bluuebunny/crossref_metadata_2025_split huggingface dataset:
Sign-specific stimulation ‘hot’ and ‘cold’ spots in Parkinson’s disease validated with machine learning
Authors: Boutet Alexandre , Germann Jurgen , Gwun Dave , Loh Aaron , Elias Gavin J B , Neudorfer Clemens , Paff Michelle , Horn Andreas , Kuhn Andrea A , Munhoz Renato P , Kalia Suneil K , Hodaie Mojgan , Kucharczyk Walter , Fasano Alfonso , Lozano Andres M 
Published: March 2021

Abstract
Deep brain stimulation of the subthalamic nucleus has become a standard therapy for Parkinson’s disease. Despite extensive experience, however, the precise target of optimal stimulation and the relationship between site of stimulation and alleviation of individual signs remains unclear. We examined whether machine learning could predict the benefits in specific Parkinsonian signs when informed by precise locations of stimulation. We studied 275 Parkinson’s disease patients who underwent subthalamic nucleus deep brain stimulation between 2003 and 2018. We selected pre-deep brain stimulation and best available post-deep brain stimulation scores from motor items of the Unified Parkinson's Disease Rating Scale (UPDRS-III) to discern sign-specific changes attributable to deep brain stimulation. Volumes of tissue activated were computed and weighted by (i) tremor, (ii) rigidity, (iii) bradykinesia and (iv) axial signs changes. Then, sign-specific sites of optimal (‘hot spots’) and suboptimal efficacy (‘cold spots’) were defined. These areas were subsequently validated using machine learning prediction of sign-specific outcomes with in-sample and out-of-sample data (n = 51 subthalamic nucleus deep brain stimulation patients from another institution). Tremor and rigidity hot spots were largely located outside and dorsolateral to the subthalamic nucleus whereas hot spots for bradykinesia and axial signs had larger overlap with the subthalamic nucleus. Using volume of tissue activated overlap with sign-specific hot and cold spots, support vector machine classified patients into quartiles of efficacy with ≥92% accuracy. The accuracy remained high (68–98%) when only considering volume of tissue activated overlap with hot spots but was markedly lower (41–72%) when only using cold spots. The model also performed poorly (44–48%) when using only stimulation voltage, irrespective of stimulation location. Out-of-sample validation accuracy was ≥96% when using volume of tissue activated overlap with the sign-specific hot and cold spots. In two independent datasets, distinct brain areas could predict sign-specific clinical changes in Parkinson’s disease patients with subthalamic nucleus deep brain stimulation. With future prospective validation, these findings could individualize stimulation delivery to optimize quality of life improvement.
Characterizing the Network Architecture of Emotion Regulation Neurodevelopment
Authors: Guassi Moreira João F , McLaughlin Katie A , Silvers Jennifer A 
Published: March 2021

Abstract
The ability to regulate emotions is key to goal attainment and well-being. Although much has been discovered about neurodevelopment and the acquisition of emotion regulation, very little of this work has leveraged information encoded in whole-brain networks. Here we employed a network neuroscience framework to parse the neural underpinnings of emotion regulation skill acquisition, while accounting for age, in a sample of children and adolescents (N = 70, 34 female, aged 8–17 years). Focusing on three key network metrics—network differentiation, modularity, and community number differences between active regulation and a passive emotional baseline—we found that the control network, the default mode network, and limbic network were each related to emotion regulation ability while controlling for age. Greater network differentiation in the control and limbic networks was related to better emotion regulation ability. With regards to network community structure (modularity and community number), more communities and more crosstalk between modules (i.e., less modularity) in the control network were associated with better regulatory ability. By contrast, less crosstalk (i.e., greater modularity) between modules in the default mode network was associated with better regulatory ability. Together, these findings highlight whole-brain connectome features that support the acquisition of emotion regulation in youth.
Low birth weight and its associated biopsychosocial factors over a 19-year period: findings from a national cohort study
Authors: Bizuayehu Habtamu Mellie , Harris Melissa L , Chojenta Catherine , Forder Peta M , Loxton Deborah 
Published: March 2021

Abstract

Background
In Australia, 6.7% of babies (5.2% for singletons) are born low birth weight (LBW), and over the past decade, this figure has increased by 8%. Evidence regarding LBW has largely come from hospital-based cross-sectional studies, which are not representative, lack temporality and do not examine the potential predictors of LBW using a comprehensive theoretical framework. This study, therefore, examined predictors of LBW within a biopsychosocial framework, using a community-based representative prospective cohort with 19 years of data.

Methods
The study included 11 854 singleton babies born to 5622 women from the 1973 to 1978 cohort of the Australian Longitudinal Study on Women’s Health.

Results
Among 5622 first births, 310 (5.5%) were reported as LBW. Maternal risk factors included pre-pregnancy underweight (aOR = 2.27, 95% CI: 1.43–3.62), chronic diabetes (aOR = 2.38, 95% CI: 1.14–4.95), gestational diabetes (aOR = 1.93, 95% CI: 1.27–2.94), chronic hypertension (aOR = 2.23, 95% CI: 1.50–3.33) and gestational hypertension (aOR = 2.44, 95% CI: 1.78–3.36). Among all births (N = 11 854), the overall LBW rate was 3.8% with a recurrence rate of 4.8%. Identified risk factors included menarche before 12 years (aOR = 1.57; 95% CI: 1.17–2.11), pre-pregnancy underweight (aOR = 2.25, 95% CI: 1.46–3.45), gestational diabetes (aOR = 1.74, 95% CI: 1.16–2.59), chronic hypertension (aOR = 2.01, 95% CI: 1.40–2.90) and gestational hypertension (aOR = 2.81, 95% CI: 2.05–3.84). LBW was less likely for second births (aOR = 0.39, 95% CI: 0.31–0.50) and third/above births (aOR = 0.49, 95% CI: 0.35–0.67) compared with the first births.

Conclusion
Increased nutrition counselling/supplementation for underweight women and interventions aimed at chronic disease prevention and management by using a multi-sectoral approach may be the key to the prevention of LBW.
Characterization of the binding motif for the T3SS master regulator LcrF in Yersinia pseudotuberculosis
Authors: Liu Luyi , Huang Shaojia , Fei Keke , Zhou Wei , Chen Shiyun , Hu Yangbo 
Published: March 2021

ABSTRACT
LcrF is the master regulator that positively regulates the Ysc type III secretion system (T3SS) in Yersinia and shares a high similarity with the DNA-binding domain of the T3SS master regulator ExsA in Pseudomonas aeruginosa. Based on these features, bioinformatics analysis has predicted a putative LcrF-binding site in its target promoters. Here, we experimentally characterized its binding motif. An adenine-rich LcrF-binding region in the lcrG promoter sequence, a typical regulatory target of LcrF, was first confirmed. To obtain detailed information, this binding region was cloned into a synthetized promoter and mutations in this region were further constructed. We demonstrated that the 5’-AAAAA-n5-GnCT-3’ sequence is required for LcrF regulation and this motif is strictly located 4-bp upstream of a noncanonical promoter, in which the -35 and -10 elements are separated by a 21-bp spacer. Consistently, the putative binding motif was found in promoters of nine T3SS related operons or genes positively regulated by LcrF. Transcriptome analysis further confirmed that LcrF specifically activates T3SS genes in Yersinia. Collectively, our data suggest that LcrF has evolved to be a specific T3SS activator with a stringent sequence requirement for transcriptional regulation.
The Physiological Conundrum That is the Domestic Dog
Authors: Jimenez Ana Gabriela 
Published: March 2021

SynopsisAcross Mammalia, body size and lifespan are positively correlated. However, in domestic dogs, the opposite is true: small dogs have longer lives compared with large dogs. Here, I present literature-based data on life-history traits that may affect dog lifespan, including adaptations at the whole-organism, and organ-level. Then, I compare those same traits to wild canids. Because oxidative stress is a byproduct of aerobic metabolism, I also present data on oxidative stress in dogs that suggests that small breed dogs accumulate significantly more circulating lipid peroxidation damage compared with large breed dogs, in opposition to lifespan predictions. Further, wild canids have increased antioxidant concentrations compared with domestic dogs, which may aid in explaining why wild canids have longer lifespans than similar-sized domestic dogs. At the cellular level, I describe mechanisms that differ across size classes of dogs, including increases in aerobic metabolism with age, and increases in glycolytic metabolic rates in large breed dogs across their lifespan. To address potential interventions to extend lifespan in domestic dogs, I describe experimental alterations to cellular architecture to test the “membrane pacemaker” hypotheses of metabolism and aging. This hypothesis suggests that increased lipid unsaturation and polyunsaturated fatty acids in cell membranes can increase cellular metabolic rates and oxidative damage, leading to potential decreased longevity. I also discuss cellular metabolic changes of primary fibroblast cells isolated from domestic dogs as they are treated with commercially available drugs that are linked to lifespan and health span expansion.
Parental income and mental disorders in children and adolescents: prospective register-based study
Authors: Kinge Jonas Minet , Øverland Simon , Flatø Martin , Dieleman Joseph , Røgeberg Ole , Magnus Maria Christine , Evensen Miriam , Tesli Martin , Skrondal Anders , Stoltenberg Camilla , Vollset Stein Emil , Håberg Siri , Torvik Fartein Ask 
Published: March 2021

Abstract

Background
Children with low-income parents have a higher risk of mental disorders, although it is unclear whether other parental characteristics or genetic confounding explain these associations and whether it is true for all mental disorders.

Methods
In this registry-based study of all children in Norway (n = 1 354 393) aged 5–17 years from 2008 to 2016, we examined whether parental income was associated with childhood diagnoses of mental disorders identified through national registries from primary healthcare, hospitalizations and specialist outpatient services.

Results
There were substantial differences in mental disorders by parental income, except for eating disorders in girls. In the bottom 1% of parental income, 16.9% [95% confidence interval (CI): 15.6, 18.3] of boys had a mental disorder compared with 4.1% (95% CI: 3.3, 4.8) in the top 1%. Among girls, there were 14.2% (95% CI: 12.9, 15.5) in the lowest, compared with 3.2% (95% CI: 2.5, 3.9) in the highest parental-income percentile. Differences were mainly attributable to attention-deficit hyperactivity disorder in boys and anxiety and depression in girls. There were more mental disorders in children whose parents had mental disorders or low education, or lived in separate households. Still, parental income remained associated with children’s mental disorders after accounting for parents’ mental disorders and other factors, and associations were also present among adopted children.

Conclusions
Mental disorders were 3- to 4-fold more prevalent in children with parents in the lowest compared with the highest income percentiles. Parents’ own mental disorders, other socio-demographic factors and genetic confounding did not fully explain these associations.
The Association of Coronavirus Disease 2019 Risk Perception, County Death Rates, and Voluntary Health Behaviors Among United States Adult Population
Authors: Elharake Jad A , Shafiq Mehr , McFadden SarahAnn M , Malik Amyn A , Omer Saad B 
Published: March 2021

Abstract

Background
The coronavirus disease 2019 (COVID-19) pandemic continues to adversely impact the United States socially, culturally, and economically. The purpose of this study was to understand the relationship between COVID-19 county death rates, risk perception, and US adults’ voluntary behaviors—particularly physical distancing.

Methods
Data were collected from CloudResearch/Qualtrics, Johns Hopkins University, the American Community Survey, and SafeGraph.

Results
Our results indicated that higher COVID-19 county death rates were associated with higher risk perceptions, leading to greater time spent at home.

Conclusions
These findings will help public health officials identify strategies that best encourage voluntary health behaviors to help curb the spread of COVID-19.
A1 F4/80+LY6CHI MACROPHAGES ARE KEY TO CANCER INITIATION IN COLITIS
Authors: Shin A E , Good H J , Tesfagiorgis Y , Zhang L , Kerfoot S , Sherman P M , Wang T C , Howlett C J , Asfaha S 
Published: March 2021

Abstract

Background
Colorectal cancer (CRC) is the third leading cause of cancer death, with a major risk factor being chronic inflammation. Thus, patients with inflammatory bowel disease (IBD) are at an increased risk of CRC. Despite the clear association between inflammation and cancer, the mechanism by which colitis leads to CRC is still not well understood.

Aims
In this study, we aim to explore the mechanism by which inflammation contributes to the initiation of colitis-associated cancer (CAC). We hypothesize that dextran sodium sulfate (DSS)-induced colitis leads to the infiltration of a specific immune cell type associated with tumorigenesis.

Methods
Following an injection of azoxymethane (AOM), mice were treated with the colitis-inducing agents DSS, trinitrobenzene sulfonic acid (TNBS), oxazolone (oxa), Citrobacter rodentium, or Doxorubicin (Doxo). The tumor studies were repeated using our published Cre-dependent murine model of CAC. To generate tamoxifen-inducible Cre transgenic mice that allow for Dclk1+ cell lineage tracing and cell-specific knock-out of the tumor suppressor adenomatous polyposis coli (APC), we crossed our Dclk1CreERT2 mice to both ROSA26tdTomato and APCfl/fl mice (Dclk1/APCfl/fl).

Results
Treatment with DSS, TNBS, oxa, C. rodentium, or Doxo induced colonic inflammation as detected by increased myeloperoxidase (MPO) activity and histologic analysis. DSS administration led to colonic tumors, whereas TNBS, oxa, C. rodentium, or Doxo did not lead to tumorigenesis up to 52 weeks following colitis induction. Upon flow cytometric analysis of several types of immune cells in the colonic tissue, we observed no difference in the number of T and B cells between mice treated with various colitis inducing agents. We did, however, detect significantly increased levels of Ly6G+ neutrophils and F4/80+Ly6Chi macrophages in the DSS-treated mice when compared to mice in the other models of colitis. mRNA and protein array analyses of the colonic tissue, as well as analysis of the RNA-seq data from 206 UC patients (GSE109142), revealed upregulated expression of genes associated with macrophages and neutrophils. Addition of macrophage-produced cytokines, such as IL-1β, TNF-α, or IL-6, induced lineage tracing of Dclk1+ tuft cells in intestinal organoids. Clodronate liposome-mediated depletion of F4/80+Ly6Chi macrophages significantly reduced the number of colonic tumors but did not affect tumor size in Dclk1/APCfl/fl mice.

Conclusions
Our data suggest that infiltration of F4/80+Ly6Chi macrophages, unique to DSS-induced colitis, leads to colonic tumor formation. This demonstrates that specific immune cell types, rather than the presence of colonic inflammation, plays an important role in the initiation of CAC.

Funding Agencies
CAG, CIHR
A13 A HIGH SALT DIET SYNERGIZES WITH UC MICROBIOTA TO INDUCE A PROINFLAMMATORY IMMUNE TONE IN IMMUNOCOMPETENT GNOTOBIOTIC MICE
Authors: Santiago Badenas A , Hann A , Galipeau H J , Constante M , Bercik P , Verdu E 
Published: March 2021

Abstract

Background
The exact cause for inflammatory bowel disease (IBD) is unknown, however, there is consensus that a combination of genetic, environmental, and immune factors, participate in its pathogenesis. Recently, high salt diet (HSD) has been shown to increase the severity of experimental colitis through depletion of lactobacilli in specific pathogen-free mice. However, whether HSD-microbiota interaction occurs in mice colonized with microbiota from patients with IBD, is unknown.

Aims
Our aim was to determine whether mice colonized with microbiota from patients with active ulcerative colitis (UC), one of two forms of IBD, develop more severe inflammation when fed a HSD.

Methods
10–15 week-old germ-free C57BL/6 mice were colonized with fecal microbiota from a healthy control (HC, n=13) or from a patient with UC experiencing a flare (UC, n=13). Colonized mice were housed in ISO positive cages (Techniplast) in a gnotobiotic facility during the experiment. For each group, half of the mice were kept on a control diet (7004, Teklad) and the other half were fed a HSD (7004 supplemented with 4% NaCl) plus 1% NaCl in drinking water for 3 weeks. At sacrifice, colon tissue was collected for histological analysis, RNA sequencing, and flow cytometry. Fecal samples were collected for lipocalin-2 determination.

Results
Colonic polymorphonuclear (PMN) cells were higher in UC compared with HC mice, regardless of diet (p&lt;0.01). In mice fed HSD, UC mice also had higher PMN cell counts than HC mice (p&lt;0.001). Administration of HSD to UC, but not to HC mice, also increased the proportion of α4+IFNg-producing T cells in the colonic lamina propria, compared with UC mice fed control diet (p&lt;0.01). This was paralleled by higher fecal lipocalin-2 in UC mice fed HSD compared with control diet (p&lt;0.05). Targeted analysis of RNA sequencing data revealed that 7 genes, mainly related to the JAK/STAT pathway (i.e., Stat2, Tyk2, Tlr7) were differentially expressed (p≤0.05) between HC and UC mice fed the control diet. A different gene expression signature was found in mice fed HSD compared with control diet, with an increase in proinflammatory genes in UC colonized mice compared to HC colonized mice, such as Il12a and Il6 (p&lt;0.05).

Conclusions
Immunocompetent mice colonized with microbiota from a UC patient in flare spontaneously developed a proinflammatory immune tone, which was exacerbated by HSD. The different pattern of gene induction observed in mice colonized with the microbiota from the same UC donor, but fed HSD, suggests independent and synergistic pathways conducive to inflammation. Future studies will explore the preclinical therapeutic effect of novel drug candidates for the inhibition of such pathways.

Funding Agencies
CCC
A22 PREVALENCE OF IRON DEFICIENCY AND SUPPLEMENTATION PRACTICES FOR PATIENTS ON HOME PARENTERAL NUTRITION
Authors: Russell L , Mangat R , Plant J , Hansen S , Armstrong D , Pinto-Sanchez M I 
Published: March 2021

Abstract

Background
Iron deficiency (ID) is common in patients receiving parenteral nutrition (PN), likely due to a lack of iron in the PN formula. There is no clear consensus on how often serum iron should be tested or iron supplementation should be given, at which dose or route, in patients on long-term PN. Within the Hamilton Health Sciences (HHS) home PN (HPN) program, the prevalence of ID or iron deficiency anemia (IDA) is unknown. This knowledge will contribute to better iron prescribing practices with ultimate benefit on patient’s health.

Aims
To assess the prevalence of ID and IDA in patients enrolled in the HHS HPN Program. The secondary aim was to assess supplementation practices for patients enrolled in the HPN program according to gastrointestinal(GI) diagnosis and duration on PN.

Methods
We conducted a retrospective study including consecutive adult patients enrolled in the HHS-HPN program from January 2015 to November 2020. We collected data on demographics (age, sex, and GI diagnosis), iron supplementation (dose, duration, and route), and information related to iron-deficiency (hemoglobin, serum iron, ferritin, TIBC, and folate) at pre-set intervals (enrollment, 3, 6, 12, 18, 24, 30, 36, 48, 60 months) and last measured. ID was defined as ferritin ≤45μg/L or serum iron ≤9μmol/L. IDA was defined as hemoglobin &lt;130g/L in men or &lt;120g/L in women in the context of ID. Data were expressed as median (IQR) for continuous variables and n/N(%) for categorical variables. Chi2 was performed to assess differences between groups and logistic regression to assess predictors of ID and IDA. The analysis was conducted using SPSS software(v26).

Results
The analysis included 125 HPN patients (50 males, median age of 55 (40–65) years). Patients received PN for a median of 195 (83–521) days. The most common diagnoses were malignancy (36.8%) and inflammatory bowel disease (23.2%); the most common indications for HPN was short bowel (29.6%) and bowel obstruction (27.2%). Iron profiles were measured in 77% of patients. At enrollment, 42.2% of patients had ID and 38.9% had IDA. Only 13% of patients with ID and 22.8% with IDA had iron supplementation (Figure 1). A total of 38 patients received iron either oral or IV (oral=44.7% vs IV=55.3%; p=0.66). There was no correlation between low levels of serum iron or ferritin with iron supplementation (p=0.23, 0.45 respectively). Age, sex, diagnosis, or reason for PN did not correlate with ID or IDA at any time point.

Conclusions
Iron-deficiency and IDA are common in patients enrolled in the HHS HPN program independently of age, sex, diagnosis and reason for PN. Prospective studies are needed to implement the most effective way to ensure proper monitoring and treatment of iron deficiency in this population.

Funding Agencies
None