bluuebunny/crossref_metadata_2025_split huggingface dataset:
Safety and tolerability of experimental hookworm infection in humans with metabolic disease: study protocol for a phase 1b randomised controlled clinical trial
Authors: Pierce Doris , Merone Lea , Lewis Chris , Rahman Tony , Croese John , Loukas Alex , McDonald Malcolm , Giacomin Paul , McDermott Robyn 
Published: December 2019

Abstract
Background
Abdominal obesity and presence of the metabolic syndrome (MetS) significantly increase the risk of developing diseases such as Type 2 diabetes mellitus (T2DM) with escalating emergence of MetS and T2DM constituting a significant public health crisis worldwide. Lower prevalence of inflammatory and metabolic diseases such as T2DM in countries with higher incidences of helminth infections suggested a potential role for these parasites in the prevention and management of certain diseases. Recent studies confirmed the potential protective nature of helminth infection against MetS and T2DM via immunomodulation or, potentially, alteration of the intestinal microbiota. This Phase 1b safety and tolerability trial aims to assess the effect of inoculation with helminths on physical and metabolic parameters, immune responses, and the microbiome in otherwise healthy women and men.

Methods
Participants eligible for inclusion are adults aged 18–50 with central obesity and a minimum of one additional feature of MetS recruited from the local community with a recruitment target of 54. In a randomised, double-blind, placebo-controlled design, three groups will receive either 20 or 40 stage three larvae of the human hookworm Necator americanus or a placebo. Eligible participants will provide blood and faecal samples at their baseline and 6-monthly assessment visits for a total of 24 months with an optional extension to 36 months. During each scheduled visit, participants will also undergo a full physical examination and complete diet (PREDIMED), physical activity, and patient health (PHQ-9) questionnaires. Outcome measurements include tolerability and safety of infection with Necator americanus, changes in metabolic and immunological parameters, and changes in the composition of the faecal microbiome.

Discussion
Rising cost of healthcare associated with obesity-induced metabolic diseases urgently calls for new approaches in disease prevention. Findings from this trial will provide valuable information regarding the potential mechanisms by which hookworms, potentially via alterations in the microbiota, may positively influence metabolic health.

Trial registration
The protocol was registered on ANZCTR.org.au on 05 June 2017 with identifier ACTRN12617000818336.
Alternatively, a Google search using the above trial registration number will yield a direct link to the trial protocol within the ANZCTR website.
Lingguizhugan decoction attenuates doxorubicin-induced heart failure in rats by improving TT-SR microstructural remodeling
Authors: Li Xueping , Xu Guangmin , Wei Shujun , Zhang Baocheng , Yao Huan , Chen Yuchi , Liu Weiwei , Wang Baojia , Zhao Juan , Gao Yongxiang 
Published: December 2019

Abstract
Background
Lingguizhugan decoction (LGZG), an ancient Chinese herbal formula, has been used to treat cardiovascular diseases in eastern Asia. We investigated whether LGZG has protective activity and the mechanism underlying its effect in an animal model of heart failure (HF).

Methods
A rat model of HF was established by administering eight intraperitoneal injections of doxorubicin (DOX) (cumulative dose of 16 mg/kg) over a 4-week period. Subsequently, LGZG at 5, 10, and 15 mL/kg/d was administered to the rats intragastrically once daily for 4 weeks. The body weight, heart weight index (HWI), heart weight/tibia length ratio (HW/TL), and serum BNP level were investigated to assess the effect of LGZG on HF. Echocardiography was performed to investigate cardiac function, and H&E staining to visualize myocardial morphology. Myocardial ultrastructure and T-tubule-sarcoplasmic reticulum (TT-SR) junctions were observed by transmission electron microscopy. The JP-2 protein level was determined by Western blotting. The mRNA level of CACNA1S and RyR2 and the microRNA-24 (miR-24) level were assayed by quantitative RT-PCR.

Results
Four weeks after DOX treatment, rats developed cardiac damage and exhibited a significantly increased BNP level compared with the control rats (169.6 ± 29.6 pg/mL versus 80.1 ± 9.8 pg/mL, P < 0.001). Conversely, LGZG, especially at the highest dose, markedly reduced the BNP level (93.8 ± 17.9 pg/mL, P < 0.001). Rats treated with DOX developed cardiac dysfunction, characterized by a strong decrease in left ventricular ejection fraction compared with the control (58.5 ± 8.7% versus 88.7 ± 4.0%; P < 0.001). Digoxin and LGZG improved cardiac dysfunction (79.6 ± 6.1%, 69.2 ± 2.5%, respectively) and preserved the left ventricular ejection fraction (77.9 ± 5.1, and 80.5 ± 4.9, respectively, P < 0.01). LGZG also improved the LVEDD, LVESD, and FS and eliminated ventricular hypertrophy, as indicated by decreased HWI and HW/TL ratio. LGZG attenuated morphological abnormalities and mitochondrial damage in the myocardium. In addition, a high dose of LGZG significantly downregulated the expression of miR-24 compared with that in DOX-treated rats (fold change 1.4 versus 3.4, P < 0.001), but upregulated the expression of JP-2 and antagonized DOX-induced T-tubule TT-SR microstructural remodeling. These activities improved periodic Ca2+ transients and cell contraction, which may underly the beneficial effect of LGZG on HF.

Conclusions
LGZG exerted beneficial effects on DOX-induced HF in rats, which were mediated in part by improved TT-SR microstructural remodeling.
Antibiotic resistance in porcine pathogenic bacteria and relation to antibiotic usage
Authors: Holmer I. , Salomonsen C. M. , Jorsal S. E. , Astrup L. B. , Jensen V. F. , Høg B. Borck , Pedersen K. 
Published: December 2019

AbstractBackgroundOptimal treatment and prudent use of antimicrobials for pigs is imperative to secure animal health and prevent development of critical resistance. An important step in this one-health context is to monitor resistance patterns of important animal pathogens. The aim of this study was to investigate the antimicrobial resistance patterns of five major pathogens in Danish pigs during a period from 2004 to 2017 and elucidate any developments or associations between resistance and usage of antibiotics.ResultsThe minimum inhibitory concentration (MIC) forEscherichia coli, Actinobacillus pleuropneumoniae, Streptococcus suis, Bordetella bronchiseptica,andStaphylococcus hyicuswas determined to representatives of antibiotic classes relevant for treatment or surveillance.Escherichia coliisolates were mostly sensitive to fluoroquinolones and colistin, whereas high levels of resistance were observed to ampicillin, spectinomycin, streptomycin, sulfonamides and tetracycline. While resistance levels to most compounds remained relatively stable during the period, resistance to florfenicol increased from 2.1% in 2004 to 18.1% in 2017, likely in response to a concurrent increase in usage. A temporal association between resistance and usage was also observed for neomycin.E. coliserovars O138 and O149 were generally more resistant than O139. ForA. pleuropneumoniae, the resistance pattern was homogenous and predictable throughout the study period, displaying high MIC values only to erythromycin whereas almost all isolates were susceptible to all other compounds. MostS. suisisolates were sensitive to penicillin whereas high resistance levels to erythromycin and tetracycline were recorded, and resistance to erythromycin and trimethoprim increasing over time. ForS. hyicus,sensitivity to the majority of the antimicrobials tested was observed. However, penicillin resistance was recorded in 69.4–88.9% of the isolates. AllB. bronchisepticaisolates were resistant to ampicillin, whereas all but two isolates were sensitive to florfenicol. The data obtained have served as background for a recent formulation of evidence-based treatment guidelines for pigs.ConclusionsAntibiotic resistance varied for some pathogens over time and in response to usage. Resistance to critically important compounds was low. The results emphasize the need for continuous surveillance of resistance patterns also in pig pathogenic bacteria.
Urban Moveability and physical activity in children: longitudinal results from the IDEFICS and I.Family cohort
Authors:   on behalf of the IDEFICS and the I.Family consortia, Buck Christoph , Eiben Gabriele , Lauria Fabio , Konstabel Kenn , Page Angie , Ahrens Wolfgang , Pigeot Iris 
Published: December 2019

Abstract
Background
Physical activity (PA) is one of the major protective behaviours to prevent non-communicable diseases. Positive effects of the built environment on PA are well investigated, although evidence of this association is mostly based on cross-sectional studies. The present study aims to investigate the longitudinal effects of built environment characteristics in terms of a moveability index on PA of children in their transition phase to adolescence using data of the IDEFICS/I.Family cohort.

Methods
We used data on 3394 accelerometer measurements of 2488 children and adolescents aged 3 to 15 years old from survey centres of three countries, Germany, Italy, and Sweden, who participated in up to three surveys over 6 years. In network-dependent home neighbourhoods, a moveability index was calculated based on residential density, land use mix, street connectivity, availability of public transport and public open spaces such as green spaces and public playgrounds in order to quantify opportunities for PA of children and adolescents. Linear trajectories of light PA (LPA) and moderate-to-vigorous PA (MVPA) were estimated using linear mixed models accounting for repeated measurements nested within individuals. Least squares means were estimated to quantify differences in trajectories over age.

Results
LPA and MVPA declined annually with age by approximately 20 min/day and 2 min/day respectively. In girls, the moveability index showed a consistent significantly positive effect on MVPA ($$ \hat{\beta} $$β̂ = 2.14, 95% CI: (0.11; 4.16)) for all ages, while in boys the index significantly lessened the decline in LPA with age for each year. ($$ \hat{\beta} $$β̂ = 2.68, 95% CI: (0.46; 4.90)).
Availability of public open spaces was more relevant for MVPA in girls and LPA in boys during childhood, whereas in adolescence, residential density and intersection density became more important.

Conclusion
Built environment characteristics are important determinants of PA and were found to have a supportive effect that ameliorates the decline in PA during the transition phase from childhood to adolescence. In childhood environmental support for leisure time PA through public open spaces was found to be the most protective factor whereas in adolescence the positive influence of street connectivity and residential density was most supportive of physical activity.
Ontogeny of the facial phenotypic variability in Mexican patients with 22q11.2 deletion syndrome
Authors: Farrera Arodi , Villanueva María , Vizcaíno Alfredo , Medina-Bravo Patricia , Balderrábano-Saucedo Norma , Rives Mariana , Cruz David , Hernández-Carbajal Elizabeth , Granados-Riveron Javier , Sánchez-Urbina Rocío 
Published: December 2019

AbstractBackground22q11.2 deletion syndrome is a medical condition that results from genomic loss at chromosome 22. Affected patients exhibit large variability that ranges from a severe condition to mild symptoms. In addition, the spectrum of clinical features differs among populations and even within family members. The facial features related to this syndrome are not an exception, and although part of its variation arises through development, few studies address this topic in order to understand the intra and inter-population heterogeneities. Here, we analyze the ontogenetic dynamics of facial morphology of Mexican patients with del22q11.2 syndrome.MethodsFrontal facial photographs of 37 patients (mean age = 7.65 ± 4.21 SE) with del22q11.2DS and 200 control subjects (mean age = 7.69 ± 4.26 SE) were analyzed using geometric morphometric methods. Overall mean shape and size differences between patients and controls were analyzed, as well as differences in ontogenetic trajectories (i.e. development, growth, and allometry).ResultsWe found that Mexican patients show typical traits that have been reported for the Caucasian population. Additionally, there were significant differences between groups in the facial shape and size when all the ontogenetic stages were considered together and, along ontogeny. The developmental and allometric trajectories of patients and controls were similar, but they differed in allometric scaling. Finally, patients and controls showed different growth trajectories.ConclusionThe results suggest that the typical face of patients with del22q11.2DS is established prenatally; nonetheless, the postnatal ontogeny could influence the dysmorphology and its variability through size-related changes.
Harnessing the power of theorising in implementation science
Authors: Kislov Roman , Pope Catherine , Martin Graham P. , Wilson Paul M. 
Published: December 2019

AbstractTheories occupy different positions in the scientific circle of enquiry as they vary in scope, abstraction, and complexity. Mid-range theories play a crucial bridging role between raw empirical observations and all-encompassing grand-theoretical schemes. A shift of perspective from ‘theories’ as products to ‘theorising’ as a process can enable empirical researchers to capitalise on the two-way relationships between empirical data and different levels of theory and contribute to the advancement of knowledge. This can be facilitated by embracing theoretically informative (in addition to merely theoretically informed) research, developing mechanism-based explanations, and broadening the repertoire of grand-theoretical orientations.
PI3K/Akt inhibitor partly decreases TNF-α-induced activation of fibroblast-like synoviocytes in osteoarthritis
Authors: Liu Songyang , Cao Chenxi , Zhang Yujun , Liu Guangyu , Ren Weixia , Ye Yanqi , Sun Tiezheng 
Published: December 2019

Abstract
Background
The Cadherin-11 and PI3K/Akt pathway are increasingly recognized as the potential therapeutic target of osteoarthritis (OA) synovitis. The study aimed to investigate the role of PI3K/Akt signaling pathway in the expression of Cadherin-11 and migration and invasive capacity of fibroblast-like synoviocytes (FLS) of OA patients under stimulation of TNF-α and to explore the effect of the PI3K/Akt inhibitor and Cadherin-11 antibody in the therapy of the collagenase-induced osteoarthritis (CIOA) mice.

Methods
FLS were primarily cultured from synovium of osteoarthritic patients during total knee arthroplasty. Under the simulation of TNF-α, with or without PI3K/Akt inhibitor LY294002, Cadherin-11 expression was detected by real-time PCR and Western blot, as well as the migration and invasive capacity changes of OA FLS. Cadherin-11 antibody was injected intraarticularly or LY294002 was injected intraperitoneally in CIOA mice to evaluate the changes of synovitis score, cartilage damage, and Cadherin-11 expression.

Results
TNF-α stimulation increased Cadherin-11 expression at mRNA and protein level in OA FLS and also increased the phosphorylation-dependent activation of Akt. PI3K inhibitor LY294002 attenuated TNF-α-induced overexpression of Cadherin-11 and decreased the invasive capacity of OA FLS. Intraperitoneal injection of PI3K inhibitor LY294002 could decrease the Cadherin-11 protein expression in synovium of CIOA mice, although it has no significant inhibitory effect on synovitis and cartilage damage. Intraarticular injection of Cadherin-11 antibody attenuated the synovitis and cartilage damage in the CIOA joints and decreased Cadherin-11 expression in the synovial lining.

Conclusions
PI3K/Akt pathway was associated with TNF-α-induced activation of OA FLS, which may involve in the pathogenesis of osteoarthritis. Anti-Cadherin-11 therapy in CIOA mice could attenuate the pathological changes of OA joints.
Risk analysis and clinical outcomes of intraoperative periprosthetic fractures: a retrospective study of 481 bipolar hemiarthroplasties
Authors: Bellova Petri , Baecker Hinnerk , Lotzien Sebastian , Brandt Marvin , Schildhauer Thomas A. , Gessmann Jan 
Published: December 2019

AbstractBackgroundIntraoperative periprosthetic fractures (IPF) are a well-described complication following hip hemiarthroplasty. Our aims were to identify risk factors that characterize IPF and to investigate postoperative mobility.MethodsWe retrospectively reviewed 481 bipolar hemiarthroplasties for displaced femoral neck fractures; of which, 421 (87.5%) were performed without cement, from January 2013 to March 2018. Data on the patients’ demographics, comorbidities, femoral canal geometry (Dorr canal type, Canal Flare Index), surgeon’s experience (junior vs. senior surgeon), and timing of surgery (daytime vs. on-call duty) were obtained. In patients with intraoperative fractures, further information was obtained. Patient mobility was assessed using matched-pair analysis. Mobility was classified according to the NHFD mobility score. The chi-square test, Fisher’s exact test, and Fisher-Freeman-Halton exact test were used for comparison between categorical variables, while the Mann-WhitneyUtest was used for continuous variables. The data analysis was performed using SPSS.ResultsOf 481 procedures, 34 (7.1%) IPFs were encountered. The Dorr canal type C was identified as a significant risk factor (p= .004). Other risk factors included female sex (OR 2.30, 95% CI .872–6.079), stovepipe femur (OR 1.749, 95% CI .823–3.713), junior surgeon (OR 1.204, 95% CI .596–2.432), and on-call-duty surgery (OR 1.471, 95% CI .711–3.046), although none showed a significant difference. Of 34 IPFs, 25 (73.5%) were classified as Vancouver type A. The treatment of choice was cerclage wiring. Within the 12 matched pairs identified, the postoperative mobility was slightly worse for the IPF group (delta = .41).ConclusionsIPF is a serious complication with bipolar hemiarthroplasty. The identification of risk factors preoperatively, in particular femur shape, is crucial and should be incorporated into the decision-making process.
Predicting outcome in patients with moderate to severe traumatic brain injury using electroencephalography
Authors: Haveman Marjolein E. , Van Putten Michel J. A. M. , Hom Harold W. , Eertman-Meyer Carin J. , Beishuizen Albertus , Tjepkema-Cloostermans Marleen C. 
Published: December 2019

Abstract
Background
Better outcome prediction could assist in reliable quantification and classification of traumatic brain injury (TBI) severity to support clinical decision-making. We developed a multifactorial model combining quantitative electroencephalography (qEEG) measurements and clinically relevant parameters as proof of concept for outcome prediction of patients with moderate to severe TBI.

Methods
Continuous EEG measurements were performed during the first 7 days of ICU admission. Patient outcome at 12 months was dichotomized based on the Extended Glasgow Outcome Score (GOSE) as poor (GOSE 1–2) or good (GOSE 3–8). Twenty-three qEEG features were extracted. Prediction models were created using a Random Forest classifier based on qEEG features, age, and mean arterial blood pressure (MAP) at 24, 48, 72, and 96 h after TBI and combinations of two time intervals. After optimization of the models, we added parameters from the International Mission for Prognosis And Clinical Trial Design (IMPACT) predictor, existing of clinical, CT, and laboratory parameters at admission. Furthermore, we compared our best models to the online IMPACT predictor.

Results
Fifty-seven patients with moderate to severe TBI were included and divided into a training set (n = 38) and a validation set (n = 19). Our best model included eight qEEG parameters and MAP at 72 and 96 h after TBI, age, and nine other IMPACT parameters. This model had high predictive ability for poor outcome on both the training set using leave-one-out (area under the receiver operating characteristic curve (AUC) = 0.94, specificity 100%, sensitivity 75%) and validation set (AUC = 0.81, specificity 75%, sensitivity 100%). The IMPACT predictor independently predicted both groups with an AUC of 0.74 (specificity 81%, sensitivity 65%) and 0.84 (sensitivity 88%, specificity 73%), respectively.

Conclusions
Our study shows the potential of multifactorial Random Forest models using qEEG parameters to predict outcome in patients with moderate to severe TBI.
Human leucocyte antigen class I in hormone receptor-positive, HER2-negative breast cancer: association with response and survival after neoadjuvant chemotherapy
Authors: Sinn Bruno Valentin , Weber Karsten E. , Schmitt Wolfgang Daniel , Fasching Peter A. , Symmans William Fraser , Blohmer Jens-Uwe , Karn Thomas , Taube Eliane Tabea , Klauschen Frederick , Marmé Frederik , Schem Christian , Stickeler Elmar , Ataseven Beyhan , Huober Jens , von Minckwitz Gunter , Seliger Barbara , Denkert Carsten , Loibl Sibylle 
Published: December 2019

Abstract
Background
Clinical application of cancer immunotherapy requires a better understanding of tumor immunogenicity and the tumor microenvironment. HLA class I molecules present antigens to CD8+ cytotoxic cells. Their loss or downregulation is frequently found in tumors resulting in reduced T cell responses and worse prognosis.

Methods
We evaluated HLA class I heavy chain expression by immunohistochemistry in 863 biopsies (GeparTrio trial). Patients received neoadjuvant chemotherapy and adjuvant endocrine treatment if tumors were hormone receptor-positive (HR+). In parallel, the expression of HLA-A was analyzed using a microarray cohort of 320 breast cancer patients from the MD Anderson Cancer Center. We evaluated its association with clinical outcome, tumor-infiltrating lymphocytes (TILs), and immune cell metagenes.

Results
In HR+/HER2− breast cancer, HLA class I heavy chain expression was associated with increased TILs and better response to chemotherapy (7% vs. 14% pCR rate, P = 0.029), but worse disease-free survival (hazard ratio (HR) 1.6 (1.1–2.4); P = 0.024). The effect was significant in a multivariate model adjusted for clinical and pathological variables (HR 1.7 (1.1–2.6); P = 0.016) and was confirmed by analysis of HLA-A in a microarray cohort. HLA-A was correlated to most immune cell metagenes. There was no association with response or survival in triple-negative or HER2+ disease.

Conclusions
The study confirms the negative prognostic role of lymphocytes in HR+ breast cancer and points at a complex interaction between chemotherapy, endocrine treatment, and tumor immunogenicity. The results point at a subtype-specific and potentially treatment-specific role of tumor-immunological processes in breast cancer with different implications in triple-negative and hormone receptor-positive disease.