bluuebunny/crossref_metadata_2025_split huggingface dataset:
Investigation of a nonsense mutation located in the complex KIV-2 copy number variation region of apolipoprotein(a) in 10,910 individuals
Authors: Di Maio Silvia , Grüneis Rebecca , Streiter Gertraud , Lamina Claudia , Maglione Manuel , Schoenherr Sebastian , Öfner Dietmar , Thorand Barbara , Peters Annette , Eckardt Kai-Uwe , Köttgen Anna , Kronenberg Florian , Coassin Stefan 
Published: August 2020

Abstract
Background
The concentrations of the highly atherogenic lipoprotein(a) [Lp(a)] are mainly genetically determined by the LPA gene locus. However, up to 70% of the coding sequence is located in the complex so-called kringle IV type 2 (KIV-2) copy number variation, a region hardly accessible by common genotyping and sequencing technologies. Despite its size, little is known about genetic variants in this complex region. The R21X variant is a functional variant located in this region, but it has never been analyzed in large cohorts.

Methods
We typed R21X in 10,910 individuals from three European populations using a newly developed high-throughput allele-specific qPCR assay. R21X allelic location was determined by separating the LPA alleles using pulsed-field gel electrophoresis (PFGE) and typing them separately. Using GWAS data, we identified a proxy SNP located outside of the KIV-2. Linkage disequilibrium was determined both statistically and by long-range haplotyping using PFGE. Worldwide frequencies were determined by reanalyzing the sequencing data of the 1000 Genomes Project with a dedicated pipeline.

Results
R21X carriers (frequency 0.016–0.021) showed significantly lower mean Lp(a) concentrations (− 11.7 mg/dL [− 15.5; − 7.82], p = 3.39e−32). The variant is located mostly on medium-sized LPA alleles. In the 1000 Genome data, R21X mostly occurs in Europeans and South Asians, is absent in Africans, and shows varying frequencies in South American populations (0 to 0.022). Of note, the best proxy SNP was another LPA null mutation (rs41272114, D′ = 0.958, R2 = 0.281). D′ was very high in all 1000G populations (0.986–0.996), although rs41272114 frequency varies considerably (0–0.182). Co-localization of both null mutations on the same allele was confirmed by PFGE-based long-range haplotyping.

Conclusions
We performed the largest epidemiological study on an LPA KIV-2 variant so far, showing that it is possible to assess LPA KIV-2 mutations on a large scale. Surprisingly, in all analyzed populations, R21X was located on the same haplotype as the splice mutation rs41272114, creating “double-null” LPA alleles. Despite being a nonsense variant, the R21X status does not provide additional information beyond the rs41272114 genotype. This has important implications for studies using LPA loss-of-function mutations as genetic instruments and emphasizes the complexity of LPA genetics.
Effect of supplementation with vitamins D3 and K2 on undercarboxylated osteocalcin and insulin serum levels in patients with type 2 diabetes mellitus: a randomized, double-blind, clinical trial
Authors: Aguayo-Ruiz J. I. , García-Cobián T. A. , Pascoe-González S. , Sánchez-Enríquez S. , Llamas-Covarrubias I. M. , García-Iglesias T. , López-Quintero A. , Llamas-Covarrubias M. A. , Trujillo-Quiroz J. , Rivera-Leon E. A. 
Published: August 2020

Abstract
Background
Patients with type 2 diabetes mellitus (T2DM) are characterized by chronic hyperglycemia as a consequence of decreased insulin sensitivity, which contributes to bone demineralization and could also be related to changes in serum levels of osteocalcin and insulin, particularly when coupled with a deficiency in the daily consumption of vitamins D3 and K2. The objective of this study was to evaluate the effect of vitamin D3 and vitamin K2 supplements alone or in combination on osteocalcin levels and metabolic parameters in patients with T2DM.

Methods
A double-blind, randomized clinical trial was carried out in 40 patients aged between 30 and 70 years old for 3 months. Clinical and laboratory assessment was carried out at the beginning and at the end of the treatment. The patients were divided into three groups: (a) 1000 IU vitamin D3 + a calcinated magnesium placebo (n = 16), (b) 100 µg of Vitamin K2 + a calcinated magnesium placebo (n = 12), and (c) 1000 IU vitamin D3 + 100 µg vitamin K2 (n = 12).

Results
After treatment in the total studied population, a significant decrease in glycemia (p = 0.001), HOMA-IR (Homeostatic model assessment-insulin resistance) (p = 0.040), percentage of pancreatic beta cells (p < 0.001), uOC/cOC index and diastolic blood pressure (p = 0.030) were observed; in vitamin D3 group, differences in serum undercarboxylated osteocalcin (p = 0.026), undercarboxylated to carboxylated osteocalcin index (uOC/cOC) (p = 0.039) glucose (p < 0.001) and % of functional pancreatic beta cells (p < 0.001) were demonstrated. In vitamin K2 group a significant decrease in glycemia (p = 0.002), HOMA-IR (p = 0.041), percentage of pancreatic beta cells (p = 0.002), and in cOC (p = 0.041) were observed, conversely cOC concentration was found high. Finally, in the vitamins D3 + K2 a significant decrease in glycemia (p = 0.002), percentage of pancreatic beta cells (p = 0.004), and in the uOC/cOC index (p = 0.023) were observed.

Conclusion
Individual or combined supplementation with vitamins D3 and K2 significantly decreases the glucose levels and % of functional pancreatic beta cells, while D3 and D3 + K2 treatments also induced a reduction in the uOC/cOC index. Only in the group with vitamin D3 supplementation, it was observed a reduction in undercarboxylated osteocalcin while vitamin K2 increased the carboxylated osteocalcin levels.
Trial registration NCT04041492
Identification of residues for chaperone-like activity of OppA protein in Yersinia pseudotuberculosis
Authors: Escobar Garduño Elena , Scior Thomas , Soto Urzúa Lucia , Martínez Morales Luis Javier 
Published: August 2020

AbstractPeriplasmic oligopeptide binding protein (OppA) is part of a multimeric cytoplasmic membrane protein complex, whose function is known as peptide transporters found in Gram-negative bacteria. A chaperone-like activity has been found for the OppA from Yersinia pseudotuberculosis, using biochemical experiments. Through computational analysis, we selected two amino acid residues (R41 and D42) that probably are involved in the chaperone-like activity. Our results to corroborate how OppA assists refolding and renaturation of lactate dehydrogenase and alpha-glucosidase denatured enzymes.
Obstacles to using online health services among adults age 50 and up and the role of family support in overcoming them
Authors: Mizrachi Y. , Shahrabani S. , Nachmani M. , Hornik A. 
Published: August 2020

Abstract
Background
Using Online Health Services (OHS) could benefit older adults greatly and could also reduce the burden on the health system. Yet invisible obstacles or barriers appear to impede mass adoption of these services among this population group. The aim of the current research is to provide a qualitative picture of these invisible obstacles and to profile their main features, with special attention to the role of family members in supporting OHS use among this population group.

Methods
This qualitative study entailed a series of in-depth, semi-structured, open phone interviews conducted with 31 individuals age 50 and up in Israel, who constituted a sample of OHS users and non-users among older adults.

Results
Four major themes and primary observations emerge from our data:

While older adults are aware of OHS to some extent, they often do not fully understand the specific benefits of using these services;

Older adults need to acquire much more experience with OHS use. OHS user interfaces still have a long way to go for older adults to feel comfortable using them. People age 50 and up seem to be less concerned about privacy and security issues than about seemingly more trivial issues such as recovering forgotten passwords;

Family members can play key roles in helping older adults adopt OHS by providing technical support as well as encouragement;

Older adults have worthwhile recommendations for innovations and policy improvements that would facilitate wider adoption of OHS.

Conclusions
The results of the current study reveal important nuances regarding the importance of awareness, user interface and experience for OHS use among older adults, as well as the critical role of family members in OHS adoption. Based on these findings, we recommend the following: expanding advertising on media channels to emphasize the benefits of OHS use; improving HMO websites to make them more user-friendly for older people; developing HMO-run community OHS guidance programs geared to older people to reduce the gap between required skills and user competencies, thus enabling older people to benefit from OHS use.
Efficacy and safety of secondary procedures for maintaining arteriovenous hemodialysis access patency: protocol for a systematic review and network meta-analysis
Authors: Rockley Mark , Nagpal Sudhir , Gupta Ashish , Roberts Derek J. 
Published: August 2020

AbstractBackgroundArteriovenous (AV) hemodialysis access creation is recommended by international guidelines as the preferred method of hemodialysis access. However, most AV access sites will require revision to maintain patency. Although several treatment options exist, many have not been directly compared. We intend to compare the relative effectiveness of methods to maintain post-intervention primary patency of failing AV access.MethodsWe will search EMBASE, MEDLINE, CENTRAL, trial registries, the grey literature, and ancestry and citation search from January 1977 to present, for randomized controlled trials comparing interventions to maintain primary patency of AV access. Two investigators will independently and blindly review all identified citations and extract data from included studies. The primary outcome is the primary patency 6 months after intervention. Secondary outcomes include immediate technical and functional success, reinterventions, patency, and mortality. Risk of bias, subgroup analyses, and sensitivity analyses are planned.DiscussionThere are a number of treatment modalities for the management of failing AV access. However, most modalities have only been directly compared with plain old balloon angioplasty, and currently synthesized evidence focuses on individual pairwise comparisons. In light of the lack of comprehensively synthesized evidence and clinical equipoise, our study intends to synthesize currently available evidence though it is unclear which treatment modality is most effective.Systematic review registrationPROSPERO ID CRD42020148224
“Looking at Myself in the Future”: how mentoring shapes scientific identity for STEM students from underrepresented groups
Authors: Atkins Kaitlyn , Dougan Bryan M. , Dromgold-Sermen Michelle S. , Potter Hannah , Sathy Viji , Panter A. T. 
Published: August 2020

Abstract
Background
Mentorship has been well-established in the literature as fostering scientific identity and career pathways for underrepresented minority students in science, technology, engineering, and mathematics (STEM) fields. Mentorship is prioritized by programs that aim to increase diversity and support future leadership in STEM fields, but in-depth understanding of mentorship in these contexts remains limited. Drawing on qualitative interview data, we sought to understand the relationship between mentoring and scientific identity among a diverse sample of 24 students in one such program, in order to inform program development.

Results
Qualitative analysis of the data revealed that mentorship, especially research mentorship, was common and played a role in formation of scientific identity. Students with research mentors tended to say they strongly identified as scientists, whereas those who lacked research mentorship varied in their level of scientific identity. In interviews, research-mentored students described mentors as colleagues who gave them opportunities to grow and as examples to look up to. Students valued mentors with whom they identified on the basis of demographic similarity or shared values, as well as those who challenged them in their academic and research endeavors.

Conclusions
Our analysis highlights how different mentoring experiences can contribute to development of future STEM leadership. We discuss implications for practice, including the need for tailored mentoring approaches and research-focused mentoring, and offer several recommendations for research and programming.
Health Care Cost Associated With Contemporary Chronic Myelogenous Leukemia Therapy Compared With That of Other Hematologic Malignancies
Authors: Wilkes Jennifer J. , Lyman Gary H. , Doody David R. , Chennupati Shasank , Becker Laura K. , Morin Pamela E. , Winestone Lena E. , Henk Henry J. , Chow Eric J. 
Published: August 2020

PURPOSE: Given the widespread introduction of tyrosine kinase inhibitors (TKIs), we evaluated the cost associated with chronic myelogenous leukemia (CML) care compared with the cost of care for patients with hematologic malignancies (HEM) and for patients without cancer (GEN), to aid with resource allocation and clinical decision making. METHODS: A retrospective cohort was constructed from the OptumLabs Data Warehouse using claims from 2000 to 2016. Eligible patients had ≥ 2 CML claims and were enrolled continuously for ≥ 6 months before diagnosis and ≥ 1 year afterward (n = 1,909). Patients with CML were frequency matched 4:1 with HEM and GEN cohorts and were observed through October 2017. We used generalized linear models to assess the variation in total mean annualized health care costs in the 3 cohorts and to examine the influence of factors associated with costs. RESULTS: Mean annualized costs for CML were $82,054 (ie, $25,471 [95% CI, $20,808 to $30,133] more than those for HEM and $74,993 [95% CI, $70,818 to $79,167] more than those for GEN); these differences were driven by pharmacy costs in the CML group. The cost of CML care exceeded that for HEM and GEN for all index years in this study and increased over each diagnostic interval until 2015, peaking at $91,990. The mean annual cost of all TKIs increased. Imatinib’s mean annualized cost was $41,546 in the period 2000-2004 but increased to $105,069 in the period 2015-2017. In multivariable analysis, percent days on TKIs had the greatest influence on cost: ≥ 75% of the time versus none showed a difference in cost of $108,716 (95% CI, $99,193 to $118,239). CONCLUSION: Contemporary CML costs exceeded the cost of treatment of other hematologic malignancies. Cost was primarily driven by TKIs, whose cost continued to increase over time.
Bone Regulation of Insulin Secretion and Glucose Homeostasis
Authors: Ducy Patricia 
Published: August 2020

Abstract
For centuries our image of the skeleton has been one of an inert structure playing a supporting role for muscles and a protective role for inner organs like the brain. Cell biology and physiology modified this view in the 20st century by defining the constant interplay between bone-forming and bone resorbing cells that take place during bone growth and remodeling, therefore demonstrating that bone is as alive as any other tissues in the body. During the past 40 years human and, most important, mouse genetics, have allowed not only the refinement of this notion by identifying the many genes and regulatory networks responsible for the crosstalk existing between bone cells, but have redefined the role of bone by showing that its influence goes way beyond its own physiology. Among its newly identified functions is the regulation of energy metabolism by 2 bone-derived hormones, osteocalcin and lipocalin-2. Their biology and respective roles in this process are the topic of this review.
Androgen Therapy in Neurodegenerative Diseases
Authors: Bianchi Vittorio Emanuele , Rizzi Laura , Bresciani Elena , Omeljaniuk Robert J , Torsello Antonio 
Published: August 2020

AbstractNeurodegenerative diseases, including Alzheimer disease (AD), Parkinson disease (PD), multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), and Huntington disease, are characterized by the loss of neurons as well as neuronal function in multiple regions of the central and peripheral nervous systems. Several studies in animal models have shown that androgens have neuroprotective effects in the brain and stimulate axonal regeneration. The presence of neuronal androgen receptors in the peripheral and central nervous system suggests that androgen therapy might be useful in the treatment of neurodegenerative diseases. To illustrate, androgen therapy reduced inflammation, amyloid-β deposition, and cognitive impairment in patients with AD. As well, improvements in remyelination in MS have been reported; by comparison, only variable results are observed in androgen treatment of PD. In ALS, androgen administration stimulated motoneuron recovery from progressive damage and regenerated both axons and dendrites. Only a few clinical studies are available in human individuals despite the safety and low cost of androgen therapy. Clinical evaluations of the effects of androgen therapy on these devastating diseases using large populations of patients are strongly needed.
Management of Familial Hypercholesterolemia: Current Status and Future Perspectives
Authors: Lui David T W , Lee Alan C H , Tan Kathryn C B 
Published: August 2020

Abstract
Familial hypercholesterolemia (FH) is the most common monogenic disorder associated with premature atherosclerotic cardiovascular disease. Early diagnosis and effective treatment can significantly improve prognosis. Recent advances in the field of lipid metabolism have shed light on the molecular defects in FH and new therapeutic options have emerged. A search of PubMed database up to March 2020 was performed for this review using the following keywords: “familial hypercholesterolemia,” “diagnosis,” “management,” “guideline,” “consensus,” “genetics,” “screening,” “lipid lowering agents.” The prevalence rate of heterozygous FH is approximately 1 in 200 to 250 and FH is underdiagnosed and undertreated in many parts of the world. Diagnostic criteria have been developed to aid the clinical diagnosis of FH. Genetic testing is now available but not widely used. Cascade screening is recommended to identify affected family members, and the benefits of early interventions are clear. Treatment strategy and target is currently based on low-density lipoprotein (LDL) cholesterol levels as the prognosis of FH largely depends on the magnitude of LDL cholesterol-lowering that can be achieved by lipid-lowering therapies. Statins with or without ezetimibe are the mainstay of treatment and are cost-effective. Addition of newer medications like PCSK9 inhibitors is able to further lower LDL cholesterol levels substantially, but the cost is high. Lipoprotein apheresis is indicated in homozygous FH or severe heterozygous FH patients with inadequate response to cholesterol-lowering therapies. In conclusion, FH is a common, treatable genetic disorder, and although our understanding of this disease has improved, many challenges still remain for its optimal management.
Blood Flow Restriction Training Blunts Chronic Kidney Disease Progression in Humans
Authors: Corrêa Hugo Luca , Neves Rodrigo Vanerson Passos , Deus Lysleine Alves , Souza Michel Kendy , Haro Anderson Sola , Costa Fernando , Silva Victor Lopes , Santos Claudio Avelino Rodrigues , Moraes Milton Rocha , Simões Herbert Gustavo , Navalta James Wilfred , Prestes Jonato , Rosa Thiago Santos 
Published: August 2020

ABSTRACT

Purpose
This study aimed to verify the effect of 6 months of periodized resistance training (RT) with and without blood flow restriction (BFR) in patients with stage 2 chronic kidney disease (CKD) on glomerular filtration rate (GFR), uremic parameters, cytokines, and klotho–fibroblast growth factor 23 (FGF23) axis.

Methods
A total of 105 subjects were randomized in three groups of 35 each: control (CTL), RT, and RT + BFR. A first visit was required for an anamnesis to evaluate the number of medications and anthropometric measurements (body weight, height, and body mass index). Muscle strength (one-repetition maximum) was assessed. Venous blood samples were collected at baseline and after 6 months of training in all patients for the analysis of markers of renal function and integrity, as well as for the determination of the inflammatory profile. Statistical significances were adopted with P < 0.05.

Results
Both training therapies attenuated the decline of GFR (P < 0.05). The majority of CTL patients declined to stage 3 CKD (88.5%), whereas fewer incidents were noted with RT (25.7%) and RT + BFR (17.1%). Improved uremic parameters as well as inflammation (IL-6, IL-10, IL-15, IL-17a, IL-18, and TNF-α) and klotho–FGF23 axis in RT and RT + BFR (P < 0.05) were observed. Monocyte chemoattractant protein 1 was not changed (P > 0.05) but presented a large effect size (Cohen’s d), demonstrating a propensity for improvement.

Conclusion
Six months of periodized RT with and without BFR in patients with stage 2 CKD attenuated the progression of the disease by maintaining GFR, improving uremic parameters, cytokine profile regulation, and klotho–FGF23 axis.
Aerobic Fitness Is Related to Myocardial Fibrosis Post–Anthracycline Therapy
Authors: Kirkham Amy Ashley , Paterson D. Ian , Haykowsky Mark J. , Beaudry Rhys I. , Mackey John R. , Pituskin Edith , Grenier Justin G. , Thompson Richard B. 
Published: August 2020

ABSTRACT
Adjuvant anthracycline chemotherapy for breast cancer is associated with cardiotoxicity and reduced cardiorespiratory fitness (V˙O2peak).

Purpose
We evaluated the impact of anthracyclines on left ventricular function and myocardial tissue characteristics using cardiovascular magnetic resonance (CMR) imaging to determine their relationship with V˙O2peak.

Methods
Women with breast cancer who had not yet received treatment (No-AT, n = 16) and had received anthracycline treatment ~1 yr earlier (Post-AT, n = 16) and controls without cancer (CON, n = 16) performed a maximal exercise test and a comprehensive 3T CMR examination, including native myocardial T
1 mapping, where elevated T
1 times are indicative of myocardial fibrosis. ANOVA and linear regression were used to compare CMR variables between groups and to determine associations with V˙O2peak. Subgroup analysis was performed by categorizing participants as “fit” or “unfit” based on whether their V˙O2peak value was greater or less than 100% of reference value for age, respectively.

Results
Left ventricular end-diastolic volume, ejection fraction, and mass were similar between groups. Post-AT, T
1 times were elevated (1534 ± 32 vs 1503 ± 28 ms, P < 0.01), and V˙O2peak was reduced (23.1 ± 7.5 vs 29.5 ± 7.7 mL·kg−1⋅min−1, P = 0.02) compared with CON. In No-AT, T
1 times and V˙O2peak were similar to CON. In the Post-AT group, T
1 time was associated with V˙O2peak (R
2 = 64%), whereas in the absence of anthracyclines (i.e., No-AT and CON groups), T
1 time was not associated with V˙O2peak. Regardless of group, all fit women had similar T
1 times, whereas unfit women Post-AT had higher T
1 than unfit CON (1546 ± 22 vs 1500 ± 33 ms, P < 0.01).

Conclusions
After anthracycline chemotherapy, an elevated T
1 time suggesting greater extent of myocardial fibrosis, was associated with lower V˙O2peak. However, those who were fit did not have evidence of myocardial fibrosis after anthracycline treatment.