bluuebunny/crossref_metadata_2025_split huggingface dataset:
Effect of leukoreduction on transfusion‐related immunomodulation in patients undergoing cardiac surgery
Authors: Khan Atif Irfan , Patidar Gopal Kumar , Lakshmy R. , Makhija Neeti , Talwar Sachin , Hazarika Anjali 
Published: September 2020

SummaryObjectivesIn this study, we aimed to determine the consequences of different amounts of leukocyte transfusion on the outcome of patients undergoing cardiac surgery.DesignThis was a prospective, single‐blinded cohort study conducted for 1 year from July 2018 to June 2019.SettingThe study setting was the Department of Transfusion Medicine, along with Cardiac Anaesthesia, Cardiac Surgery and Cardiac biochemistry departments in a tertiary care cardiac centre.ParticipantsA total of 150 patients undergoing cardiac surgery during the study period were divided into three groups (50 in each): Leukofiltered (LR), Buffy coat depleted (BCD) and Non‐leukoreduced (NLR).InterventionThe intervention was intra‐ and postoperative transfusion of packed red blood cells (PRBCs) having different amounts of leukocytes.Measurements and main resultsPatient details about length of intensive care unit (ICU) and hospital stay, blood usage, inotropic drug duration, mechanical ventilation, urine output and infection were recorded from the patient data sheet, whereas patients were followed up for 30 days post‐operation, and any mortality was noted. Haematological parameters and biochemical parameters for renal function test were analysed on pre‐ and post‐surgical days 1, 3, 5 and 7, whereas on postoperative days 1 and 7, cytokine‐like FAS ligands, Interleukin‐10 (IL‐10) and Interferon‐γ (INF‐γ) were tested.Patients in all three groups received an average of four, two and two units of packed red blood cells, platelets and fresh frozen plasma, respectively. There was a statistically significant (P < .05) rise in total leukocyte, neutrophil and lymphocyte count in all three groups from day 0 to day 3, but it reduced to preoperative level on day 5. There was shorter ICU and hospital stay in the LR group of patients (46 ± 19.9 hours and 7.5 ± 2.4 days) compared to NLR (52.1 ± 24.2 hours and 7.9 ± 4.1 days) and BCD (53.3 ± 26.7 hours and 8.8 ± 3.1 days) group of patients, but it was statistically non‐significant. The duration of mechanical ventilation was significantly lesser in LR group patients (10.2 ± 6.2 hours) as compared to NLR group (14.7 ± 12.7 hours). On risk ratio calculation of developing postoperative kidney injury, the NLR group had 1.3 and 2.6 times more risk compared to the BCD and LR groups, respectively. On postoperative days 1 and 7, FAS‐L levels significantly increased in all three group of patients, whereas IL‐10 increased in the NLR and BCD groups and decreased in the LR group non‐significantly. The INF‐γ levels decreased on day 1 in the NLR and BCD groups but increased in the LR group, but it was inversed on day 7.ConclusionDepletion of leukocytes decreased Transfusion Related Immunomodulation (TRIM) effects in patients undergoing cardiac surgery, but this also depends on the degree of leukoreduction. As found in our study, leukofiltration is more effective compared to buffy‐coat depletion only.
Maintaining population health in low‐ and middle‐income countries during the COVID‐19 pandemic: Why we should be investing in Community Health Workers
Authors: Palafox Benjamin , Renedo Alicia , Lasco Gideon , Palileo‐Villanueva Lia , Balabanova Dina , McKee Martin 
Published: September 2020

SummaryCommunity health workers in low‐ and middle‐income country primary health care systems are well suited to perform essential functions on the frontlines of Covid‐19 pandemic responses. However, clear and coordinated guidance, updated infection control training, and reliable access to personal protective equipment must be ensured in order to deploy them safely and effectively. With these additional responsibilities, community health workers must also be supported to ensure that hard‐fought gains in population health, including progress on non‐communicable diseases, are sustained throughout the pandemic.
Metabolic Fluxes of Nitrogen and Pyrophosphate in Chemostat Cultures of Clostridium thermocellum and Thermoanaerobacterium saccharolyticum
Authors: Holwerda Evert K. , Zhou Jilai , Hon Shuen , Stevenson David M. , Amador-Noguez Daniel , Lynd Lee R. , van Dijken Johannes P. 
Published: September 2020

This study discusses the fate of pyrophosphate in the metabolism of two thermophilic anaerobes that lack a soluble irreversible pyrophosphatase as present in
Escherichia coli
but instead use a reversible membrane-bound proton-pumping enzyme. In such organisms, the charging of tRNA with amino acids may become more reversible. This may contribute to the observed excretion of amino acids during sugar fermentation by
Clostridium thermocellum
and
Thermoanaerobacterium saccharolyticum
. Calculation of the energetic advantage of reversible pyrophosphate-dependent glycolysis, as occurs in
Clostridium thermocellum
, could not be properly evaluated, as currently available genome-scale models neglect the anabolic generation of pyrophosphate in, for example, polymerization of amino acids to protein. This anabolic pyrophosphate replaces ATP and thus saves energy. Its amount is, however, too small to cover the pyrophosphate requirement of sugar catabolism in glycolysis. Consequently, pyrophosphate for catabolism is generated according to ATP + P
i
→ ADP + PP
i
.
Managing Machine Learning Workflow Components
Authors: Moreno Marcio , Lourenço Vítor , Fiorini Sandro Rama , Costa Polyana , Brandão Rafael , Civitarese Daniel , Cerqueira Renato 
Published: September 2020

Machine Learning Workflows (MLWfs) have become an essential and disruptive approach in problem-solving over several industries. However, the development process of MLWfs may be complex, time-consuming, and error-prone. To handle this problem, we introduce machine learning workflow management (MLWfM) as a technique to aid the development and reuse of MLWfs and their components through three aspects: representation, execution, and creation. We introduce our approach to structure MLWfs’ components and metadata in order to aid component retrieval and reuse of new MLWfs. We also consider the execution of these components within a tool. A hybrid knowledge representation, called Hyperknowledge, frames our methodology, supporting the three MLWfM’s aspects. To validate our approach, we show a practical use case in the Oil & Gas industry. In addition, to evaluate the feasibility of the proposed technique, we create a dataset of MLWfs executions and discuss the MLWfM’s performance in loading and querying this dataset.
Holistic geoethical slope portfolio risk assessment
Authors: Oboni Franco , Oboni César Henri 
Published: September 2020

Abstract
Landslides of natural and man-made slopes represent hazardous geomorphological processes that contribute to highly variable risks. Their consequences generally include loss of life and infrastructural, environmental and cultural assets damage.
Prioritizing and mitigating slope risks in a sustainable manner, while considering climate change, is related to geoethics, as any misallocation of resources will likely lead to increased risk to the public.
Until recently there was little recognition of the causes and global impacts of human actions. Today, threat-denying humans can be identified as acting inappropriately and ultimately unethically. Sustainable risk management and ethical issues should be discussed simultaneously to avoid the ‘discipline silo trap’ and hazardous omissions.
This contribution discusses slope risk management at various scales, i.e. how to ensure better allotment of mitigative funds while complying with sustainability goals and geoethical requirements. In 1987, the World Commission on Environment and Development published a report (also known as the Brundtland Report (Brundtland 1987. World Commission on Environment and Development Report)) that defined sustainable development as meeting the needs of the present without compromising the ability of future generations to meet their own needs.
The three case histories discussed in this contribution show how sustainability and ethics can be fostered by using rational, repeatable, transparent quantitative risk assessment applicable at the local scale as well as on a large scale.
High Dose of Intravenous Allogeneic Umbilical Cord-Derived Mesenchymal Stem Cells (CLV-100) Infusion Displays Better Immunomodulatory Effect among Healthy Volunteers: A Phase 1 Clinical Study
Authors: Chin Sze-Piaw , Mohd-Shahrizal Mohd-Yusoff , Liyana Mohd-Zuhar , Then Kong Yong , Cheong Soon Keng , Yong Kar Wey 
Published: September 2020

Background. Mesenchymal stem cells (MSCs) express growth factors and other cytokines that stimulate repair and control the immune response. MSCs are also immunoprivileged with low risk of rejection. Umbilical cord-derived MSCs (UCMSCs) are particularly attractive as an off-the-shelf allogeneic treatment in emergency medical conditions. We aim to determine the safety and efficacy of intravenous allogeneic infusion of UCMSCs (CLV-100) by Cytopeutics® (Selangor, Malaysia) in healthy volunteers, and to determine the effective dose at which an immunomodulatory effect is observed. Methodology. Umbilical cord samples were collected after delivery of full-term, healthy babies with written consent from both parents. All 3 generations (newborn, parents, and grandparents) were screened for genetic mutations, infections, cancers, and other inherited diseases. Samples were transferred to a certified Good Manufacturing Practice laboratory for processing. Subjects were infused with either low dose (LD, 65 million cells) or high dose (HD, 130 million cells) of CLV-100 and followed up for 6 months. We measured cytokines using ELISA including anti-inflammatory cytokines interleukin 1 receptor antagonist (IL-1RA), interleukin 10 (IL-10), pro-/anti-inflammatory cytokine interleukin 6 (IL-6), and the proinflammatory cytokine tumor necrosis factor-alpha (TNF-α). Results. 11 healthy subjects (LD,

n
=
5

; HD,

n
=
6

; mean age of

55
±
13

years) were recruited. All subjects tolerated the CLV-100 infusion well with no adverse reaction throughout the study especially in vital parameters and routine blood tests. At 6 months, the HD group had significantly higher levels of anti-inflammatory markers IL1-RA (

705
±
160

vs.

306
±
36

pg
/
mL

;

p
=
0.02

) and IL-10 (

321
±
27

vs.

251
±
28

pg
/
m

L;

p
=
0.02

); and lower levels of proinflammatory marker TNF-α (

74
±
23

vs.

115
±
15

pg
/
mL

;

p
=
0.04

) compared to LD group. Conclusion. Allogeneic UCMSCs CLV-100 infusion is safe and well-tolerated in low and high doses. Anti-inflammatory effect is observed with a high-dose infusion.
Relapse and Clinical Characteristics of Patients with Bipolar Disorders in Central Ethiopia: A Cross-Sectional Study
Authors: Belete Habte , Ali Tilahun , Legas Getasew , Pavon Lenin 
Published: September 2020

Background. Bipolar disorder is a severe mental illness and has huge morbidity and mortality. Relapse is a challenging treatment failure in patients with mental illness, especially in patients with bipolar which causes high economic and social burdens. In the mental health delivery system, relapse is common and can be defined as becoming ill again after apparent recovery and a worsening condition of psychiatric patients. Due to psychiatric patients that may stop medication on their own in contrary to the advice of mental health professionals, relapse of mood episodes, delayed remission, and residual symptoms usually leads to hospitalization, increased suicide risk, and/or impede psychosocial recover. Therefore, understanding the nature of relapse in patients in low-income countries helps to prevent recurrence and related health care expenses. Objective. The objective of this study was to assess the prevalence and factors associated with relapse among patients with bipolar disorders in central Ethiopia. Method. Facility-based cross-sectional study was conducted from May to June 2015 at Amanuel Mental Specialized Hospital. Relapse was calculated among 400 samples of people with bipolar disorder, and systematic random sampling was used to select the study participants. Oslo’s social support scale and ASSIST were used to identify factors with relapse, and a binary and multivariable logistic regression analysis model was performed to control the confounding factors. Odds ratios (OR) with the corresponding 95% confidence interval (95% CI) were determined to evaluate the strength of association. Results. The prevalence of relapse was 71% among patients with bipolar disorder. The longer morbidity (longer than 5 years) had a higher risk of relapse [

adjusted

odd

ratio

AOR

=
3.91

, 95% confidence interval (CI): 2.44 to 6.27], while good medication adherence found to be a protective factor for relapse [

AOR
=
0.39

, 95% CI: 0.22 to 0.72]. Conclusion. The prevalence of relapse was found pretty high among patients with bipolar disorders (71%). Working on treatment adherence and controlling the psychopathology is important to prevent relapse among bipolar patients.
AZD4320, A Dual Inhibitor of Bcl-2 and Bcl-xL, Induces Tumor Regression in Hematologic Cancer Models without Dose-limiting Thrombocytopenia
Authors: Balachander Srividya B. , Criscione Steven W. , Byth Kate F. , Cidado Justin , Adam Ammar , Lewis Paula , Macintyre Terry , Wen Shenghua , Lawson Deborah , Burke Kathleen , Lubinski Tristan , Tyner Jeffrey W. , Kurtz Stephen E. , McWeeney Shannon K. , Varnes Jeffrey , Diebold R. Bruce , Gero Thomas , Ioannidis Stephanos , Hennessy Edward J. , McCoull William , Saeh Jamal C. , Tabatabai Areya , Tavana Omid , Su Nancy , Schuller Alwin , Garnett Mathew J. , Jaaks Patricia , Coker Elizabeth A. , Gregory Gareth P. , Newbold Andrea , Johnstone Ricky W. , Gangl Eric , Wild Martin , Zinda Michael , Secrist J. Paul , Davies Barry R. , Fawell Stephen E. , Gibbons Francis D. 
Published: September 2020

Abstract

Purpose:
Targeting Bcl-2 family members upregulated in multiple cancers has emerged as an important area of cancer therapeutics. While venetoclax, a Bcl-2–selective inhibitor, has had success in the clinic, another family member, Bcl-xL, has also emerged as an important target and as a mechanism of resistance. Therefore, we developed a dual Bcl-2/Bcl-xL inhibitor that broadens the therapeutic activity while minimizing Bcl-xL–mediated thrombocytopenia.

Experimental Design:
We used structure-based chemistry to design a small-molecule inhibitor of Bcl-2 and Bcl-xL and assessed the activity against in vitro cell lines, patient samples, and in vivo models. We applied pharmacokinetic/pharmacodynamic (PK/PD) modeling to integrate our understanding of on-target activity of the dual inhibitor in tumors and platelets across dose levels and over time.

Results:
We discovered AZD4320, which has nanomolar affinity for Bcl-2 and Bcl-xL, and mechanistically drives cell death through the mitochondrial apoptotic pathway. AZD4320 demonstrates activity in both Bcl-2– and Bcl-xL–dependent hematologic cancer cell lines and enhanced activity in acute myeloid leukemia (AML) patient samples compared with the Bcl-2–selective agent venetoclax. A single intravenous bolus dose of AZD4320 induces tumor regression with transient thrombocytopenia, which recovers in less than a week, suggesting a clinical weekly schedule would enable targeting of Bcl-2/Bcl-xL–dependent tumors without incurring dose-limiting thrombocytopenia. AZD4320 demonstrates monotherapy activity in patient-derived AML and venetoclax-resistant xenograft models.

Conclusions:
AZD4320 is a potent molecule with manageable thrombocytopenia risk to explore the utility of a dual Bcl-2/Bcl-xL inhibitor across a broad range of tumor types with dysregulation of Bcl-2 prosurvival proteins.
A Randomized Placebo Controlled Phase II Trial Evaluating Exemestane with or without Enzalutamide in Patients with Hormone Receptor–Positive Breast Cancer
Authors: Krop Ian , Abramson Vandana , Colleoni Marco , Traina Tiffany , Holmes Frankie , Garcia-Estevez Laura , Hart Lowell , Awada Ahmad , Zamagni Claudio , Morris Patrick G. , Schwartzberg Lee , Chan Stephen , Gucalp Ayca , Biganzoli Laura , Steinberg Joyce , Sica Lorenzo , Trudeau Maureen , Markova Denka , Tarazi Jamal , Zhu Zhou , O'Brien Thomas , Kelly Catherine M. , Winer Eric , Yardley Denise A. 
Published: September 2020

Abstract

Purpose:
To determine whether the androgen receptor (AR) inhibitor, enzalutamide, improves effectiveness of endocrine therapy (ET) in hormone receptor–positive (HR+) breast cancer.

Patients and Methods:
In this phase II trial, patients with HR+/HER2 normal advanced/metastatic breast cancer were randomized 1:1 to exemestane 25 mg with placebo or exemestane 50 mg with enzalutamide 160 mg daily (NCT02007512). Two parallel cohorts enrolled patients with 0 (cohort 1) or 1 (cohort 2) prior ET for advanced disease. Progression-free survival (PFS) was the primary endpoint in the intent-to-treat (ITT) population of each cohort. Biomarkers were evaluated in an exploratory analysis.

Results:
Overall, 247 patients were randomized (cohort 1, n = 127 and cohort 2, n = 120). PFS was not improved in either cohort of the ITT population [HR, 0.82 (95% confidence interval (CI), 0.54–1.26); P = 0.3631 for cohort 1 and HR, 1.02 (95% CI, 0.66–1.59); P = 0.9212 for cohort 2]. In cohort 1, high levels of AR mRNA were associated with greater benefit of enzalutamide (Pinteraction = 0.0048). This effect was particularly apparent in patients with both high levels of AR mRNA and low levels of ESR1 mRNA [HR, 0.24 (95% CI, 0.10–0.60); P = 0.0011]. The most common any grade adverse events in the enzalutamide arms were nausea (39%) in cohort 1 and fatigue (37%) in cohort 2.

Conclusions:
Enzalutamide with exemestane was well tolerated. While PFS was not improved by the addition of enzalutamide to exemestane in an unselected population, ET-naïve patients with high AR mRNA levels, particularly in combination with low ESR1 mRNA levels, may benefit from enzalutamide with exemestane.
Clinical Outcome–Related Mutational Signatures Identified by Integrative Genomic Analysis in Nasopharyngeal Carcinoma
Authors: Dai Wei , Chung Dittman Lai-Shun , Chow Larry Ka-Yue , Yu Valen Zhuoyou , Lei Lisa Chan , Leong Merrin Man-Long , Chan Candy King-Chi , Ko Josephine Mun-Yee , Lung Maria Li 
Published: September 2020

Abstract

Purpose:
Investigation of biological mechanisms underlying genetic alterations in cancer can assist the understanding of etiology and identify the potential prognostic biomarkers.

Experimental Design:
We performed an integrative genomic analysis for a total of 731 nasopharyngeal carcinoma cases from five independent nasopharyngeal carcinoma cohorts to identify the genetic events associated with clinical outcomes.

Results:
In addition to the known mutational signatures associated with aging, APOBEC and mismatch repair (MMR), a new signature for homologous recombination deficiency (BRCAness) was discovered in 64 of 216 (29.6%) cases in the discovery set including three cohorts. This signature appeared more frequently in the recurrent and metastatic tumors and significantly correlated with shorter overall survival (OS) in the primary tumors. Independent prognostic value of MMR and BRCAness signatures was revealed by multivariable Cox analysis after adjustment for clinical parameters and stratification by studies. The cases with both signatures had much worse clinical outcome than those without these signatures [hazard ratio (HR), 12.4; P = 0.002]. This correlation was confirmed in the validation set (HR, 8.9; P = 0.003). The BRCAness signature is highly associated with BRCA2 pathogenic germline or somatic alterations (7.8% vs. 0%; P = 0.002). Targeted sequencing results from a prospective nasopharyngeal carcinoma cohort (N = 402) showed that the cases carrying BRCA2 germline rare variants are more likely to have poor OS and progression-free survival.

Conclusions:
Our study highlights importance of defects of DNA repair machinery in nasopharyngeal carcinoma pathogenesis and their prognostic values for clinical implications. These signatures will be useful for patient stratification to evaluate conventional and new treatment for precision medicine in nasopharyngeal carcinoma.
DNA Methylation Profiling of Premalignant Lesions as a Path to Ovarian Cancer Early Detection
Authors: Ishak Charles A. , De Carvalho Daniel D. 
Published: September 2020

Abstract
Genome-wide DNA methylation profiles of serous tubal intraepithelial carcinomas (STIC) resemble methylation profiles of high-grade serous ovarian carcinomas (HGSOC) more closely than normal fallopian tube epithelium. While STICs and HGSOCs share subsets of common hypermethylated regions, DNA methylation can distinguish STICs from HGSOCs to provide proof-of-principle that DNA methylation can identify HGSOC initiation.
See related article by Pisanic et al., p. 6310
Arterial Stiffness Preceding Diabetes
Authors: Zheng Mengyi , Zhang Xinyuan , Chen Shuohua , Song Yongjian , Zhao Quanhui , Gao Xiang , Wu Shouling 
Published: September 2020

Rationale:
Previous studies on the relationship between diabetes and arterial stiffness were mostly cross-sectional. A few longitudinal studies focused on one single direction. Whether the association between arterial stiffness and diabetes is bidirectional remains unclear to date.

Objective:
To explore the temporal relationship between arterial stiffness and fasting blood glucose (FBG) status.

Methods and Results:
Included were 14 159 participants of the Kailuan study with assessment of brachial-ankle pulse wave velocity (baPWV) from 2010 to 2015, and free of diabetes, cardiovascular and cerebrovascular diseases, and chronic kidney disease at baseline. FBG and baPWV were repeatedly measured at baseline and follow-ups. Cox proportional hazard regression model was used to estimate hazard ratios and 95% confidence intervals (CIs) of incident diabetes across baseline baPWV groups: <1400 cm/s (ref), 1400≤ baPWV <1800 cm/s, and ≥1800 cm/s. Path analysis was used to analyze the possible temporal causal relationship between baPWV and FBG, among 8956 participants with repeated assessment of baPWV and FBG twice in 2010 to 2017. The mean baseline age of the observed population was 48.3±12.0 years. During mean 3.72 years of follow-up, 979 incident diabetes cases were identified. After adjusting for potential confounders, the hazard ratio (95% CI) for risk of diabetes was 1.59 (1.34–1.88) for the borderline arterial stiffness group and 2.11 (1.71–2.61) for the elevated arterial stiffness group, compared with the normal ideal arterial stiffness group. In the path analysis, baseline baPWV was associated with follow-up FBG (the standard regression coefficient was 0.09 [95% CI, 0.05–0.10]). In contrast, the standard regression coefficient of baseline FBG for follow-up baPWV (β=0.00 [95% CI, −0.02 to 0.02]) was not significant.

Conclusions:
Arterial stiffness, as measured by baPWV, was associated with risk of developing diabetes. Arterial stiffness appeared to precede the increase in FBG.