bluuebunny/crossref_metadata_2025 huggingface dataset:
Quantitative response of healthy muscle following the induction of capsaicin: an exploratory randomized controlled trial
Authors: Evans Valerie , Behr Michael , Masani Kei , Kumbhare Dinesh
Published: December 2020

Background

Myofascial pain syndrome (MPS) is a prevalent chronic pain disorder primarily characterized by myofascial trigger points (MTrPs). There is limited knowledge on the pathophysiology and mechanisms underlying MTrP and its development. Research has previously demonstrated the identification of MTrPs using ultrasound and vibration sonoelastography, although there is some contradictory evidence regarding if MTrPs present as hyper or hypoechoic regions. Electromyography (EMG) investigations of MTrP have demonstrated that MTrPs are usually located proximal to innervation zones where the peak surface EMG signals are obtained from. Central sensitization has been proposed as the primary mechanism underlying MTrP development. Central sensitization is associated with hyperexcitability of neuronal responses to normal or noxious stimuli. There is a need for a study that measures ultrasound image textural changes and motor unit activity responses in the muscle following sensitization. The purpose of this study is to determine whether sensitizing healthy muscle using capsaicin induces a regional change in image texture variables within the specific and surrounding muscles, as well as the motor unit frequency and amplitude changes that accompany them. This is an exploratory trial that aims to provide preliminary evidence on whether central sensitization is a direct cause of taut band and MTrP development.

Methods

Ethical approval was obtained from the University Health Network (UHN) Research Ethics Board. This proposed study is a single centered, factorial, randomized placebo-controlled trial with two independent variables, depth of capsaicin application and dose of capsaicin, for a total of six treatment arms and three control treatment groups.

Discussion

This will be the first study that assesses the B-mode ultrasound image texture of induced sensitized muscles and will provide more evidence on muscle motor unit activity and regional changes of central sensitization. Findings from this study may support one of few hypotheses proposed delineating the involvement of central sensitization in the development of trigger points.

Trial registration

National Institutes of Health ClinicalTrials.gov NCT03944889. Registered on May 07, 2019
Strategy for addressing research-site overlap in pragmatic clinical trials: lessons learned from the NIH-DOD-VA Pain Management Collaboratory (PMC)
Authors:   on behalf of the NIH-DoD-VA Pain Management Collaboratory, Geda Mary , George Steven Z. , Burgess Diana J. , Scarton Dylan V. , Roddy William T. , Gordon Kirsha S. , Pasquina Paul F. , Brandt Cynthia A. , Kerns Robert D. , Peduzzi Peter
Published: December 2020

Background

The Pain Management Collaboratory (PMC) is a multi-site network of pragmatic clinical trials (PCTs) focused on nonpharmacological approaches to pain management, conducted in health care systems of the US Department of Defense (DoD) and Department of Veterans Affairs (VA) and co-funded by the National Institutes of Health (NIH). Concerns about potential research-site overlap prompted the PMC investigator community to consider strategies to avert this problem that could negatively affect recruitment and contaminate interventions and thus pose a threat to trial integrity.

Methods

We developed a two-step strategy to identify and remediate research-site overlap by obtaining detailed recruitment plans across all PMC PCTs that addressed eligibility criteria, recruitment methods, trial settings, and timeframes. The first, information-gathering phase consisted of a 2-month period for data collection from PIs, stakeholders, and ClinicalTrials.gov. The second, remediation phase consisted of a series of moderated conference calls over a 1-month time period to develop plans to address overlap. Remediation efforts focused on exclusion criteria and recruitment strategies, and they involved collaboration with sponsors and stakeholder groups such as the Military Treatment Facility Engagement Committee (MTFEC). The MTFEC is comprised of collaborating DoD and university-affiliated PIs, clinicians, and educators devoted to facilitating successful pragmatic trials in DoD settings.

Results

Of 61 recruitment sites for the 11 PMC PCTs, 17 (28%) overlapped. Four PCTs had five overlapping Military Treatment Facilities (MTFs), and eight PCTs had 12 overlapping VA Medical Centers (VAMCs). We developed three general strategies to avoid research-site overlap: (i) modify exclusion criteria, (ii) coordinate recruitment efforts, and/or (iii) replace or avoid any overlapping sites. Potential overlap from competing studies outside of the PMC was apparent at 26 sites, but we were not able to confirm them as true conflicts.

Conclusion

Proactive strategies can be used to resolve the issue of overlapping research sites in the PMC. These strategies, combined with open and impartial mediation approaches that include researchers, sponsors, and stakeholders, provide lessons learned from this large and complex pragmatic research effort.
Molecular characterization and serodiagnostic potential of two serpin proteins in Psoroptes ovis var. cuniculi
Authors: Gu Xiaobin , Chen Yuhang , Zhang Chongyang , Xie Yue , Shen Nengxing , Wang Ce , Zhou Xuan , Yang Guangyou , He Ran , Peng Xuerong , Yang Deying , He Zhi , Zhong Zhijun
Published: December 2020

Background

Psoroptes ovis var. cuniculi is a common ectoparasite of wild and domestic rabbits worldwide that causes economically devastating losses in commercial rabbit husbandry and significantly affects the overall health of rabbits. Serine proteinase inhibitor (serpin) is present in almost all organisms that are involved in host–pathogen interactions, inflammatory responses, and reproductive development, among others. However, very little research has been carried out on P. ovis var. cuniculi serpins.

Methods

Two serpin genes of P. ovis var. cuniculi (Pso c 27 and PsoSP2 cDNAs) were cloned and molecularly characterized. The transcriptional profiles and tissue localization of these two serpins in P. ovis var. cuniculi were investigated by quantitative real-time PCR and immunohistochemistry, respectively. The potential function of recombinant Pso c 27 and PsoSP2 (rPso c 27 and rPsoSP2) in the serodiagnosis of P. ovis var. cuniculi infestation in rabbits was evaluated using a newly devleoped indirect enzyme-linked immunosorbent assay.

Results

Both the 523-residue Pso c 27 and the 240-residue PsoSP2 proteins contained typical serpin domains and signatures. Both Pso c 27and PsoSP2 cDNAs were expressed throughout the life-cycle; specifically, the cDNAs showed significantly higher expression in female mites than in larva, nymph, and male mites (Pso c 27: F(3, 8) = 1935.953, P < 0.0001; PsoSP2: F(3, 8) = 660.669, P < 0.0001). The native Pso c 27 and PsoSP2 proteins localized in the ovary and mouthparts of adult female mites, respectively. Compared to rPsoSP2, rPso c 27 showed better diagnostic efficiency, with higher values of sensitivity, specificity, and area under the receiver operating characteristic curve (rPso c 27 vs rPsoSP2: 96.0 vs 90.0%; 90.91 vs 78.18%; 0.988 vs 0.964, respectively). Moreover, rPso c 27 showed seropositivity in 80% of the rabbits as early as the 2 weeks post-infestation, prior to visible clinical signs and microscopy-positive of skin scrapings.

Conclusions

These results suggest that these two serpins may play essential roles in reproductive development, serum-feeding, and pathogenicity of P. ovis var. cuniculi. Compared to PsoSP2, Pso c 27 appears to be a potential antigen for serodiagnosis of P. ovis var. cuniculi infestation in rabbits, especially at the early stage of infestation.

Graphical Abstract
Global hypermethylation of intestinal epithelial cells is a hallmark feature of neonatal surgical necrotizing enterocolitis
Authors: Good Misty , Chu Tianjiao , Shaw Patricia , McClain Lora , Chamberlain Austin , Castro Carlos , Rimer Jamie M. , Mihi Belgacem , Gong Qingqing , Nolan Lila S. , Cooksey Krista , Linneman Laura , Agrawal Pranjal , Finegold David N. , Peters David
Published: December 2020

Background

Necrotizing enterocolitis (NEC) remains one of the overall leading causes of death in premature infants, and the pathogenesis is unpredictable and not well characterized. The aim of our study was to determine the molecular phenotype of NEC via transcriptomic and epithelial cell-specific epigenomic analysis, with a specific focus on DNA methylation.

Methods

Using laser capture microdissection, epithelial cell-specific methylation signatures were characterized by whole-genome bisulfite sequencing of ileal and colonic samples at the time of surgery for NEC and after NEC had healed at reanastomosis (n = 40). RNA sequencing was also performed to determine the transcriptomic profile of these samples, and a comparison was made to the methylome data.

Results

We found that surgical NEC has a considerable impact on the epigenome by broadly increasing DNA methylation levels, although these effects are less pronounced in genomic regions associated with the regulation of gene expression. Furthermore, NEC-related DNA methylation signatures were influenced by tissue of origin, with significant differences being noted between colon and ileum. We also identified numerous transcriptional changes in NEC and clear associations between gene expression and DNA methylation.

Conclusions

We have defined the intestinal epigenomic and transcriptomic signatures during surgical NEC, which will advance our understanding of disease pathogenesis and may enable the development of novel precision medicine approaches for NEC prediction, diagnosis and phenotyping.
Evidence for the placenta-brain axis: multi-omic kernel aggregation predicts intellectual and social impairment in children born extremely preterm
Authors: Santos Jr Hudson P. , Bhattacharya Arjun , Joseph Robert M. , Smeester Lisa , Kuban Karl C. K. , Marsit Carmen J. , O’Shea T. Michael , Fry Rebecca C.
Published: December 2020

Background

Children born extremely preterm are at heightened risk for intellectual and social impairment, including Autism Spectrum Disorder (ASD). There is increasing evidence for a key role of the placenta in prenatal developmental programming, suggesting that the placenta may, in part, contribute to origins of neurodevelopmental outcomes.

Methods

We examined associations between placental transcriptomic and epigenomic profiles and assessed their ability to predict intellectual and social impairment at age 10 years in 379 children from the Extremely Low Gestational Age Newborn (ELGAN) cohort. Assessment of intellectual ability (IQ) and social function was completed with the Differential Ability Scales-II and Social Responsiveness Scale (SRS), respectively. Examining IQ and SRS allows for studying ASD risk beyond the diagnostic criteria, as IQ and SRS are continuous measures strongly correlated with ASD. Genome-wide mRNA, CpG methylation and miRNA were assayeds with the Illumina Hiseq 2500, HTG EdgeSeq miRNA Whole Transcriptome Assay, and Illumina EPIC/850 K array, respectively. We conducted genome-wide differential analyses of placental mRNA, miRNA, and CpG methylation data. These molecular features were then integrated for a predictive analysis of IQ and SRS outcomes using kernel aggregation regression. We lastly examined associations between ASD and the multi-omic-predicted component of IQ and SRS.

Results

Genes with important roles in neurodevelopment and placental tissue organization were associated with intellectual and social impairment. Kernel aggregations of placental multi-omics strongly predicted intellectual and social function, explaining approximately 8% and 12% of variance in SRS and IQ scores via cross-validation, respectively. Predicted in-sample SRS and IQ showed significant positive and negative associations with ASD case–control status.

Limitations

The ELGAN cohort comprises children born pre-term, and generalization may be affected by unmeasured confounders associated with low gestational age. We conducted external validation of predictive models, though the sample size (N = 49) and the scope of the available out-sample placental dataset are limited. Further validation of the models is merited.

Conclusions

Aggregating information from biomarkers within and among molecular data types improves prediction of complex traits like social and intellectual ability in children born extremely preterm, suggesting that traits within the placenta-brain axis may be omnigenic.
Gene functional networks and autism spectrum characteristics in young people with intellectual disability: a dimensional phenotyping study
Authors: Brkić Diandra , Ng-Cordell Elise , O’Brien Sinéad , Scerif Gaia , Astle Duncan , Baker Kate
Published: December 2020

Background

The relationships between specific genetic aetiology and phenotype in neurodevelopmental disorders are complex and hotly contested. Genes associated with intellectual disability (ID) can be grouped into networks according to gene function. This study explored whether individuals with ID show differences in autism spectrum characteristics (ASC), depending on the functional network membership of their rare, pathogenic de novo genetic variants.

Methods

Children and young people with ID of known genetic origin were allocated to two broad functional network groups: synaptic physiology (n = 29) or chromatin regulation (n = 23). We applied principle components analysis to the Social Responsiveness Scale to map the structure of ASC in this population and identified three components—Inflexibility, Social Understanding and Social Motivation. We then used Akaike information criterion to test the best fitting models for predicting ASC components, including demographic factors (age, gender), non-ASC behavioural factors (global adaptive function, anxiety, hyperactivity, inattention), and gene functional networks.

Results

We found that, when other factors are accounted for, the chromatin regulation group showed higher levels of Inflexibility. We also observed contrasting predictors of ASC within each network group. Within the chromatin regulation group, Social Understanding was associated with inattention, and Social Motivation was predicted by hyperactivity. Within the synaptic group, Social Understanding was associated with hyperactivity, and Social Motivation was linked to anxiety.

Limitations

Functional network definitions were manually curated based on multiple sources of evidence, but a data-driven approach to classification may be more robust. Sample sizes for rare genetic diagnoses remain small, mitigated by our network-based approach to group comparisons. This is a cross-sectional study across a wide age range, and longitudinal data within focused age groups will be informative of developmental trajectories across network groups.

Conclusion

We report that gene functional networks can predict Inflexibility, but not other ASC dimensions. Contrasting behavioural associations within each group suggest network-specific developmental pathways from genomic variation to autism. Simple classification of neurodevelopmental disorder genes as high risk or low risk for autism is unlikely to be valid or useful.
Endothelial progenitor cells promote osteogenic differentiation in co-cultured with mesenchymal stem cells via the MAPK-dependent pathway
Authors: Xu Chu , Liu Haijie , He Yuanjia , Li Yuanqing , He Xiaoning
Published: December 2020

Background

The role of bone tissue engineering is to regenerate tissue using biomaterials and stem cell-based approaches. Combination of two or more cell types is one of the strategies to promote bone formation. Endothelial progenitor cells (EPCs) may enhance the osteogenic properties of mesenchymal stem cells (MSCs) and promote bone healing; this study aimed to investigate the possible mechanisms of EPCs on promoting osteogenic differentiation of MSCs.

Methods

MSCs and EPCs were isolated and co-cultured in Transwell chambers, the effects of EPCs on the regulation of MSC biological properties were investigated. Real-time PCR array, and western blotting were performed to explore possible signaling pathways involved in osteogenesis. The expression of osteogenesis markers and calcium nodule formation was quantified by qRT-PCR, western blotting, and Alizarin Red staining.

Results

Results showed that MSCs exhibited greater alkaline phosphatase (ALP) activity and increased calcium mineral deposition significantly when co-cultured with EPCs. The mitogen-activated protein kinase (MAPK) signaling pathway was involved in this process. p38 gene expression and p38 protein phosphorylation levels showed significant upregulation in co-cultured MSCs. Silencing expression of p38 in co-cultured MSCs reduced osteogenic gene expression, protein synthesis, ALP activity, and calcium nodule formation.

Conclusions

These data suggest paracrine signaling from EPCs influences the biological function and promotes MSCs osteogenic differentiation. Activation of the p38MAPK pathway may be the key to enhancing MSCs osteogenic differentiation via indirect interactions with EPCs.
Autologous adipose mesenchymal stem cell administration in arteriosclerosis and potential for anti-aging application: a retrospective cohort study
Authors: Ohta Hiroki , Liu Xiaolan , Maeda Miho
Published: December 2020

Objective

Arteriosclerosis is an age-related disease and a leading cause of cardiovascular disease. In animal experiments, mesenchymal stem cells and its culture-conditioned medium have been shown to be promising tools for prevention or treatment of arteriosclerosis. On the basis of these evidences, we aimed to assess whether administration of autologous adipose-derived mesenchymal stem cells (Ad-MSC) is safe and effective for treatment of arteriosclerosis.

Methods

We retrospectively reviewed clinical records of patients with arteriosclerosis who had received autologous Ad-MSC administration at our clinic. Patients’ characteristics were recorded and data on lipid profile, intimal-media thickness (IMT), cardio-ankle vascular index (CAVI), and ankle-brachial index (ABI) before and after Ad-MSC administration were collected and compared.

Results

Treatment with Ad-MSC significantly improved HDL, LDL, and remnant-like particle (RLP) cholesterol levels. No adverse effect or toxicity was observed in relation to the treatment. Of the patients with abnormal HDL values before treatment, the vast majority showed improvement in the values. Overall, the measurements after treatment were significantly increased compared with those before treatment (p < 0.01). In addition, decreases in LDL cholesterol and RLP levels were observed after treatment in patients who had abnormal LDL cholesterol or RLP levels before treatment. The majority of patients with pre-treatment abnormal CAVI values had improved values after treatment. In patients with available IMT values, a significant decrease in the IMT values was found after therapy (p < 0.01). All patients with borderline arteriosclerosis disease had improved laboratory findings after treatment. In general, post-treatment values were significantly decreased as compared with pre-treatment values. Of the patients with normal ABI values before treatment at the same time as CAVI, the vast majority remained normal after treatment.

Conclusions

These findings suggest that Ad-MSC administration is safe and effective in patients developing arteriosclerosis, thereby providing an attractive tool for anti-aging application.
Mitochondrial dysfunction and consequences in calpain-3-deficient muscle
Authors: Jahnke Vanessa E. , Peterson Jennifer M. , Van Der Meulen Jack H. , Boehler Jessica , Uaesoontrachoon Kitipong , Johnston Helen K. , Defour Aurelia , Phadke Aditi , Yu Qing , Jaiswal Jyoti K. , Nagaraju Kanneboyina
Published: December 2020

Background

Nonsense or loss-of-function mutations in the non-lysosomal cysteine protease calpain-3 result in limb-girdle muscular dystrophy type 2A (LGMD2A). While calpain-3 is implicated in muscle cell differentiation, sarcomere formation, and muscle cytoskeletal remodeling, the physiological basis for LGMD2A has remained elusive.

Methods

Cell growth, gene expression profiling, and mitochondrial content and function were analyzed using muscle and muscle cell cultures established from healthy and calpain-3-deficient mice. Calpain-3-deficient mice were also treated with PPAR-delta agonist (GW501516) to assess mitochondrial function and membrane repair. The unpairedttest was used to assess the significance of the differences observed between the two groups or treatments. ANOVAs were used to assess significance over time.

Results

We find that calpain-3 deficiency causes mitochondrial dysfunction in the muscles and myoblasts. Calpain-3-deficient myoblasts showed increased proliferation, and their gene expression profile showed aberrant mitochondrial biogenesis. Myotube gene expression analysis further revealed altered lipid metabolism in calpain-3-deficient muscle. Mitochondrial defects were validated in vitro and in vivo. We used GW501516 to improve mitochondrial biogenesis in vivo in 7-month-old calpain-3-deficient mice. This treatment improved satellite cell activity as indicated by increased MyoD and Pax7 mRNA expression. It also decreased muscle fatigability and reduced serum creatine kinase levels. The decreased mitochondrial function also impaired sarcolemmal repair in the calpain-3-deficient skeletal muscle. Improving mitochondrial activity by acute pyruvate treatment improved sarcolemmal repair.

Conclusion

Our results provide evidence that calpain-3 deficiency in the skeletal muscle is associated with poor mitochondrial biogenesis and function resulting in poor sarcolemmal repair. Addressing this deficit by drugs that improve mitochondrial activity offers new therapeutic avenues for LGMD2A.
Measurement site of inferior vena cava diameter affects the accuracy with which fluid responsiveness can be predicted in spontaneously breathing patients: a post hoc analysis of two prospective cohorts
Authors: Caplan Morgan , Durand Arthur , Bortolotti Perrine , Colling Delphine , Goutay Julien , Duburcq Thibault , Drumez Elodie , Rouze Anahita , Nseir Saad , Howsam Michael , Onimus Thierry , Favory Raphael , Preau Sebastien
Published: December 2020

Background

The collapsibility index of the inferior vena cava (cIVC) has potential for predicting fluid responsiveness in spontaneously breathing patients, but a standardized approach for measuring the inferior vena cava diameter has yet to be established.

The aim was to test the accuracy of different measurement sites of inferior vena cava diameter to predict fluid responsiveness in spontaneously breathing patients with sepsis-related circulatory failure and examine the influence of a standardized breathing manoeuvre.

Results

Among the 81 patients included in the study, the median Simplified Acute Physiologic Score II was 34 (24; 42). Sepsis was of pulmonary origin in 49 patients (60%). Median volume expansion during the 24 h prior to study inclusion was 1000 mL (0; 2000). Patients were not severely ill: none were intubated, only 20% were on vasopressors, and all were apparently able to perform a standardized breathing exercise. Forty-one (51%) patients were responders to volume expansion (i.e. a ≥ 10% stroke volume index increase). The cIVC was calculated during non-standardized (cIVC-ns) and standardized breathing (cIVC-st) conditions. The accuracy with which both cIVC-ns and cIVC-st predicted fluid responsiveness differed significantly by measurement site (interaction p < 0.001 and < 0.0001, respectively). Measuring inferior vena cava diameters 4 cm caudal to the right atrium predicted fluid responsiveness with the best accuracy. At this site, a standardized breathing manoeuvre also significantly improved predictive power: areas under ROC curves [mean and (95% CI)] for cIVC-ns = 0.85 [0.78–0.94] versus cIVC-st = 0.98 [0.97–1.0], p < 0.001. When cIVC-ns is superior or equal to 33%, fluid responsiveness is predicted with a sensitivity of 66% and a specificity of 92%. When cIVC-st is superior or equal to 44%, fluid responsiveness is predicted with a sensitivity of 93% and a specificity of 98%.

Conclusion

The accuracy with which cIVC measurements predict fluid responsiveness in spontaneously breathing patients depends on both the measurement site of inferior vena cava diameters and the breathing regime. Measuring inferior vena cava diameters during a standardized inhalation manoeuvre at 4 cm caudal to the right atrium seems to be the method by which to obtain cIVC measurements best-able to predict patients’ response to volume expansion.
Lie symmetry reductions and conservation laws for fractional order coupled KdV system
Authors: Jafari Hossein , Sun Hong Guang , Azadi Marzieh
Published: December 2020

Lie symmetry analysis is achieved on a new system of coupled KdV equations with fractional order, which arise in the analysis of several problems in theoretical physics and numerous scientific phenomena. We determine the reduced fractional ODE system corresponding to the governing factional PDE system.

In addition, we develop the conservation laws for the system of fractional order coupled KdV equations.
The role of phagocytic leukocytes following flexible ureterenoscopy, for the treatment of kidney stones: an observational, clinical pilots-study
Authors: Hughes Stephen Fôn , Moyes Alyson Jayne , Lamb Rebecca May , Ella-tongwiis Peter , Snyper Nana Yaa Frempomaa , Shergill Iqbal
Published: December 2020

Background

The number of patients undergoing flexible ureterenoscopy (FURS) for the treatment of kidney stones (renal calculi) is increasing annually, and as such the development of post-operative complications, such as acute kidney injury (AKI), haematuria and infection is likely to increase. Phagocytic leukocytes are white blood cells that help fight foreign material such as bacteria and viruses, and they are intrinsically involved in the inflammatory reaction. Investigating the role of phagocytic leukocytes following FURS has not been widely researched. The main aim of the study was to evaluate the role phagocytic leukocytes (neutrophils and monocytes) function, in patients undergoing FURS for the treatment of kidney stones (renal calculi).

Methods

Fourteen consecutive patients aged between 27 and 70 years (median 49.5 years) undergoing FURS for the treatment of kidney stones were recruited (seven males, seven females). Blood samples were collected from each patient at four time points: baseline (pre-operatively) followed by 30, 120 and 240 min post-operatively. Mononuclear (MN) and polymorphonuclear (PMN) leukocyte sub-populations were isolated by density gradient centrifugation techniques. Neutrophil and monocyte cell function was investigated by measuring the cell surface expression of CD62L (L-selectin), CD11b (Mac-1), CD99 and the intracellular production of hydrogen peroxide (H2O2), via flow cytometry.

Results

Significant increases was observed in monocyte CD62L expression post FURS for the treatment of kidney stones (p ≤ 0.05); while significant decreases were observed in neutrophil CD62L. The levels of the other activation markers CD11b, CD99 and H2O2corresponded to the increases and decreases seen in CD62L for monocytes and neutrophils respectively, though the changes were not statistically significant (p > 0.05). Limiting factors for this study were the relatively small sample size, and restriction on the recruitment time points.

Conclusions

This study demonstrates that following FURS for the treatment of kidney stones, monocytes are rapidly activated and produce potent reactive oxygen intermediates. Interestingly, the pattern of expression in neutrophils suggests that these cells are deactivated in response to the treatment. The leukocyte biomarkers assessed during this investigation may have a role in monitoring the ‘normal’ post-operative response, as no complications occurred in any of the patients; or may help predict potential infectious complications (e.g. urosepsis) that can occur during the post-operative period. This data, however, will need to be validated and reproduced in larger multi-centre studies.
A model to illustrate the potential pairing of animal biotelemetry with individual-based modeling
Authors: Brosnan Ian G. , Welch David W.
Published: December 2020

Background

Animal biotelemetry and individual-based modeling (IBM) are natural complements, but there are few published examples where they are applied together to address fundamental or applied ecological questions. Existing studies are often found in the modeling literature and frequently re-use small datasets collected for purposes other than the model application. Animal biotelemetry can provide the robust measurements that capture relevant ecological patterns needed to parameterize, calibrate, and assess hypotheses in IBMs; together they could help meet demand for predictive modeling and decision-support in the face of environmental change.

Results

We used an simple exemplar IBM that uses spatio-temporal movement patterns of 103 acoustic-tagged juvenile yearling Chinook salmon (Oncorhynchus tshawytscha), termed ‘smolts’, to quantitatively assess plausibility of two migratory strategies that smolts are hypothesized to use while migrating north through the plume of the Columbia River (United States of America). We find that model smolts that seek to maximize growth demonstrate movement patterns consistent with those of tagged smolts. Model smolts that seek to move quickly out of the plume region by seeking favorable currents do not reproduce the same patterns.

Conclusions

Animal biotelemetry and individual-based modeling are maturing fields of inquiry. Our hope is that this model description and the basic analytical techniques will effectively illustrate individual-based models for the biotelemetry community, and perhaps inspire new collaborations between biotelemetry researchers and individual-based modelers.
Isotope-reinforced polyunsaturated fatty acids improve Parkinson’s disease-like phenotype in rats overexpressing α-synuclein
Authors: Beal M. Flint , Chiluwal Jayandra , Calingasan Noel Y. , Milne Ginger L. , Shchepinov Mikhail S. , Tapias Victor
Published: December 2020

Lipid peroxidation is a key to a portfolio of neurodegenerative diseases and plays a central role in α-synuclein (α-syn) toxicity, mitochondrial dysfunction and neuronal death, all key processes in the pathogenesis of Parkinson’s disease (PD). Polyunsaturated fatty acids (PUFAs) are important constituents of the synaptic and mitochondrial membranes and are often the first molecular targets attacked by reactive oxygen species (ROS). The rate-limiting step of the chain reaction of ROS-initiated PUFAs autoxidation involves hydrogen abstraction at bis-allylic sites, which can be slowed down if hydrogens are replaced with deuteriums. In this study, we show that targeted overexpression of human A53T α-syn using an AAV vector unilaterally in the rat substantia nigra reproduces some of pathological features seen in PD patients. Chronic dietary supplementation with deuterated PUFAs (D-PUFAs), specifically 0.8% D-linoleic and 0.3% H-linolenic, produced significant disease-modifying beneficial effects against α-syn-induced motor deficits, synaptic pathology, oxidative damage, mitochondrial dysfunction, disrupted trafficking along axons, inflammation and DA neuronal loss. These findings support the clinical evaluation of D-PUFAs as a neuroprotective therapy for PD.
A solitary hypothalamic metastasis from prostatic cancer mimicking a giant thrombotic aneurysm and presenting with intraventricular hemorrhage and acute hydrocephalus: a case report
Authors: Saadatpour Zarhra , Rezaei Ali , Singhal Aparna , Sotoudeh Houman , Tavakol Kamran
Published: December 2020

Background

Despite the high prevalence of prostate cancer, its brain parenchymal metastasis is not common and intracranial hemorrhage due to such a metastasis is even less common. This report presents a challenging case of solitary brain metastasis secondary to prostate cancer that gave rise to intraventricular hemorrhage and acute hydrocephalus mimicking a giant aneurysm.

Case presentation

A 77-year-old man with a history of prostate cancer, hypertension, and morbid obesity presented to the emergency room with a severe headache. He was afebrile with a blood pressure of 144/79 mmHg, alert, without any sign of sensory or motor deficit. Shortly after admission, he became unresponsive and was immediately intubated. His blood tests revealed hypernatremia at 154 mmol/L; otherwise, the lab data including the COVID-19 screening proved normal. The cerebral CT and MR images, with and without contrast, were interpreted as a giant thrombotic aneurysm extending to the suprasellar region by the emergency radiologist. Also, moderate intraventricular hemorrhage, acute hydrocephalus, and sub-ependymal interstitial edema were observed. Upon further evaluation of the images, the lesion was determined to be an exophytic hemorrhagic hypothalamic mass, and the subsequent biopsy was consistent with prostate cancer metastasis.

Conclusions

The exophytic hemorrhagic hypothalamic metastasis can mimic a ruptured aneurysm on imaging. Given the improved survival of patients with prostate cancer, radiologists may encounter such unusual cerebral metastases from prostate cancers more frequently in the future.
Development and Validation of a Tool Integrating the 21-Gene Recurrence Score and Clinical-Pathological Features to Individualize Prognosis and Prediction of Chemotherapy Benefit in Early Breast Cancer
Authors: Sparano Joseph A. , Crager Michael R. , Tang Gong , Gray Robert J. , Stemmer Salomon M. , Shak Steven
Published: December 2020

PURPOSE

The 21-gene recurrence score (RS) is prognostic for distant recurrence (DR) and predictive for chemotherapy benefit in early breast cancer, whereas clinical-pathological factors are only prognostic. Integration of genomic and clinical features offers the potential to guide adjuvant chemotherapy use with greater precision.

METHODS

We developed a new tool (RSClin) that integrates RS with tumor grade, tumor size, and age using a patient-specific meta-analysis including 10,004 women with hormone receptor–positive, human epidermal growth factor receptor 2–negative, and node-negative breast cancer who received endocrine therapy alone in the B-14 (n = 577) and TAILORx (n = 4,854) trials or plus chemotherapy in TAILORx (n = 4,573). Cox models for RSClin were compared with RS alone and clinical-pathological features alone using likelihood ratio tests. RSClin estimates of DR used a baseline risk with TAILORx event rates to reflect current medical practice. A patient-specific estimator of absolute chemotherapy benefit was computed using individualized relative chemotherapy effect from the randomized TAILORx and B-20 trials. External validation of risk estimation was performed by comparing RSClin estimated risk and observed risk in 1,098 women in the Clalit registry.

RESULTS

RSClin provides more prognostic information (likelihood ratio χ2) for DR than RS or clinical-pathological factors alone (both P < .001, likelihood ratio test). In external validation, the RSClin risk estimate was prognostic for DR risk in the Clalit registry ( P < .001) and the estimated risk closely approximated the observed 10-year risk (Lin concordance 0.962). The absolute chemotherapy benefit estimate ranges from 0% to 15% as the RS ranges from 11 to 50 using RSClin in a 55-year-old woman with a 1.5-cm intermediate-grade tumor.

CONCLUSION

The RSClin tool integrates clinical-pathological and genomic risk to guide adjuvant chemotherapy in node-negative breast cancer and provides more individualized information than clinical-pathological or genomic data alone.
Rapid Conversion of a Palliative Care Outpatient Clinic to Telehealth
Authors: Lally Kate , Kematick Benjamin S. , Gorman Daniel , Tulsky James
Published: December 2020

PURPOSE:

The coronavirus pandemic has transformed the practice of medicine, forcing a rapid transition to telehealth. As a specialty, palliative care relies upon expert-level communication and interdisciplinary care. We describe the transition of the Dana-Farber Cancer Institute palliative care clinic into a predominantly telemedicine model.

RESULTS:

We document how we significantly increased goals of care conversations while maintaining patient volume and interdisciplinary care. We present how the components of a palliative visit translate into a virtual model.

DISCUSSION:

While the transition away from in person visits occurred rapidly, telehealth is likely here to stay. We define the challenges and benefits encountered through increased use of telehealth and identify disparities in healthcare access that will become more pronounced as we move into a communication technology dependent future. We discuss how the pandemic changed the delivery of palliative care in ways that will endure beyond the coronavirus pandemic.
PLEKHG4B enables actin cytoskeletal remodeling during epithelial cell–cell junction formation
Authors: Ninomiya Komaki , Ohta Kai , Yamashita Kazunari , Mizuno Kensaku , Ohashi Kazumasa
Published: December 2020

Cell–cell junction formation requires actin cytoskeletal remodeling. Here, we show that PLEKHG4B, a Rho-guanine nucleotide exchange factor (Rho-GEF), plays a crucial role in epithelial cell–cell junction formation. Knockdown of PLEKHG4B decreased Cdc42 activity and tended to increase RhoA activity in A549 cells. A549 monolayer cells showed ‘closed junctions’ with closely packed actin bundles along the cell–cell contacts, but PLEKHG4B knockdown suppressed closed junction formation, and PLEKHG4B-knockdown cells exhibited ‘open junctions’ with split actin bundles located away from the cell–cell boundary. In Ca2+-switch assays, PLEKHG4B knockdown delayed the conversion of open junctions to closed junctions and β-catenin accumulation at cell–cell junctions. Furthermore, PLEKHG4B knockdown abrogated the reduction in myosin activity normally seen in the later stage of junction formation. The aberrant myosin activation and impairments in closed junction formation in PLEKHG4B-knockdown cells were reverted by ROCK inhibition or LARG/PDZ-RhoGEF knockdown. These results suggest that PLEKHG4B enables actin remodeling during epithelial cell–cell junction maturation, probably by reducing myosin activity in the later stage of junction formation, through suppressing LARG/PDZ-RhoGEF and RhoA–ROCK pathway activities. We also showed that annexin A2 participates in PLEKHG4B localization to cell–cell junctions.

This article has an associated First Person interview with the first author of the paper.
RNA structure probing to characterize RNA–protein interactions on low abundance pre-mRNA in living cells
Authors: Bubenik Jodi L. , Hale Melissa , McConnell Ona , Wang Eric T. , Swanson Maurice S. , Spitale Robert C. , Berglund J. Andrew
Published: December 2020

In vivo RNA structure analysis has become a powerful tool in molecular biology, largely due to the coupling of an increasingly diverse set of chemical approaches with high-throughput sequencing. This has resulted in a transition from single target to transcriptome-wide approaches. However, these methods require sequencing depths that preclude studying low abundance targets, which are not sufficiently captured in transcriptome-wide approaches. Here we demonstrate that enrichment of low abundance targets before reverse transcription broadens the range of molecules analyzed and results in improved analysis for low abundance transcripts. In addition, this method is compatible with any choice of chemical adduct or read-out approach. We combine this method with inducible expression of an RBP of interest to study an autoregulated event in the pre-mRNA of the splicing factor, muscleblind-like splicing regulator 1 (MBNL1) in a cellular context.
Loot Box Pricing and Design
Authors: Chen Ningyuan , Elmachtoub Adam N. , Hamilton Michael L. , Lei Xiao
Published: December 2020

In the online video game industry, a significant portion of the revenue is generated from microtransactions, where a small amount of real-world currency is exchanged for virtual items to be used in the game. One popular way to conduct microtransactions is via a loot box, which is a random allocation of virtual items whose contents are not revealed until after purchase. In this work, we consider how to optimally price and design loot boxes from the perspective of a revenue-maximizing video game company and analyze customer surplus under such selling strategies. Our paper provides the first formal treatment of loot boxes, with the aim to provide customers, companies, and regulatory bodies with insights into this popular selling strategy. We consider two types of loot boxes: a traditional one where customers can receive (unwanted) duplicates and a unique one where customers are guaranteed to never receive duplicates. We show that as the number of virtual items grows large, the unique box strategy is asymptotically optimal among all possible strategies, whereas the traditional box strategy only garners 36.7% of the optimal revenue. On the other hand, the unique box strategy leaves almost zero customer surplus, whereas the traditional box strategy leaves positive surplus. Further, when designing traditional and unique loot boxes, we show it is asymptotically optimal to allocate the items uniformly, even when the item valuation distributions are heterogeneous. We also show that, when the seller purposely misrepresents the allocation probabilities, their revenue may increase significantly, and thus, strict regulation is needed. Finally, we show that, even if the seller allows customers to salvage unwanted items, then the customer surplus can only increase by at most 1.4%.

This paper was accepted by Victor Martinez-de-Albeniz, operations management.
Impacts of Counterfeiting on a Global Supply Chain
Authors: Yi Zelong , Yu Man , Cheung Ki Ling
Published: December 2020

Problem definition: This paper investigates how counterfeits influence a global supply chain and how the supply chain should effectively take anticounterfeit actions. Academic/practical relevance: The impacts of counterfeiting have been increasingly profound on global supply chains. It is critical to understand how counterfeiting impacts supply chains when supply chain members act in their own interests, and how supply chains can effectively combat counterfeiting when all the members can contribute to it. This is the first paper that offers insights into these important questions. In particular, we examine who among the supply chain members is in the best position to perform counteracting activities, how these members can cooperate in anticounterfeiting, and what economic implications the anticounterfeit actions have to the supply chain, individual firms, consumer surplus, and social welfare. Methodology: We consider a supply chain consisting of a manufacturer and a retailer, and analyze a game-theoretical framework to derive the equilibrium. Results: The manufacturer prefers to induce the retailer to combat counterfeits rather than to combat itself. Contrary to conventional wisdom, counterfeits can increase the supply chain’s profit even in the absence of network externality effects. The crux is that the manufacturer lowers wholesale price to incentivize the retailer’s counteraction and, consequently, the threat of counterfeits can mitigate double marginalization and benefit the supply chain. Managerial implications: Our results demonstrate that a sustainability risk can trigger collaborative endeavors of supply chain members and thus be advantageous to the supply chain. The findings also underscore the important role that retailers should play in anticounterfeiting. Particularly, it can be in the supply chain’s interest that the manufacturer does not execute the counteraction, either jointly with the retailer or by itself.
Modified oblique high tibial osteotomy with minimal fixation for correction of adolescent tibia vara: A prospective case series study
Authors: Aly Ahmad Saeed , Abdelhamid Alsabir Ahmed Refaat , Fahmy Hesham Ahmad , Fayyad Tamer A.
Published: December 2020

Purpose

To assess the reliability and efficacy of the modified oblique high tibial osteotomy for correction of complex deformity in adolescent tibia vara.

Methods

A total of 19 patients (25 legs) with adolescent tibia vara were enrolled in this study. There were 16 male (84.2%) and three female (15.8%) patients who had modified Rab oblique osteotomy with minimal fixation performed. The age of the patients at time of surgery ranged from 12 years to 30 years (mean 17.23 (sd 5.27)). The body mass index ranged from 22 kg/m2 to 42 kg/m2 (mean 32.05 (sd 6.13)). All patients were followed up for over two years (mean 3.4; 2 to 5).

Results

The femoro-tibial angle was improved from -34° to -12° (mean -20.04° (sd 5.24°) preoperatively and from -12° to 7°, postoperatively (mean 2.04° (sd 4.07)). Medial deviation of the mechanical axis corrected from 38 mm to 125 mm (mean 76.13 (sd 23.29)) preoperatively to 0 mm to 36 mm (mean 5.74 (sd 7.3)) postoperatively. The time needed to achieve union ranged from eight weeks to 16 weeks (mean 10.2 (sd 2.42)). According to the Lysholm functional knee score scale, there were 15 excellent (78.9%), two good (10.5%), one fair (5.2%) and one poor (5.2%) after correction of the deformity.

Conclusion

Modified Rab osteotomy with minimal fixation by two or three screws shows promising results with good correction of varus deformity (coronal plane), internal torsion (axial plane) and procurvatum (sagittal plane), in management of adolescent tibia vara with minimal morbidity and complications.

Level of evidence

IV
Simulations and experimental demonstration of three different regimes
of optofluidic manipulation
Authors: Wang Hao , Tarriela Joseph , Shiveshwarkar Priyanka , Pyayt Anna
Published: December 2020

It has been demonstrated that optically controlled microcurrents can be used to capture and move around a variety of microscopic objects ranging from cells and nanowires to whole live worms. Here, we present our findings on several new regimes of optofluidic manipulation that can be engineered using careful design of microcurrents. We theoretically optimize these regimes using COMSOL Multiphysics and present three sets of simulations and corresponding optofluidic experiments. In the first regime, we use local fluid heating to create a microcurrent with a symmetric toroid shape capturing particles in the center. In the second regime, the microcurrent shifts and tilts because external fluid flow is introduced into the microfluidic channel. In the third regime, the whole microfluidic channel is tilted, and the resulting microcurrent projects particles in a fan-like fashion. All three configurations provide interesting opportunities to manipulate small particles in fluid droplets and microfluidic channels.
Optical system of a micro-nano high-precision star sensor based on
combined stray light suppression technology
Authors: Meng Yao , Zhong Xing , Liu Yong , Zhang Kun , Ma Chi
Published: December 2020

The micro-nano design of a high-precision star sensor is studied. Point source transmittance (PST, the ratio of the irradiance generated by the external field source on the image surface to the irradiance at the entrance pupil) is used as the evaluation index of stray light suppression ability, the stray light suppression theory of star sensors is analyzed, and the mathematical model between stray light suppression ability and detectable magnitude is established. In view of the limited volume of micro-nano star sensors, a new design principle of combined anti-stray-light design of the baffle and optical system is proposed. The high stray light suppression of the micro-nano star sensor is realized by using the imaging optical path design of active stray light suppression and the design of a conical extinction cavity, which breaks through the technical problem of coupling system volume and stray light suppression ability. The results of the simulation and on-orbit experiments show that the star sensor based on the joint stray light technology can achieve a PST of

2

×

10

−
8

at the avoidance angle under the premise of limited optical system volume, and it has a stray light suppression ability of 6.5 magnitude stars.