eAPs from single neurons and propose how our automated method complements spike sorting and could be adapted to in vivo use.
Silicone Oil-Induced Glaucomatous Neurodegeneration in Rhesus Macaques
Authors: Moshiri Ala , Fang Fang , Zhuang Pei , Huang Haoliang , Feng Xue , Li Liang , Dalal Roopa , Hu Yang
Published: June 2022

Previously, we developed a simple procedure of intracameral injection of silicone oil (SO) into mouse eyes and established the mouse SOHU (SO-induced ocular hypertension under-detected) glaucoma model with reversible intraocular pressure (IOP) elevation and significant glaucomatous neurodegeneration. Because the anatomy of the non-human primate (NHP) visual system closely resembles that of humans, it is the most likely to predict human responses to diseases and therapies. Here we replicated the SOHU glaucoma model in rhesus macaque monkeys. All six animals that we tested showed significant retinal ganglion cell (RGC) death, optic nerve (ON) degeneration, and visual functional deficits at both 3 and 6 months. In contrast to the mouse SOHU model, IOP changed dynamically in these animals, probably due to individual differences in ciliary body tolerance capability. This acute NHP glaucoma model closely recapitulates the major features of glaucomatous neurodegeneration in humans, and is therefore suitable for studying the pathology of primate RGC/ON, assessing experimental therapies for neuroprotection and regeneration, and therefore for translating relevant findings into novel and effective treatments for patients with glaucoma and other neurodegenerations.
A kinesin mediates VEGFR2 recycling and regulates VE-cadherin phosphorylation, essential for vascular permeability
Authors: Cho Hyun-Dong , Zhou Christopher , Tu Kayeman , Nguyen Tara , Sarich Nicolene A. , Yamada Kaori H.
Published: June 2022

Excessive vascular endothelial growth factor-A (VEGF-A) signaling induces vascular leakage and angiogenesis in diseases. VEGFR2 trafficking to the cell surface, mediated by kinesin-3 family protein KIF13B, is essential to respond to VEGF-A in inducing angiogenesis. However, the precise mechanism of how KIF13B regulates VEGF-induced signaling and endothelial permeability is unknown. Here we show that KIF13B-mediated recycling of internalized VEGFR2 through Rab11-positive recycling vesicle regulates VE-cadherin phosphorylation and endothelial permeability. Phosphorylated VEGFR2 at the cell-cell junction was internalized and associated with KIF13B in Rab5-positive early endosomes. KIF13B mediated VEGFR2 recycling through Rab11-positive recycling vesicle, and inhibition of this recycling attenuated phosphorylation of VEGFR2 at Y951, Src, and VE-cadherin at Y685, which are necessary for endothelial permeability. Failure of VEGFR2 trafficking to the cell surface induced accumulation and degradation of VEGFR2 in lysosomes. Furthermore, in the animal model of wet age-related macular degeneration (AMD), inhibition of KIF13B-mediated VEGFR2 trafficking also mitigated vascular leakage. Thus, the present results identify the fundamental role of VEGFR2 recycling to the cell surface in mediating vascular permeability, suggesting a promising strategy for mitigating vascular leakage associated with inflammatory diseases.
Modeling membrane curvature generation using mechanics and machine learning
Authors: Malingen S. A. , Rangamani P.
Published: June 2022

The deformation of cellular membranes regulates trafficking processes, such as exocytosis and endocytosis. Classically, the Helfrich continuum model is used to characterize the forces and mechanical parameters that cells tune to accomplish membrane shape changes. While this classical model effectively captures curvature generation, one of the core challenges in using it to approximate a biological process is selecting a set of mechanical parameters (including bending modulus and membrane tension) from a large set of reasonable values. We used the Helfrich model to generate a large synthetic dataset from a random sampling of realistic mechanical parameters and used this dataset to train machine learning models. These models produced promising results, accurately classifying model behavior and predicting membrane shape from mechanical parameters. We also note emerging methods in machine learning that can leverage the physical insight of the Helfrich model to improve performance and draw greater insight into how cells control membrane shape change.