bluuebunny/crossref_metadata_2025 huggingface dataset:
Platelet necrosis mediates ischemic stroke outcome in mice
Authors: Denorme Frederik , Manne Bhanu Kanth , Portier Irina , Eustes Alicia S. , Kosaka Yasuhiro , Kile Benjamin T. , Rondina Matthew T. , Campbell Robert A.
Published: December 2019

Dysregulated platelet functions contribute to the development and progression of ischemic stroke. Utilizing mice with a platelet-specific deletion of cyclophilin D (CypD), a mediator of necrosis, we found that platelet necrosis regulates tissue damage and outcomes during ischemic stroke in vivo. Mice with loss of CypD in platelets (CypDplt−/−mice) exhibited significantly enhanced cerebral blood flow, improved neurological and motor functions, and reduced ischemic stroke infarct volume after cerebral ischemia-reperfusion injury. These effects were attributable, at least in part, to platelet-neutrophil interactions. Twenty-four hours after stroke, significantly more circulating platelet-neutrophil aggregates (PNAs) were found in CypDplt+/+ mice. Underscoring the role of platelet necrosis in PNA formation, we observed a significant number of phosphatidylserine (PS)+ platelets in PNAs in CypDplt+/+ mice. In contrast, significantly fewer platelets in PNAs were PS+ in CypDplt−/− counterparts. Accordingly, mice with CypD-deficient platelets had fewer neutrophils and PNAs recruited to their brain following stroke relative to wild-type counterparts. Neutrophil depletion in wild-type mice conferred protection from ischemic stroke to a similar degree as observed in mice with CypD-deficient platelets. Neutrophil depletion in CypDplt−/− mice did not further reduce infarct size. Transmission electron microscopy of ex vivo–formed PNAs revealed a propensity of necrotic platelets to interact with neutrophils. These results suggest that necrotic platelets interact with neutrophils to exacerbate brain injury during ischemic stroke. Because inhibiting platelet necrosis does not compromise hemostasis, targeting platelet CypD may be a potential therapeutic strategy to limit brain damage following ischemic stroke.
Erythroferrone lowers hepcidin by sequestering BMP2/6 heterodimer from binding to the BMP type I receptor ALK3
Authors: Wang Chia-Yu , Xu Yang , Traeger Lisa , Dogan Deniz Y. , Xiao Xia , Steinbicker Andrea U. , Babitt Jodie L.
Published: December 2019

The authors dissect the transcriptional regulatory pathway by which the iron regulatory hormone hepcidin is suppressed by erythroferrone in response to erythropoietin.
Targeting CD20: teaching an old dog new tricks
Authors: Sharman Jeff P.
Published: December 2019

Rituximab was the first monoclonal antibody used for the treatment of a malignancy. In the 22 years since initial approval, it has become a vital component of therapy for a multitude of B-cell malignancies. Within the last several years, however, there has been a robust development of novel agents targeting CD20, including second generation anti-CD20 antibodies, biosimilar antibodies, and subcutaneous formulations that have been approved. The era of passive immunotherapy is now yielding to therapeutic approaches that actively engage the immune system. Emerging approaches leverage immunomodulatory drugs or novel checkpoint inhibitors to enhance CD20 therapy. Recent data sets on bispecific CD3/CD20 antibodies demonstrate exciting early findings, and CD20-directed chimeric antigen receptor T-cell therapies are now entering clinical trials. Anti-CD20 therapies are a vital component of the treatment of B-cell malignancies, and there is a dynamic therapeutic environment with multiple new data sets reviewed here.
Complications in pregnant women with sickle cell disease
Authors: Smith-Whitley Kim
Published: December 2019

Pregnancy in women with sickle cell disease (SCD) is associated with increased maternal and fetal morbidity and mortality. Outcomes vary widely owing to methodological limitations of clinical studies, but overall, hypertensive disorders of pregnancy, venothromboembolism, poor fetal growth, and maternal and perinatal mortality are increased globally. Few therapeutic interventions have been explored other than prophylactic and selective transfusion therapy. Unfortunately, existing data are limited, and it remains unclear whether prophylactic use of chronic transfusions will improve pregnancy outcomes. Management of pregnant women with SCD is best accomplished with a multidisciplinary team that includes a sickle cell expert and an obstetrician familiar with high-risk pregnancies. Women with SCD should have individualized care plans that outline management of acute pain and guidelines for transfusion therapy. Neonates require close monitoring for neonatal abstinence syndrome and hemolytic disease of the newborn. Ideally all young women with SCD will have a "reproductive life plan" developed as a component of preconception counseling and health promotion. Research leading to improved pregnancy management focused on diminishing adverse maternal and neonatal outcomes is overdue. International collaborations should be considered to improve subject recruitment and foster timely completion of clinical trials. Additional therapeutic interventions outside of transfusion therapy should be explored.
Genome-wide association and genotype by environment interactions for growth traits in U.S. Gelbvieh cattle
Authors: Smith Johanna L. , Wilson Miranda L. , Nilson Sara M. , Rowan Troy N. , Oldeschulte David L. , Schnabel Robert D. , Decker Jared E. , Seabury Christopher M.
Published: December 2019

Background

Single nucleotide polymorphism (SNP) arrays have facilitated discovery of genetic markers associated with complex traits in domestic cattle; thereby enabling modern breeding and selection programs. Genome-wide association analyses (GWAA) for growth traits were conducted on 10,837 geographically diverse U.S. Gelbvieh cattle using a union set of 856,527 imputed SNPs. Birth weight (BW), weaning weight (WW), and yearling weight (YW) were analyzed using GEMMA and EMMAX (via imputed genotypes). Genotype-by-environment (GxE) interactions were also investigated.

Results

GEMMA and EMMAX produced moderate marker-based heritability estimates that were similar for BW (0.36–0.37, SE = 0.02–0.06), WW (0.27–0.29, SE = 0.01), and YW (0.39–0.41, SE = 0.01–0.02). GWAA using 856K imputed SNPs (GEMMA; EMMAX) revealed common positional candidate genes underlying pleiotropic QTL for Gelbvieh growth traits on BTA6, BTA7, BTA14, and BTA20. The estimated proportion of phenotypic variance explained (PVE) by the lead SNP defining these QTL (EMMAX) was larger and most similar for BW and YW, and smaller for WW. Collectively, GWAAs (GEMMA; EMMAX) produced a highly concordant set of BW, WW, and YW QTL that met a nominal significance level (P ≤ 1e-05), with prioritization of common positional candidate genes; including genes previously associated with stature, feed efficiency, and growth traits (i.e.,PLAG1,NCAPG,LCORL,ARRDC3,STC2). Genotype-by-environment QTL were not consistent among traits at the nominal significance threshold (P ≤ 1e-05); although some shared QTL were apparent at less stringent significance thresholds (i.e.,P ≤ 2e-05).

Conclusions

Pleiotropic QTL for growth traits were detected on BTA6, BTA7, BTA14, and BTA20 for U.S. Gelbvieh beef cattle. Seven QTL detected for Gelbvieh growth traits were also recently detected for feed efficiency and growth traits in U.S. Angus, SimAngus, and Hereford cattle. Marker-based heritability estimates and the detection of pleiotropic QTL segregating in multiple breeds support the implementation of multiple-breed genomic selection.
Burden of anemia and its association with HAART in HIV infected children in Ethiopia: a systematic review and meta-analysis
Authors: Wagnew Fasil , Eshetie Setegn , Alebel Animut , Tesema Cheru , Kibret Getiye Dejenu , Gebrie Alemu , Dessie Getenet , Abajobir Amanuel Alemu
Published: December 2019

Background

Anemia is a common problem in HIV (human immunodeficiency virus) infected patients, and is associated with decreased functional capacity and quality of life. Ethiopia is one of the countries which has expanded highly active antiretroviral treatment (HAART) over the past years. The effect of HAART on anemia among HIV remains inconsistent and inconclusive, particularly in children. This study thus aimed to synthesize the prevalence of anemia among HIV infected Ethiopian children and its association with HAART initiation.

Methods

MEDLINE/PubMed, EMBASE, PsycINFO, Web of Science and Google scholar were used to identify 12 eligible studies reporting an association between anemia and HIV using a priori set criteria. PRISMA guideline was used to systematically review and meta-analysis these studies. Details of sample size, magnitude of effect sizes, including odds ratio (OR) and standard errors were extracted. Random-effects model was used to calculate the pooled estimates using STATA/SE version-14. I2and meta-bias statistics assessed heterogeneity and publication bias of the included studies. Sub-group analyses, based on study designs, were also carried out.

Results

In Ethiopia, the overall prevalence of anemia in HIV infected children was 22.3% (95% CI: 18.5–26.0%). The OR of anemia-HIV/AIDS comorbidity was 0.4 (95% CI, 0.2–0.5) in HAART initiated children as compared to non-initiated counterparts. Meta-bias and funnel plot detected no publication bias.

Conclusion

On aggregate, anemia is a common comorbidity in pediatric HIV patients. HAART was significantly associated with a reduced anemia-HIV/AIDS comorbidity. Prompt start of HAART might help decreasing the prevalence of anemia and its subsequent complications.
Validation of the kidney failure risk equation for end-stage kidney disease in Southeast Asia
Authors: Wang Yeli , Nguyen Francis Ngoc Hoang Long , Allen John C. , Lew Jasmine Quan Lan , Tan Ngiap Chuan , Jafar Tazeen H.
Published: December 2019

Background

Patients with chronic kidney disease (CKD) are at high risk of end-stage kidney disease (ESKD). The Kidney Failure Risk Equation (KFRE), which predicts ESKD risk among patients with CKD, has not been validated in primary care clinics in Southeast Asia (SEA). Therefore, we aimed to (1) evaluate the performance of existing KFRE equations, (2) recalibrate KFRE for better predictive precision, and (3) identify optimally feasible KFRE thresholds for nephrologist referral and dialysis planning in SEA.

Methods

All patients with CKD visiting nine primary care clinics from 2010 to 2013 in Singapore were included and applied 4-variable KFRE equations incorporating age, sex, estimated glomerular filtration rate (eGFR), and albumin-to-creatinine ratio (ACR). ESKD onset within two and five years were acquired via linkage to the Singapore Renal Registry. A weighted Brier score (the squared difference between observed vs predicted ESKD risks), bias (the median difference between observed vs predicted ESKD risks) and precision (the interquartile range of the bias) were used to select the best-calibrated KFRE equation.

Results

The recalibrated KFRE (named Recalibrated Pooled KFRE SEA) performed better than existing and other recalibrated KFRE equations in terms of having a smaller Brier score (square root: 2.8% vs. 4.0–9.3% at 5 years; 2.0% vs. 6.1–9.1% at 2 years), less bias (2.5% vs. 3.3–5.2% at 5 years; 1.8% vs. 3.2–3.6% at 2 years), and improved precision (0.5% vs. 1.7–5.2% at 5 years; 0.5% vs. 3.8–4.2% at 2 years). Area under ROC curve for the Recalibrated Pooled KFRE SEA equations were 0.94 (95% confidence interval [CI]: 0.93 to 0.95) at 5 years and 0.96 (95% CI: 0.95 to 0.97) at 2 years. The optimally feasible KFRE thresholds were > 10–16% for 5-year nephrologist referral and > 45% for 2-year dialysis planning. Using the Recalibrated Pooled KFRE SEA, an estimated 82 and 89% ESKD events were included among 10% of subjects at highest estimated risk of ESKD at 5-year and 2-year, respectively.

Conclusions

The Recalibrated Pooled KFRE SEA performs better than existing KFREs and warrants implementation in primary care settings in SEA.
Understanding cause of stillbirth: a prospective observational multi-country study from sub-Saharan Africa
Authors: Aminu Mamuda , Bar-Zeev Sarah , White Sarah , Mathai Matthews , van den Broek Nynke
Published: December 2019

Background

Every year, an estimated 2.6 million stillbirths occur worldwide, with up to 98% occurring in low- and middle-income countries (LMIC). There is a paucity of primary data on cause of stillbirth from LMIC, and particularly from sub-Saharan Africa to inform effective interventions. This study aimed to identify the cause of stillbirths in low- and middle-income settings and compare methods of assessment.

Methods

This was a prospective, observational study in 12 hospitals in Kenya, Malawi, Sierra Leone and Zimbabwe. Stillbirths (28 weeks or more) were reviewed to assign the cause of death by healthcare providers, an expert panel and by using computer-based algorithms. Agreement between the three methods was compared using Kappa (κ) analysis. Cause of stillbirth and level of agreement between the methods used to assign cause of death.

Results

One thousand five hundred sixty-three stillbirths were studied. The stillbirth rate (per 1000 births) was 20.3 in Malawi, 34.7 in Zimbabwe, 38.8 in Kenya and 118.1 in Sierra Leone. Half (50.7%) of all stillbirths occurred during the intrapartum period.

Cause of death (range) overall varied by method of assessment and included: asphyxia (18.5–37.4%), placental disorders (8.4–15.1%), maternal hypertensive disorders (5.1–13.6%), infections (4.3–9.0%), cord problems (3.3–6.5%), and ruptured uterus due to obstructed labour (2.6–6.1%). Cause of stillbirth was unknown in 17.9–26.0% of cases.

Moderate agreement was observed for cause of stillbirth as assigned by the expert panel and by hospital-based healthcare providers who conducted perinatal death review (κ = 0.69; p < 0.0005). There was only minimal agreement between expert panel review or healthcare provider review and computer-based algorithms (κ = 0.34; 0.31 respectively p < 0.0005).

Conclusions

For the majority of stillbirths, an underlying likely cause of death could be determined despite limited diagnostic capacity. In these settings, more diagnostic information is, however, needed to establish a more specific cause of death for the majority of stillbirths. Existing computer-based algorithms used to assign cause of death require revision.
High nutrient uptake efficiency and high water use efficiency facilitate the spread of Stellera chamaejasme L. in degraded grasslands
Authors: Guo Lizhu , Li Jiahuan , He Wei , Liu Li , Huang Ding , Wang Kun
Published: December 2019

Background

Stellera chamaejasme L. is a poisonous plant widely distributes in degraded grasslands in China. The mechanism underlying its spread remains unknown. In some degraded grasslands, S. chamaejasme has gradually replaced previous dominant species, such as Leymus chinensis, Stipa krylovii, Artemisia eriopoda on typical steppes. Apart from its unpalatability by livestock, we hypothesized that the survival strategy (nutrient uptake and water use efficiency) of S. chamaejasme in degraded grasslands could be distinct from other coexisting species in the community. Recently, ecological stoichiometry has been suggested as a new approach for studying the demand for natural resources of plants in a changing world, and the leaf carbon isotopic composition (δ13C leaf) as a rapid and effective high throughput phenotyping method for water use efficiency (WUE), both of which can reveal the survival and adaptive strategies of plants. Therefore, in this study we aimed to fill the knowledge gap concerning ecological stoichiometry in the leaf, stem, and root of S. chamaejasme and its surrounding soil on grasslands with different degrees of degradation, and comparing the leaf nutrient content and δ13C of S. chamaejasme with the coexisting species (L. chinensis, S. krylovii, A. eriopoda) in the communities. Toward this goal, we conducted a field survey in which plants and soils were sampled from four different degraded grasslands on typical steppes in China.

Results

Our results showed that there is no significant difference of carbon content (C%) and nitrogen content (N%) in leaves of S. chamaejasme in different degraded grasslands, and all element contents and element ratios in stems did not differ significantly. Meanwhile, ecological stoichiometry of S. chamaejasme is distinct from the coexisting species, with low C%, high N% and phosphorus content (P%) in the leaf, indicating high nutrient uptake efficiency of S. chamaejasme in nutrient-poor environments like degraded grasslands. Additionally, S. chamaejasme showed significant higher WUE than other species.

Conclusions

Our results indicated that high nutrient uptake efficiency and high WUE of S. chamaejasme might together contribute to the spread of S. chamaejasme in degraded grasslands.
National recruitment scheme for pre-registration pharmacist training in England and Wales: a mixed method evaluation of experiences of applicant pharmacy students
Authors: McEwen-Smith Laura , Price Malcolm James , Fleming Gail , Swanwick Tim , Hirsch Christine , Yahyouche Asma , Ward Jonathan , Buckley Sharon , Shamim Atif , Paudyal Vibhu
Published: December 2019

Background

A national pre-registration pharmacist training recruitment scheme, which replaces local recruitment models, was introduced in England and Wales in 2017. The national recruitment system allows pharmacy students to apply for the 52 weeks training programmes (mandatory requirement for registration as a pharmacist), through a single application system prior to undertaking a nationally administered assessment. This study aimed to explore experiences of pharmacy students on the national recruitment scheme, particularly their views on the selection methodology, application process, and offer outcomes.

Methods

This mixed method study involved a) an online survey of all (approximate n = 2800) year 4 (final year of MPharm degree) pharmacy students in England and Wales and b) a qualitative focus group with four students. The study population was eligible to participate in the 2017/18 national recruitment scheme. Survey respondents were invited to participate in a focus group. Quantitative data were analysed using descriptive and inferential analysis. Qualitative data were analysed using the framework technique. Participation was voluntary. Ethical approval from University of Birmingham was obtained.

Results

A total of 307 completed surveys were returned (approximate response rate 11%). Respondents were generally satisfied with the application process and commended the fairness of the selection methodology and convenience in allowing them to apply to multiple training providers. Most survey respondents (n = 181, 72.9%) were either satisfied or highly satisfied with the training programme they were offered based on their assessment performances. Three themes and eight sub-themes obtained from the analysis of over 200 open comments data from the survey and transcript of a focus group with four participants. Results suggested the need to widen the timeframe available for applicants to shortlist their preferred employers, improve the method of programme listing in the application system, and consideration of prior achievements including academic performances and placement experiences to be included in the selection methodology.

Conclusions

Experiences of pharmacy students on the national recruitment scheme suggest that respondents considered the selection methodology to be fair. Student engagement and satisfaction with the recruitment system can be maximised through improved listing of employers and widening the timescales for students to shortlist their preferred employers during application process. Inclusion of University achievements in the selection methodology will require consideration of evidence based approaches. Low response rate limits generalisation of findings.
Urinary proteome of dogs with kidney injury during babesiosis
Authors: Winiarczyk D. , Michalak K. , Adaszek L. , Winiarczyk M. , Winiarczyk S.
Published: December 2019

Background

Acute kidney injury is the most frequent complication of babesiosis in dogs and may provide a natural model for identifying early and specific markers of kidney injury in this species. There are limited data on urine proteomics in dogs, and none of the effect of babesiosis on the urine proteome. This study aimed to identify urinary proteins of dogs with kidney injury during the natural course of babesiosis caused by Babesia canis, and to compare them with proteins in a control group to reveal any potential biomarkers predicting renal injury before the presence of azotemia.

Urine samples were collected from 10 dogs of various breeds and sex with naturally occurring babesiosis, and 10 healthy dogs. Pooled urine samples from both groups were separated by 2D (two-dimensional) electrophoresis, followed by protein identification using MALDI-TOF (matrix-assisted laser desorption ionization time of flight) mass spectrometry.

Results

In total, 176 proteins were identified in the urine samples from healthy dogs, and 403 proteins were identified in the urine samples from dogs with babesiosis. Of the 176 proteins, 146 were assigned exclusively to healthy dogs, and 373 of the 403 proteins were assigned exclusively to dogs with babesiosis; 30 proteins were common for both groups. Characteristic analysis of 373 proteins found in dogs with babesiosis led to the isolation of 8 proteins associated with 10 metabolic pathways involved in immune and inflammatory responses.

Conclusions

It was hypothesized that epithelial-mesenchymal transition might play an important role in the mechanisms underlying pathological changes in renal tissue during babesiosis, as indicated by a causal relationship network built by combining 5 of the 10 selected metabolic pathways, and 4 of the 8 proteins associated with these pathways; this network included cadherins, gonadotropin releasing hormone receptors, inflammatory responses mediated by chemokine and cytokine signalling pathways, integrins, interleukins, and TGF-β (transforming growth factor β) pathways. Those pathways were linked by interleukin-13, bone morphogenetic protein 7, α2(1) collagen, and tyrosine protein kinase Fer, which are potential biomarkers of damage during babesiosis in dogs, that might indicate early renal injury.
Survival-Day @ Wiesbaden business school – evaluation of a short-term educational intervention to reduce work-associated health risks during nursing internships of students in health care economics
Authors: Strametz Reinhard , Schneider Thomas , Pitz Andreas , Raspe Matthias
Published: December 2019

Background

In 2013 RheinMain University launched its bachelor’s degree program Health Care Economics requiring each student to participate in a mandatory two-month nursing internship. A preliminary risk assessment revealed serious risks for both students and patients and had to be addressed by appropriate measures such as mandatory systematic safety training for each student.

Methods

A short-term educational intervention named “Survival-Day” was designed to minimize risks related to nursing internships of students. This intervention consists of six 45-min-units with theoretical input (2 units) and hands-on training (4 units) imparting basic knowledge and skills in CPR, hand hygiene and handling of masks and protective gowns, prevention of needle stick injuries, fire protection and firefighting. Performance of CPR was assessed using computerized manikins. Acceptance, necessity and usability were assessed anonymously by standardized written questionnaires after completion of nursing internships.

Results

462 students have completed the Survival-Day until January 2019. CPR performance showed acceptable adherence rates to guideline recommendations (mean 78.8%, SD ±22.6%). The majority of students performed aseptic health care activities (66%), treated patients with multi-resistant pathogens (62%) and disposed sharp instruments such as blood-contaminated needles (76%). According to students’ self-reports about these hazardous activities, less than 50% of these students received adequate safety training at nursing facilities. However, no sentinel events such as needle stick injuries or students becoming second victim have been reported.

Conclusion

Our study reveals severe discrepancies between legal obligation of nursing facilities to ensure safety instructions for nursing interns and initial training as perceived by this group. Mandatory initial training before conduction of hazardous tasks was mainly covered by our short-term educational intervention (Survival-Day). Regarding responsibility for their students a preliminary safety instruction program like the Survival-Day should be considered for all educational institutions sending students to nursing internships unless mandatory and sufficient safety trainings for nursing interns can be guaranteed by nursing facilities.
Lifestyle of a Roman Imperial community: ethnobotanical evidence from dental calculus of the Ager Curensis inhabitants
Authors: D’Agostino Alessia , Gismondi Angelo , Di Marco Gabriele , Lo Castro Mauro , Olevano Rosaria , Cinti Tiziano , Leonardi Donatella , Canini Antonella
Published: December 2019

Background

The analysis of ancient calcified dental plaque is a powerful archaeobotanical method to elucidate the key role of the plants in human history.

Methods

In this research, by applying both optic microscopy and gas chromatography mass spectrometry on this matrix, a detailed qualitative investigation for reconstructing the lifestyle of a Roman imperial community of theAger Curensis(Sabina Tiberina, Central Italy) was performed.

Results

The detection of animal micro-remains and molecules (e.g., hairs, feather barbules, markers of dairy products), starch granules of several cereals and legumes, pollen (e.g.,Juglans regiaL.,Hederasp. L.) and other plant micro-debris (e.g., trichome ofOleasp., hemp fibers), and phytochemicals (e.g., Brassicaceae, Lamiaceae herbs,Ferulasp.,Trigonella foenum-graecumL., wine, andHumulus lupulusL.) in the dental calculus sample demonstrated that plant-derived foods were regularly consumed together with animal resources.

Conclusions

This nutritional plan, consistent with the information reported in ancient written texts, suggested that the studied population based its own subsistence on both agriculture and husbandry, probably also including beekeeping and hunting activities. All together, these results represent proofs for the comprehension of food habits, phytotherapeutic practices, and cultural traditions of one of the first Roman settlements in the Sabina Tiberina area.
Time-synchronized immune-guided SBRT partial bulky tumor irradiation targeting hypoxic segment while sparing the peritumoral immune microenvironment
Authors: Tubin Slavisa , Ashdown Martin , Jeremic Branislav
Published: December 2019

Background

A novel unconventional SBRT-based PArtial Tumor irradiation targeting HYpoxic clonogenic cells (SBRT-PATHY) for induction of the tumoricidal bystander (BE) and abscopal effects (AE) was developed by translating our preclinical findings to a clinic in 2016. In order to further improve BE/AE response rate, SBRT-PATHY was upgraded in 2018 by the sparing of peritumoral immune microenvironment as a new OAR, defined by its own dose-constraints. Considering the anti-tumor immune response homeostatic fluctuation, which is cyclically suppressed and incited (“switched off and on”), we synchronized SBRT-PATHY with its most excitable phase, in order to overcome tumor tolerance locally and systemically. The aim of this study, therefore, was to report on the initial results of our latest innovation aimed to further improve BE/AE response rate by testing the effectiveness of the time-synchronized immune-guided SBRT-PATHY.

Materials and methods

In order to serially map the homeostatic anti-tumor immune response-fluctuations, High Sensitive C-Reactive Protein (HS-CRP), Lactate Dehydrogenase (LDH) and Lymphocyte/Monocyte Ratio (LMR) were analyzed using high-order polynomial trend analysis as surrogate of immune system response. After the biomarker data analysis detected the immune fluctuations and related idiosyncratic immune cycle periodicity, we determined the “most favourable” and “least favourable” treatment time-positions in the immune cycle. In order to evaluate the impact of an idiosyncratic immune cycle on treatment outcomes, our first consecutive four patients were treated on the “most favourable” while the remaining four on the “least favourable” day.

Results

The median follow-up was 11.8 months. The biomarker data analysis showed periodic immune response fluctuations of regular frequency. The “right” synchronization of SBRT-PATHY with the “most favorable day” of anti-tumor immune response was accompanied with improved clinical outcomes in terms of BE/AE-response rate.

Conclusion

We believe the right synchronization of radiotherapy with the homeostatically oscillating immune response may improve the probability of inducing BE/AE.

Present study has been retrospectively registered on 18th of October 2019 by the ethic committee for Austrian region „Kärnten “in Klagenfurt (AUT), under study number A 37/19.
Combination of mTORC1/2 inhibitor vistusertib plus fulvestrant in vitro and in vivo targets oestrogen receptor-positive endocrine-resistant breast cancer
Authors: Pancholi Sunil , Leal Mariana Ferreira , Ribas Ricardo , Simigdala Nikiana , Schuster Eugene , Chateau-Joubert Sophie , Zabaglo Lila , Hills Margaret , Dodson Andrew , Gao Qiong , Johnston Stephen R. , Dowsett Mitch , Cosulich Sabina C. , Maragoni Elisabetta , Martin Lesley-Ann
Published: December 2019

Background

Endocrine therapies are still the main strategy for the treatment of oestrogen receptor-positive (ER+) breast cancers (BC), but resistance remains problematic. Cross-talk between ER and PI3K/AKT/mTORC has been associated with ligand-independent transcription of ER. We have previously reported the anti-proliferative effects of the combination of everolimus (an mTORC1 inhibitor) with endocrine therapy in resistance models, but potential routes of escape via AKT signalling can lead to resistance; therefore, the use of dual mTORC1/2 inhibitors has met with significant interest.

Methods

To address this, we tested the effect of vistusertib, a dual mTORC1 and mTORC2 inhibitor, in a panel of endocrine-resistant and endocrine-sensitive ER+ BC cell lines, with varying PTEN, PIK3CA and ESR1 mutation status. End-points included proliferation, cell signalling, cell cycle and effect on ER-mediated transcription. Two patient-derived xenografts (PDX) modelling endocrine resistance were used to assess the efficacy of vistusertib, fulvestrant or the combination on tumour progression, and biomarker studies were conducted using immunohistochemistry and RNA-seq technologies.

Results

Vistusertib caused a dose-dependent decrease in proliferation of all the cell lines tested and reduced abundance of mTORC1, mTORC2 and cell cycle markers, but caused an increase in abundance of EGFR, IGF1R and ERBB3 in a context-dependent manner. ER-mediated transcription showed minimal effect of vistusertib. Combined therapy of vistusertib with fulvestrant showed synergy in two ER+ PDX models of resistance to endocrine therapy and delayed tumour progression after cessation of therapy.

Conclusions

These data support the notion that models of acquired endocrine resistance may have a different sensitivity to mTOR inhibitor/endocrine therapy combinations.
Dashing: fast and accurate genomic distances with HyperLogLog
Authors: Baker Daniel N. , Langmead Ben
Published: December 2019

Dashing is a fast and accurate software tool for estimating similarities of genomes or sequencing datasets. It uses the HyperLogLog sketch together with cardinality estimation methods that are specialized for set unions and intersections. Dashing summarizes genomes more rapidly than previous MinHash-based methods while providing greater accuracy across a wide range of input sizes and sketch sizes. It can sketch and calculate pairwise distances for over 87K genomes in 6 minutes. Dashing is open source and available athttps://github.com/dnbaker/dashing.
Fire needle acupuncture or moxibustion for chronic plaque psoriasis: study protocol for a randomized controlled trial
Authors: Chen Zhaoxia , Zhou Dongmei , Wang Yan , Lan Haibing , Duan Xingwu , Li Bohua , Zhao Jingxia , Li Wei , Liu Zhengrong , Di Tingting , Guo Xinwei , Zhang Jinchao , Li Bo , Feng Shuo , Li Ping
Published: December 2019

Background

Psoriasis is a chronic, immune-mediated disorder with chronic plaque psoriasis being the primary manifestation during the remission stage. Patients often have a slow course and long history of the disease. The refractory type of psoriasis is a stubborn rash that does not subside easily. We designed this randomized controlled trial to compare the effectiveness and relapse rates of plaque psoriasis in patients treated with either acupuncture, moxibustion or calcipotriol ointment. The ultimate aim of the study is to select an effective traditional Chinese medicine therapy for patients with plaque psoriasis.

Methods

The study will be a multicenter, prospective, randomized controlled trial that compares the effectiveness of fire needle therapy, moxibustion and calcipotriol ointment. In total, 160 patients with plaque psoriasis who meet the inclusion criteria will be recruited from three hospitals in Beijing and then randomly assigned to receive either fire needle therapy (group A1), moxibustion (group A2) or calcipotriol ointment (group B). All participants will receive an 8-week treatment and will then be followed up for another 24 weeks, with time points at weeks 12 and 24 after treatment completion. The primary outcomes to be measured are relapse rates and psoriasis area and severity index score of the target lesions. In addition, the target lesion onset time, dermatology life quality index, traditional Chinese medicine syndrome score, and the relapse interval of the target lesion will be measured. Adverse events will be recorded for safety assessment.

Discussion

The aim of this study is to determine whether fire needle therapy or moxibustion could improve the clinical effectiveness for psoriasis lesions and reduce the relapse rate. Once completed, it will provide information regarding therapeutic evaluation on fire needle therapy or moxibustion for plaque psoriasis, which will assist clinicians in selecting the most effective treatment options for patients.

Trial registration

International Clinical Trials Registry Platform (ICTRP), ChiCTR1800019588. Registered on 19 November 2018.
Effectiveness of upgraded maternity waiting homes and local leader training in improving institutional births among women in the Jimma zone, Ethiopia: study protocol for a cluster-randomized controlled trial
Authors: Kurji Jaameeta , Kulkarni Manisha A. , Gebretsadik Lakew Abebe , Wordofa Muluemebet Abera , Morankar Sudhakar , Bedru Kunuz Haji , Bulcha Gebeyehu , Thavorn Kednapa , Labonte Ronald , Taljaard Monica
Published: December 2019

Background

Ethiopia is one of the ten countries in the world that together account for almost 60% of all maternal deaths. Recent reductions in maternal mortality have been seen, yet just 26% of women who gave birth in Ethiopia in 2016 reported doing so at a health facility. Maternity waiting homes (MWHs) have been introduced to overcome geographical and financial barriers to institutional births but there is no conclusive evidence as to their effectiveness. We aim to evaluate the effects of upgraded MWHs and local leader training in increasing institutional births in the Jimma zone of Ethiopia.

Methods

A parallel, three-arm, stratified, cluster-randomized controlled trial design is being employed to evaluate intervention effects on institutional births, which is the primary outcome. Trial arms are: (1) upgraded MWH + religious/community leader training; (2) leader training alone; and (3) standard care. Twenty-four primary health care unit catchment areas (clusters) have been randomized and 3840 women of reproductive age who had a pregnancy outcome (livebirth, stillbirth or abortion) are being randomly recruited for each survey round. Outcome assessments will be made using repeat cross-sectional surveys at baseline and 24 months postintervention. An intention to treat approach will be used and the primary outcome analysed using generalized linear mixed models with a random effect for cluster and time. A cost-effectiveness analysis will also be conducted from a societal perspective.

Discussion

This is one of the first trials to evaluate the effectiveness of upgraded MWHs and will provide much needed evidence to policy makers about aspects of functionality and the community engagement required as they scale-up this programme in Ethiopia.

Trial registration

ClinicalTrial.gov, NCT03299491. Retrospectively registered on 3 October 2017.
Arthritis sensory and motor scale: predicting functional deficits from the clinical score in collagen-induced arthritis
Authors: Mausset-Bonnefont Anne-Laure , Cren Maïlys , Vicente Rita , Quentin Julie , Jorgensen Christian , Apparailly Florence , Louis-Plence Pascale
Published: December 2019

Background

In the collagen-induced arthritis (CIA) mouse model, inflammation readouts are usually quantified using operator-dependent clinical scoring systems, and no systematic relationship with functional deficits has been detected. In this study, we extensively quantified sensory and motor deficits in CIA mice during natural disease progression and therapeutic treatment. Then, we used these data to build a scale to predict functional deficits on the basis of the classical clinical score.

Methods

Using the CIA mouse model, we longitudinally screened multiple approaches to assess locomotion (open field test, Catwalk™), sensitivity (Von Frey, Hargreaves, static weight-bearing tests), and inflammation (skin temperature), and identified the most accurate tests to correlate sensory and motor deficits with disease severity, measured by clinical score. We then used these tests to characterize functional deficits in control (naïve and mice injected with complete Freund’s adjuvant) and CIA mice, either untreated or treated with methotrexate to prevent functional deficits. By mathematical approaches, we finally investigated the relationship between functional deficits and clinical score.

Results

We found that the functional disability scores obtained with the open field, Catwalk™, Hargreaves, and skin temperature tests significantly correlated with the clinical score in CIA mice, either untreated or treated with methotrexate. Mathematical correlation showed that motor deficits, robustly characterized by two different tests, were twice more responsive than thermal sensitivity deficits.

Conclusion

We propose the arthritis sensory and motor (ArthriSM) scale as a new theranostic tool to predict motor and sensory deficit based on the clinical score, in the experimental mouse model of CIA. This ArthriSM scale may facilitate the transfer of knowledge between preclinical and clinical studies.
Epigenome-wide base-resolution profiling of DNA methylation in chorionic villi of fetuses with Down syndrome by methyl-capture sequencing
Authors: Lim Ji Hyae , Kang Yu-Jung , Lee Bom Yi , Han You Jung , Chung Jin Hoon , Kim Moon Young , Kim Min Hyoung , Kim Jin Woo , Cho Youl-Hee , Ryu Hyun Mee
Published: December 2019

Background

Epigenetic mechanisms provide an interface between environmental factors and the genome and are influential in various diseases. These mechanisms, including DNA methylation, influence the regulation of development, differentiation, and establishment of cellular identity. Here, we performed high-throughput methylome profiling to determine whether differential patterns of DNA methylation correlate with Down syndrome (DS).

Materials and methods

We extracted DNA from the chorionic villi cells of five normal and five DS fetuses at the early developmental stage (12–13 weeks of gestation). Methyl-capture sequencing (MC-Seq) was used to investigate the methylation levels of CpG sites distributed across the whole genome to identify differentially methylated CpG sites (DMCs) and regions (DMRs) in DS. New functional annotations of DMR genes using bioinformatics tools were predicted.

Results

DNA hypermethylation was observed in DS fetal chorionic villi cells. Significant differences were evident for 4,439 DMCs, including hypermethylation (n = 4,261) and hypomethylation (n = 178). Among them, 140 hypermethylated DMRs and only 1 hypomethylated DMR were located on 121 genes and 1 gene, respectively. One hundred twenty-two genes, including 141 DMRs, were associated with heart morphogenesis and development of the ear, thyroid gland, and nervous systems. The genes were significantly associated with DS and various diseases, including hepatopulmonary syndrome, conductive hearing loss, holoprosencephaly, heart diseases, glaucoma, and musculoskeletal abnormalities.

Conclusions

This is the first study to compare the whole-epigenome DNA methylation pattern of the chorionic villi cells from normal and DS fetuses at the early developmental-stage using MC-seq. Overall, our results indicate that the chorionic villi cells of DS fetuses are hypermethylated in all autosomes and suggested that altered DNA methylation may be a recurrent and functionally relevant downstream response to DS in human cells. This study provides basic information for future research focused on the pathophysiology of the DS and its potential effects, as well as the role DNA methylation plays in the early developmental stage of DS fetuses.
Epigenetic silencing of the ANKRD26 gene correlates to the pro-inflammatory profile and increased cardio-metabolic risk factors in human obesity
Authors: Desiderio Antonella , Longo Michele , Parrillo Luca , Campitelli Michele , Cacace Giuseppe , de Simone Sonia , Spinelli Rosa , Zatterale Federica , Cabaro Serena , Dolce Pasquale , Formisano Pietro , Milone Marco , Miele Claudia , Beguinot Francesco , Raciti Gregory A.
Published: December 2019

Background

Obesity is a major worldwide threat to human health. Increasing evidence indicates that epigenetic modifications have a major impact on the natural history of this disorder. Ankyrin Repeat Domain 26 (Ankrd26) is involved in the development of both obesity and diabetes in mice and is modulated by environmentally induced epigenetic modifications. This study aims at investigating whether impaired ANKRD26 gene expression and methylation occur in human obesity and whether they correlate to the phenotype of these subjects.

Results

We found that downregulation of ANKRD26 mRNA and hyper-methylation of a specific region of the ANKRD26 promoter, embedding the CpG dinucleotides − 689, − 659, and − 651 bp, occur in peripheral blood leukocytes from obese compared with the lean subjects. ANKRD26 gene expression correlates inversely to the percentage of DNA methylation at these 3 CpG sites. Luciferase assays reveal a cause-effect relationship between DNA methylation at the 3 CpG sites and ANKRD26 gene expression. Finally, both ANKRD26 mRNA levels and CpG methylation correlate to body mass index and to the pro-inflammatory status and the increased cardio-metabolic risk factors of these same subjects.

Conclusion

Downregulation of the ANKRD26 gene and hyper-methylation at specific CpGs of its promoter are common abnormalities in obese patients. These changes correlate to the pro-inflammatory profile and the cardio-metabolic risk factors of the obese individuals, indicating that, in humans, they mark adverse health outcomes.
Mechanism(s) of prolonged attenuation of allergic responses after modulation of idiotypic regulatory network
Authors: Gorczynski R. M. , Maqbool T. , Hoffmann G.
Published: December 2019

Background

We showed previously that allergic reactivity to ovalbumin (OVA) could be regulated in mice following perturbation of immune networks using combinations of an immune Ig along with anti-idiotypic Ig. We have explored features of this regulation including: its persistence after cessation of administration of combined Igs; the ability of heterologous Igs to produce immunoregulation; a role for Treg induction in regulation; and the ability to attenuate responses in mice pre-sensitized to an allergic stimulus.

Methods

BALB/c mice were sensitized to OVA. Mice also received 5 weekly injections of immune Ig or anti-idiotype Ig (at separate sites) from either homologous (mouse) or heterologous (human) sources. In the latter case pooled IVIG (given IM, hence hereafter IMIG) was used as a source of anti-idiotype Ig, and human anti-Tet as immune Ig. Injections of the Ig were given from the time of OVA sensitization (to attenuate development of immunity), or after pre-sensitization of mice (to attenuate existing allergic responses). All mice were assayed for development of OVA-specific serum IgE and IgG, as well as the production of OVA-induced IL-2, IL-4, IL-13, IL-31 and IL-33 in splenocytes cultured for 72 h. In studies examining possible mechanism(s) responsible for inhibition of immunity mice received, in addition to the Ig treatments described, infusion of depleting anti-CD4, and/or anti-CD8 antibodies, or a mAb to TNFSFR25, known to expand Tregs implicated in regulation of Allo immunity.

Results

Combinations of both heterologous and homologous immune Igs and anti-idiotype Igs attenuated OVA allergic responses in both naïve and pre-sensitized mice. This attenuation persisted in mice greater than 14 weeks after cessation of treatment with the Igs used. Finally, depletion of either CD4 or CD8 cells ameliorated the suppressive effect seen, while the combination of anti-CD4 and anti-CD8 essentially abolished suppression. Suppression was further enhanced by anti-TNFSFR25 mAb.

Conclusions

We conclude that the combine Ig treatment protocols used produced a long-lasting suppression of allergic immunity, even in pre-sensitized animals. The effects seem to depend upon induction and expansion of Tregs and represents a novel approach to treatment of allergic disease in humans and other animals.
Non-neoplastic pathology at the crossroads between neck imaging and cardiothoracic imaging
Authors: Nguyen Trinh T. , Melendez Patricia E. , Kaproth-Joslin Katherine , Bhatt Alok A.
Published: December 2019

The thoracic inlet is located at the crossroads between imaging of the neck and chest. It represents an important anatomic landmark, serving as the central conducting pathway for many vital structures extending from the neck into the chest and vice versa. Many important body systems are located within this region, including the enteric, respiratory, vascular, lymphatic, neurologic, and endocrine systems. A detailed examination of this region is essential when reviewing neck and thoracic imaging. This article will discuss the normal anatomic boundaries of the thoracic inlet and present an image-rich systematic discussion of the non-neoplastic pathology that can occur in this region. The neoplastic pathology of the thoracic inlet will be covered in a companion article.