bluuebunny/crossref_metadata_2025_split huggingface dataset:
Sex and Estrous Cycle in Memory for Sequences of Events in Rats
Authors: Jayachandran M. , Langius P. , Pazos Rego F. , Vertes R. P. , Allen T. A. 
Published: November 2021

ABSTRACTThe ability to remember sequences of events is fundamental to episodic memory. While rodent studies have examined sex and estrous cycle in episodic-like spatial memory tasks, little is known about these biological variables in memory for sequences of events that depend on representations of temporal context. We investigated the role of sex and estrous cycle in rats during all training and testing stages of a cross-species validated sequence memory task (Jayachandran et al., 2019). Rats were trained on a task composed of two sequences, each with four unique odors delivered on opposite ends of a linear track. Training occurred in six successive stages starting with learning to poke in a nose port for ≥1.2s; eventually demonstrating sequence memory by holding their nose in the port for ≥1s for in-sequence odors and <1s for out-of-sequence odors in order to receive a water reward. Performance was analyzed across sex and estrous cycle (proestrus, estrus, metestrus, and diestrus), the latter being determined by the cellular composition of a daily vaginal lavage. We found no evidence of sex differences in asymptotic sequence memory performance, similar to published data in humans performing the analogous task (Reeders et al., 2021). Likewise, we found no differences in performance across the estrous cycle. One minor difference was that female rats tended to have slightly longer poke times, while males had slightly more short poke times but this did not affect their decisions. These results suggest sex and estrous cycle are not major factors in sequence memory capacities.
Serial invasions can disrupt the time course of ecosystem recovery
Authors: Karatayev Vadim A. , Rudstam Lars G. , Karatayev Alexander Y. , Burlakova Lyubov E. , Adamovich Boris V. , Zhukava Hanna A. , Holeck Kristen T. , Hetherington Amy Lee , Jackson James R. , Hotaling Christopher W. , Zhukova Tatyana V. , Mikheyeva Tamara M. , Kovalevskaya Raisa Z. , Makarevich Oleg A. , Kruk Darya V. 
Published: November 2021

AbstractThe impacts of species invasions can subside or amplify over time as ecosystems “adapt” or additional invaders arrive. These long-term changes provide important insights into ecosystem dynamics. Yet studies of long-term dynamics are rare and often confound species impacts with coincident environmental change. We synthesize many-decade time-series across ecosystems to resolve shared changes in seven key features following invasion by quagga and zebra mussels, two widespread congeners that re-engineer and increasingly co-invade freshwaters. Six polymictic shallow lakes with long-term data sets reveal remarkably similar trends, with the strongest ecosystem impacts occurring within 5-10 years of zebra mussel invasion. Surprisingly, plankton communities then exhibited a partial, significant recovery. This recovery was absent, and impacts of initial invasion amplified, in lakes where quagga mussels outcompeted zebra mussels and more completely depleted phytoplankton. Thus, invasion impacts subside over time but can amplify with serial introductions of competing, even closely similar, taxa.
Asparagine metabolism in tumors is linked to poor survival in females with colorectal cancer: A cohort study
Authors: Shen Xinyi , Cai Yuping , Lu Lingeng , Huang Huang , Yan Hong , Paty Philip B. , Muca Engjel , Ahuja Nita , Zhang Yawei , Johnson Caroline H. , Khan Sajid A. 
Published: November 2021

AbstractBackground or PurposeThe interplay between the sex-specific differences in tumor metabolome and colorectal cancer (CRC) prognosis has never been studied and represents an opportunity to improve patient outcomes. This study aims to examine the link between tumor metabolome and prognosis by sex for CRC patients.MethodsUsing untargeted metabolomics analysis, abundances of 91 metabolites were obtained from primary tumor tissues from 197 patients (N=95 females, N=102 males) after surgical colectomy for stage I-III CRC. Cox Proportional Hazards (PH) regression models were applied to estimate the associations between tumor metabolome and 5-year overall survival (OS) and 5-year recurrence-free survival (RFS), and their interactions with sex.ResultsEleven metabolites had significant sex differences in their associations with 5-year OS, and five metabolites for 5-year RFS (Pinteraction < .05). The metabolites asparagine and serine had sex interactions for both OS and RFS. Furthermore, sex-specific differences were found in the associations between prognosis and metabolic pathways. Notably, in the asparagine synthetase (ASNS)-catalyzed asparagine synthesis pathway, asparagine was associated with substantially poorer OS (hazard ratio [HR] = 6.39, 95% confidence interval [CI] = 1.78-22.91, P = .004) and RFS (HR = 4.36, 95% CI = 1.39-13.68, P = .01) for female patients only (Pinteraction, OS = .02, Pinteraction, RFS = .003). Similar prognostic disadvantages in females were seen in lysophospholipid and polyamine synthesis.Discussion or ConclusionsUnique metabolite profiles indicated increased asparagine synthesis was associated with poorer prognosis for females only, providing insights into precision medicine for CRC treatment stratified by sex.
MFN2Influences Amyotrophic Lateral Sclerosis Pathology
Authors: Russell Kristi L. , Downie Jonathan M. , Gibson Summer B. , Figueroa Karla P. , Steely Cody J. , Bromberg Mark B. , Murtaugh L. Charles , Jorde Lynn B. , Pulst Stefan M. 
Published: November 2021

AbstractObjectiveTo better understand the pathology of amyotrophic lateral sclerosis, we used sequence data from patients seen at the University of Utah to identify novel disease-associated loci. We utilized bothin vitroandin vivostudies to determine the biological effect of patient mutations inMFN2.MethodSequence data for a total of 140 patients were run through VAAST and Phevor to determine genes that were more burdened with rare, nonsynonymous variants compared to control longevity cohort. Variants identified in MFN2 were expressed inMfn2knockout cells to determine if mutant MFN2 could rescue mitochondrial morphology defects. We identified additional rare, nonsynonymous variants in MFN2 in ALSdb that were expressed in knockout mouse embryonic fibroblasts (MEFs). Membrane potential was measured to quantify mitochondrial health upon mutant MFN2 expression.mfn2knockout zebrafish were used to examine movement compared to wildtype and protein aggregation in brain.ResultsMFN2mutations identified in ALS patients from our University of Utah cohort and ALSdb were defective in rescuing morphological defects inMfn2knockout MEFs. Selected mutants showed decreased membrane potential compared to wildtype MFN2 expression. Zebrafish heterozygous and homozygous for loss ofmfn2showed increased TDP-43 levels in their hindbrain and cerebellum.ConclusionIn total, 21 rare, deleterious mutations inMFN2were tested inMfn2knockout MEFs. Mutant MFN2 expression was not able to rescue the knockout phenotype, though at differing degrees of severity. Decreased membrane potential also argues for inhibited mitochondrial function. Increased TDP-43 levels in mutant zebrafish illustrates MFN2’s function in ALS pathology. MFN2 variants influence ALS pathology and highlight the importance of mitochondria in neurodegeneration.
Estimating treatment effect for individuals with progressive multiple sclerosis using deep learning
Authors: Falet Jean-Pierre R. , Durso-Finley Joshua , Nichyporuk Brennan , Schroeter Julien , Bovis Francesca , Sormani Maria-Pia , Precup Doina , Arbel Tal , Arnold Douglas Lorne 
Published: November 2021

AbstractProgressive forms of multiple sclerosis (MS) remain resistant to treatment. Since there are currently no suitable biomarkers to allow for phase 2 trials, pharmaceutical companies must proceed directly to financially risky phase 3 trials, presenting a high barrier to drug development. We address this problem through predictive enrichment, which randomizes individuals predicted to be most responsive in order to increase a study’s power. Specifically, deep learning is used to estimate conditional average treatment effect (CATE) using baseline clinical and imaging features, and rank individuals on the basis of their predicted response to anti-CD20 antibodies. We leverage a large dataset from six different randomized clinical trials (n = 3, 830). In a left-out test set of primary progressive patients from two anti-CD20-antibodies trials, the average treatment effect was significantly greater for the 50% (HR, 0.492; 95% CI, 0.266-0.912; p = 0.0218) and the 30% (HR, 0.361; 95% CI, 0.165-0.79; p = 0.008) predicted to be most responsive, compared to 0.743 (95% CI, 0.482-1.15; p = 0.179) for the entire group. The same model could also identify responders to laquinimod, which has a different mechanism of action. We demonstrate important increases in power that would result from the use of this model for predictive enrichment, enabling short proof-of-concept trials.
Cost-effectiveness of vitamin D3 supplementation in older adults with vitamin D deficiency in Ireland
Authors: Lacey Laurence F. , Armstrong David J. , Royle Emily , Magee Pamela J. , Pourshahidi L. Kirsty , Ray Sumantra , Strain J. J. , McSorley Emeir M. 
Published: November 2021

ABSTRACTBackgroundThis study investigated the cost-effectiveness of vitamin D3 supplementation in older adults in Ireland, with year-round vitamin D deficiency (serum 25-hydroxyvitamin D concentration <30 nmol/L) (13% of Irish adults), from the perspective of the Health Service Executive (HSE).MethodsThree age groups were investigated: (1) ≥50 years, (2) ≥60 years, (3) ≥70 years. Based on the clinical literature, vitamin D3 supplementation may (1) decrease all-cause mortality by 7%, and (2) reduce hip fractures by 16%, and non-hip fractures by 20%. A discount rate of 4% was applied to life years and QALYs gained. The annual healthcare costs per patient used in the model are based on the average annual health resource use over the 5-year time horizon of the model.ResultsThe cost/QALY estimates in all three age groups are below the usually acceptable cost-effectiveness threshold of €20,000/QALY. The most cost-effective and least costly intervention was in adults ≥70 years. For this age group, the average annual costs and outcomes would be approx. €6.2 million, 1,043 QALYs gained, with a cost/QALY of approx. €6,000. The results are most sensitive to the mortality risk reduction following vitamin D3 supplementation.ConclusionThe cost-effectiveness of vitamin D3 supplementation is most robust in adults ≥70 years. Clinical uncertainty in the magnitude of the benefits of vitamin D3 supplementation could be further addressed by means of (1) performing a clinical research study or (2) conducting a pilot/regional study, prior to reaching a decision to invest in a full nationwide programme.
Defining the Proteomic and Phosphoproteomic Landscape of Circulating Extracellular Vesicles in the Diabetes Spectrum
Authors: Lopez Yury O. Nunez , Iliuk Anton , Petrilli Alejandra , Glass Carley , Casu Anna , Pratley Richard E. 
Published: November 2021

ABSTRACTThe purpose of this study was to characterize the proteomic and phosphoproteomic profiles of circulating extracellular vesicles (EVs) from people with normal glucose tolerance (NGT), prediabetes (PDM), and diabetes (T2DM). Archived serum samples from 30 human subjects (N=10 per group, ORIGINS study, ClinicalTrials.govNCT02226640) were used. EVs were isolated using EVTRAP (Tymora). Mass spectrometry (LC-MS)-based methods were used to detect the global EV proteome and phosphoproteome. Differentially expressed features, correlation networks, enriched pathways, and enriched tissue-specific protein sets were identified using custom R scripts. A total of 2372 unique EV proteins and 716 unique EV phosphoproteins were identified. Unsupervised clustering of the differentially expressed (fold change≥2, P<0.05, FDR<0.05) proteins and, particularly, phosphoproteins, showed excellent discrimination among the three groups. Among characteristic changes in the PDM and T2DM EVs, “integrins switching” appeared to be a central feature. Proteins involved in oxidative phosphorylation (OXPHOS), known to be reduced in various tissues in diabetes, were significantly increased in EVs from PDM and T2DM, which suggests that an abnormally elevated EV-mediated secretion of OXPHOS components may underlie development of diabetes. We also detected a highly enriched signature of liver-specific markers among the downregulated EV proteins and phosphoproteins in both PDM and T2DM groups. This suggests that an alteration in liver EV composition and/or secretion may occur early in prediabetes. Levels of signaling molecules involved in cell death pathways were significantly altered in the circulating EVs. Consistent with the fact that patients with T2DM have abnormalities in platelet function, we detected a significant enrichment (FDR<<0.01) for upregulated EV proteins and phosphoproteins that play a role in platelet activation, coagulation, and chemokine signaling pathways in PDM and T2DM. Overall, this pilot study demonstrates the potential of EV proteomic and phosphoproteomic signatures to provide insight into the pathobiology of diabetes and its complications. These insights could lead to the development of new biomarkers of disease risk, classification, progression, and response to interventions that could allow personalization of interventions to improve outcomes.
Dimensionality and modularity of adaptive variation: Divergence in threespine stickleback from diverse environments
Authors: Haines Grant E. , Moisan Louis , Derry Alison M. , Hendry Andrew P. 
Published: November 2021

AbstractIn nature, populations are subjected to a wide variety of environmental conditions that affect fitness and induce adaptive or plastic responses in traits, resulting in phenotypic divergence between populations. The dimensionality of that divergence, however, remains contentious. At the extremes, some contend that populations diverge along a single axis of trait covariance with greatest availability of heritable variation, even if this does not lead a population directly to its fitness optimum. Those at the other extreme argue that selection can push populations towards their fitness optima along multiple phenotype axes simultaneously, resulting in divergence in numerous dimensions. Here, we address this debate using populations of threespine stickleback (Gasterosteus aculeatus) in the Cook Inlet region of southern Alaska from lakes with contrasting ecological conditions. We calculated effective dimensionality of divergence in several trait suites (defensive, swimming, and trophic) thought to be under correlated selection pressures, as well as across all traits. We also tested for integration among the trait suites and between each trait suite and the environment. We found that populations in the Cook Inlet radiation exhibit dimensionality of phenotype high enough to preclude a single axis of divergence.
Development and Validation of an Interpretable 3-day Intensive Care Unit Readmission Prediction Model Using Explainable Boosting Machines
Authors: Hegselmann Stefan , Ertmer Christian , Volkert Thomas , Gottschalk Antje , Dugas Martin , Varghese Julian 
Published: November 2021

AbstractIntensive care unit readmissions are associated with mortality and bad outcomes. Machine learning could help to identify patients at risk to improve discharge decisions. However, many models are black boxes, so that dangerous properties might remain unnoticed. In this study, an inherently interpretable model for 3-day ICU readmission prediction was developed. We used a retrospective cohort of 15,589 ICU stays and 169 variables collected between 2006 and 2019. A team of doctors inspected the model, checked the plausibility of each component, and removed problematic parts. Qualitative feedback revealed several challenges for interpretable machine learning in healthcare. The resulting model used 67 features and showed an area under the precision-recall curve of 0.119±0.020 and an area under the receiver operating characteristic curve of 0.680±0.025. This is on par with state-of-the-art gradient boosting machines and outperforms the Simplified Acute Physiology Score II. External validation with the Medical Information Mart for Intensive Care database version IV confirmed our findings. Hence, a machine learning model for readmission prediction with a high level of human control is feasible without sacrificing performance.
Optimum bug fixing rate and bug fixing time detection by software reliability modelling
Authors: Narvaneni Rama Rao , Suresh Babu K. 
Published: November 2021

PurposeSoftware reliability growth models (SRGMs) are used to assess and predict reliability of a software system. Many of these models are effective in predicting future failures unless the software evolves.Design/methodology/approachThis objective of this paper is to identify the best path for rectifying the BFT (bug fixing time) and BFR (bug fixing rate). Moreover, the flexible software project has been examined while materializing the BFR. To enhance the BFR, the traceability of bug is lessened by the version tag virtue in every software deliverable component. The release time of software build is optimized with the utilization of mathematical optimization mechanisms like ‘software reliability growth’ and ‘non-homogeneous Poisson process methods.’FindingsIn current market scenario, this is most essential. The automation and variation of build is also resolved in this contribution. Here, the software, which is developed, is free from the bugs or defects and enhances the quality of software by increasing the BFR.Originality/valueIn current market scenario, this is most essential. The automation and variation of build is also resolved in this contribution. Here, the software, which is developed, is free from the bugs or defects and enhances the quality of software by increasing the BFR.
Towards a theory of well-being in digital sports viewing behavior
Authors: G. Rejikumar , Jose Ajay , Mathew Sonia , Chacko Dony Peter , Asokan-Ajitha Aswathy 
Published: November 2021

Purpose
Social television (Social TV) viewing of live sports events is an emerging trend. The realm of transformative service research (TSR) envisions that every service consumption experience must lead to consumer well-being. Currently, a full appreciation of the well-being factors obtained through Social TV viewing is lacking. This study aims to gain a holistic understanding of the concept of digital sports well-being obtained through live Social TV viewing of sports events.

Design/methodology/approach
Focus group interviews were used to collect data from the 40 regular sports viewers, and the qualitative data obtained is analyzed thematically using NVivo 12. A post hoc verification of the identified themes is done to narrow down the most critical themes.

Findings
The exploration helped understand the concept of digital sports well-being (DSW) obtained through live Social TV sports spectating and identified five critical themes that constitute its formation. The themes that emerged were virtual connectedness, vividness, uncertainty reduction, online disinhibition and perceived autonomy. This study defines the concept and develops a conceptual model for DSW.

Research limitations/implications
This study adds to the body of knowledge in TSR, transformative sport service research, digital customer engagement, value co-creation in digital platforms, self-determination theory and flow theory. The qualitative study is exploratory, with participants’ views based on a single match in one particular sport, and as such, its findings are restrained by the small sample size and the specific sport. To extend this study’s implications, empirical research involving a larger and more diversified sample involving multiple sports Social TV viewing experiences would help better understand the DSW concept.

Practical implications
The research provides insights to Social TV live streamers of sporting events and digital media marketers about the DSW construct and identifies the valued DSW dimensions that could provide a competitive advantage.

Originality/value
To the best of the authors’ knowledge, the exploration is the first attempt to describe the concept of DSW and identify associated themes.
Gender associations with selection into Australian Orthopaedic Surgical Training: 2007–2019
Authors: Incoll Ian W. , Atkin Jodie , Frank Jason R. , Vrancic Sindy , Khorshid Omar 
Published: November 2021

AbstractBackgroundCommunities have better health outcomes when their clinicians reflect the diversity of the communities they serve. More than 50% of Australian medical school graduates are female, yet women represent less than 5% of Australian orthopaedic surgeons. Selection into orthopaedic surgical training in Australia is an annual, nation‐wide process, based on curriculum vitae (CV), referee reports and performance in multiple mini‐interviews (MMI). The influence of applicant gender on these selection scores was examined.MethodsThe CV, referee reports and MMI scores used for selection for each year from 2007 to 2019 were analysed from the perspective of the applicant's gender.ResultsOver the years of the study, male applicants had higher CV scores and referee report scores, which determined the gender proportions invited to interview. By contrast, the interview process and selection from interview did not demonstrate a gender association.ConclusionWe describe the impact of selection tools, utilized over the past 13 years, on the gender diversity of trainees commencing orthopaedic surgery training in Australia. Leaders in postgraduate training should examine commonly used selection procedures to identify and reduce the unconscious biases that may affect their performance and value.
Outcomes of retroperitoneal lymph node dissection for testicular cancer by a high volume surgeon from Australia: a case for centralisation
Authors: Williams Isabella S. C. , Lahoud John , Gurney Howard , Arasaratnam Malmaruha , Patel Manish I. 
Published: November 2021

AbstractBackgroundThere are few studies examining retroperitoneal lymph node dissection (RPLND) for testicular cancer in Australia. This study examines the perioperative outcomes, complications and survival rates following RPLND, by a high volume, single surgeon.MethodsA retrospective, case series of a single surgeon, multi‐centre study included all patients who underwent RPLND following testicular cancer at Westmead Public Hospital, Westmead Private Hospital, and Macquarie University Hospital 2005–2020. One hundred one patients identified, with 94 having sufficient available data.ResultsAt time of operation, median age was 29.5 years. 84.2% had T1 or T2 primary tumours at diagnosis. Most common RPLND indication was residual mass post‐chemotherapy (92.6%), with bleomycin, etoposide and cisplatin (BEP)x3 and BEPx4 most common chemotherapy regimens (50% and 35% respectively). Post‐chemotherapy, largest residual mass ranged from 0.9 to 20 cm (median 3.32 cm). Post‐chemotherapy, 95.7% masses were found in retroperitoneum (64.4% para‐aortic region). 93.6% had open approach. 42.5% had bilateral nerve sparing. Majority (97.1%) did not require blood transfusion. No complications reported in 52.1% of patients. No deaths recorded within 90 days of surgery. At time of analysis, 91.5% had recurrence free survival, and 92.6% overall survival, at a median follow‐up since surgery of 47.5 months (range 11 to 200 months).ConclusionsThis retrospective study, addressing peri‐operative surgical outcomes for RPLND surgery in Australia, is comparable to high‐volume international urological centre studies, and shows that centralisation of post‐chemotherapy RPLND to an experienced surgeon, results in low perioperative morbidity and mortality.