bluuebunny/crossref_metadata_2025 huggingface dataset:
Changes in Health Status in the Ft. Devens Gulf War Veterans Cohort: 1997-2017
Authors: Zundel Clara G , Heeren Timothy , Grasso Claudia M , Spiro Avron , Proctor Susan P , Sullivan Kimberly , Krengel Maxine
Published: August 2020

Gulf War veterans (GWVs) were exposed to numerous neurotoxicants during deployment. Upon returning home, many reported a multitude of symptoms including fatigue, pain, gastrointestinal and respiratory issues, and neurological, cognitive, and mood complaints, collectively termed “Gulf War Illness (GWI).” Now, nearly 30 years post-war, many GWVs continue to suffer from these symptoms, in addition to health concerns associated with normal aging. While most research on GWVs has been cross-sectional, it is important to evaluate the progression and onset of new GWI symptoms longitudinally. The current study investigated the health of GWVs 25+ years after the war by resurveying the Ft. Devens Cohort and comparing their current health to their health reported 15 to 20 years earlier. The sample consists of 317 GWVs (~54 years old at the latest survey, 38 women) who responded to both surveys (1997-1998 and 2013-2017). Multivariable regression analyses were used to assess changes in GWI symptomatology and prevalence of medical conditions. The rates of 12 of 25 health symptoms increased significantly from the prior 1997-1998 survey. Anxiety, numbness in extremities, depressed mood, and joint pain had the greatest increase in endorsement. The rates of 7 of 16 medical conditions increased significantly from the prior 1997-1998 survey. High blood pressure, diabetes, and cancer had the greatest increase in prevalence. In summary, this study demonstrates that both symptoms and physician-diagnosed medical conditions associated with GW deployment/exposure increased in prevalence. For GWVs, focus by providers on the treatment of cognitive and mental health issues as well as cardiovascular and cerebrovascular risk factors is warranted. Targeting symptom alleviation would help improve the quality of life in these veterans until treatments addressing the entire illness become available.
Public Engagement Events and the Management of External Stakeholders: Artifacts as Boundary Objects or Tools of Discipline and Control?
Authors: Chow Vivien , Leiringer Roine
Published: August 2020

Public engagement is founded on idealistic principles of democratic decision making and public stewardship. Yet, the logistical realities of managing these processes are fraught with difficulties. In this article, we explore the ways in which material artifacts are used in formal public engagement proceedings on urban development projects in Hong Kong. The findings show that material artifacts used—in addition to serving as boundary objects that facilitate communication across knowledge boundaries—form part of a network that directs, controls, and manages the information flow among participants. These artifacts thus play an active role in managing the divergent interests of external stakeholders on projects.
Structural, functional, and mechanistic insights uncover the fundamental role of orphan connexin-62 in platelets
Authors: Sahli Khaled A. , Flora Gagan D. , Sasikumar Parvathy , Maghrabi Ali H. , Holbrook Lisa-Marie , AlOuda Sarah K. , Elgheznawy Amro , Sage Tanya , Stainer Alexander R. , Adiyaman Recep , AboHassan Mohammad , Crescente Marilena , Kriek Neline , Vaiyapuri Sakthivel , Bye Alexander P. , Unsworth Amanda J. , Jones Chris I. , McGuffin Liam J. , Gibbins Jonathan M.
Published: August 2020

Connexins oligomerise to form hexameric hemichannels in the plasma membrane that can further dock together on adjacent cells to form gap junctions and facilitate intercellular trafficking of molecules. In this study, we report the expression and function of an orphan connexin, connexin-62 (Cx62), in human and mouse (Cx57, mouse homolog) platelets. A novel mimetic peptide (62Gap27) was developed to target the second extracellular loop of Cx62, and 3-dimensional structural models predicted its interference with gap junction and hemichannel function. The ability of 62Gap27 to regulate both gap junction and hemichannel-mediated intercellular communication was observed using fluorescence recovery after photobleaching analysis and flow cytometry. Cx62 inhibition by 62Gap27 suppressed a range of agonist-stimulated platelet functions and impaired thrombosis and hemostasis. This was associated with elevated protein kinase A–dependent signaling in a cyclic adenosine monophosphate–independent manner and was not observed in Cx57-deficient mouse platelets (in which the selectivity of 62Gap27 for this connexin was also confirmed). Notably, Cx62 hemichannels were observed to function independently of Cx37 and Cx40 hemichannels. Together, our data reveal a fundamental role for a hitherto uncharacterized connexin in regulating the function of circulating cells.
β-Catenin–TCF/LEF signaling promotes steady-state and emergency granulopoiesis via G-CSF receptor upregulation
Authors: Danek Petr , Kardosova Miroslava , Janeckova Lucie , Karkoulia Elena , Vanickova Karolina , Fabisik Matej , Lozano-Asencio Carlos , Benoukraf Touati , Tirado-Magallanes Roberto , Zhou Qiling , Burocziova Monika , Rahmatova Sarka , Pytlik Robert , Brdicka Tomas , Tenen Daniel G. , Korinek Vladimir , Alberich-Jorda Meritxell
Published: August 2020

The canonical Wnt signaling pathway is mediated by interaction of β-catenin with the T-cell factor/lymphoid enhancer-binding factor (TCF/LEF) transcription factors and subsequent transcription activation of Wnt-target genes. In the hematopoietic system, the function of the pathway has been mainly investigated by rather unspecific genetic manipulations of β-catenin that yielded contradictory results. Here, we used a mouse expressing a truncated dominant negative form of the human TCF4 transcription factor (dnTCF4) that specifically abrogates β-catenin-TCF/LEF interaction. Disruption of the β-catenin-TCF/LEF interaction resulted in the accumulation of immature cells and reduced granulocytic differentiation. Mechanistically, dnTCF4 progenitors exhibited downregulation of the Csf3r gene, reduced granulocyte colony-stimulating factor (G-CSF) receptor levels, attenuation of downstream Stat3 phosphorylation after G-CSF treatment, and impaired G-CSF-mediated differentiation. Chromatin immunoprecipitation assays confirmed direct binding of TCF/LEF factors to the promoter and putative enhancer regions of CSF3R. Inhibition of β-catenin signaling compromised activation of the emergency granulopoiesis program, which requires maintenance and expansion of myeloid progenitors. Consequently, dnTCF4 mice were more susceptible to Candida albicans infection and more sensitive to 5-fluorouracil-induced granulocytic regeneration. Importantly, genetic and chemical inhibition of β-catenin-TCF/LEF signaling in human CD34+ cells reduced granulocytic differentiation, whereas its activation enhanced myelopoiesis. Altogether, our data indicate that the β-catenin-TCF/LEF complex directly regulates G-CSF receptor levels, and consequently controls proper differentiation of myeloid progenitors into granulocytes in steady-state and emergency granulopoiesis. Our results uncover a role for the β-catenin signaling pathway in fine tuning the granulocytic production, opening venues for clinical intervention that require enhanced or reduced production of neutrophils.
Role of c-Myc haploinsufficiency in the maintenance of HSCs in mice
Authors: Sheng Yue , Ma Rui , Yu Chunjie , Wu Qiong , Zhang Steven , Paulsen Kimberly , Zhang Jiwang , Ni Hongyu , Huang Yong , Zheng Yi , Qian Zhijian
Published: August 2020

This study was conducted to determine the dosage effect of c-Myc on hematopoiesis and its distinct role in mediating the Wnt/β-catenin pathway in hematopoietic stem cell (HSC) and bone marrow niche cells. c-Myc haploinsufficiency led to ineffective hematopoiesis by inhibiting HSC self-renewal and quiescence and by promoting apoptosis. We have identified Nr4a1, Nr4a2, and Jmjd3, which are critical for the maintenance of HSC functions, as previously unrecognized downstream targets of c-Myc in HSCs. c-Myc directly binds to the promoter regions of Nr4a1, Nr4a2, and Jmjd3 and regulates their expression. Our results revealed that Nr4a1 and Nr4a2 mediates the function of c-Myc in regulating HSC quiescence, whereas all 3 genes contribute to the function of c-Myc in the maintenance of HSC survival. Adenomatous polyposis coli (Apc) is a negative regulator of the Wnt/β-catenin pathway. We have provided the first evidence that Apc haploinsufficiency induces a blockage of erythroid lineage differentiation through promoting secretion of IL6 in bone marrow endothelial cells. We found that c-Myc haploinsufficiency failed to rescue defective function of Apc-deficient HSCs in vivo but it was sufficient to prevent the development of severe anemia in Apc–heterozygous mice and to significantly prolong the survival of those mice. Furthermore, we showed that c-Myc–mediated Apc loss induced IL6 secretion in endothelial cells, and c-Myc haploinsufficiency reversed the negative effect of Apc-deficient endothelial cells on erythroid cell differentiation. Our studies indicate that c-Myc has a context-dependent role in mediating the function of Apc in hematopoiesis.
Ixazomib, dexamethasone, and rituximab in treatment-naive patients with Waldenström macroglobulinemia: long-term follow-up
Authors: Castillo Jorge J. , Meid Kirsten , Flynn Catherine A. , Chen Jiaji , Demos Maria G. , Guerrera Maria L. , Kofides Amanda , Liu Xia , Munshi Manit , Tsakmaklis Nicholas , Patterson Christopher J. , Yang Guang , Hunter Zachary , Treon Steven P.
Published: August 2020

Proteasome inhibition is a standard of care for the primary treatment of patients with Waldenström macroglobulinemia (WM). We present the long-term follow-up of a prospective, phase II clinical trial that evaluated the combination of ixazomib, dexamethasone, and rituximab (IDR) in 26 treatment-naive patients with WM. IDR was administered as 6 monthly induction cycles followed by 6 every-2-month maintenance cycles. The MYD88 L265P mutation was detected in all patients, and CXCR4 mutations were detected in 15 patients (58%). The median time to response (TTR) and time to major response (TTMR) were 2 and 6 months, respectively. Patients with and without CXCR4 mutations had median TTR of 3 months and 1 month, respectively (P = .003), and median TTMR of 10 months and 3 months, respectively (P = .31). The overall, major, and very good partial response (VGPR) rates were 96%, 77%, and 19%, respectively. The rate of VGPR in patients with and without CXCR4 mutations were 7% and 36%, respectively (P = .06). The median progression-free survival (PFS) was 40 months, the median duration of response (DOR) was 38 months, and the median time to next treatment (TTNT) was 40 months. PFS, DOR, and TTNT were not affected by CXCR4 mutational status. The safety profile was excellent with no grade 4 adverse events or deaths to date. IDR provides a safe and effective frontline treatment option for symptomatic patients with WM. This study was registered at www.clinicaltrials.gov as #NCT02400437.
Clinical and radiologic correlates of neurotoxicity after axicabtagene ciloleucel in large B-cell lymphoma
Authors: Strati Paolo , Nastoupil Loretta J. , Westin Jason , Fayad Luis E. , Ahmed Sairah , Fowler Nathan H. , Hagemeister Fredrick B. , Lee Hun J. , Iyer Swaminathan P. , Nair Ranjit , Parmar Simrit , Rodriguez Maria A. , Samaniego Felipe , Steiner Raphael E. , Wang Michael , Pinnix Chelsea C. , Adkins Sherry , Claussen Catherine M. , Martinez Charles S. , Hawkins Misha C. , Johnson Nicole A. , Singh Prachee , Mistry Haleigh E. , Horowitz Sandra , George Shirley , Feng Lei , Kebriaei Partow , Shpall Elizabeth J. , Neelapu Sattva S. , Tummala Sudhakar , Chi T. Linda
Published: August 2020

Neurotoxicity or immune effector cell-associated neurotoxicity syndrome (ICANS) is the second most common acute toxicity after chimeric antigen receptor (CAR) T-cell therapy. However, there are limited data on the clinical and radiologic correlates of ICANS. We conducted a cohort analysis of 100 consecutive patients with relapsed or refractory large B-cell lymphoma (LBCL) treated with standard of care axicabtagene ciloleucel (axi-cel). ICANS was graded according to an objective grading system. Neuroimaging studies and electroencephalograms (EEGs) were reviewed by an expert neuroradiologist and neurologist. Of 100 patients included in the study, 68 (68%) developed ICANS of any grade and 41 (41%) had grade ≥3. Median time to ICANS onset was 5 days, and median duration was 6 days. ICANS grade ≥3 was associated with high peak ferritin (P = .03) and C-reactive protein (P = .001) levels and a low peak monocyte count (P = .001) within the 30 days after axi-cel infusion. Magnetic resonance imaging was performed in 38 patients with ICANS and revealed 4 imaging patterns with features of encephalitis (n = 7), stroke (n = 3), leptomeningeal disease (n = 2), and posterior reversible encephalopathy syndrome (n = 2). Abnormalities noted on EEG included diffuse slowing (n = 49), epileptiform discharges (n = 6), and nonconvulsive status epilepticus (n = 8). Although reversible, grade ≥3 ICANS was associated with significantly shorter progression-free (P = .02) and overall survival (progression being the most common cause of death; P = .001). Our results suggest that imaging and EEG abnormalities are common in patients with ICANS, and high-grade ICANS is associated with worse outcome after CAR T-cell therapy in LBCL patients.
Exploring perceptions, attitudes and beliefs of Thai patients with type 2 diabetes mellitus as they relate to medication adherence at an out-patient primary care clinic in Chiang Mai, Thailand
Authors: Jiraporncharoen Wichuda , Pinyopornpanish Kanokporn , Junjom Korsin , Dejkriengkraikul Nisachol , Wisetborisut Anawat , Papachristou Iliatha , Hashmi Ahmar , Angkurawaranon Chaisiri
Published: August 2020

Background

Within the sphere of diabetes self-management, much emphasis has been placed on medication adherence. There has been a shift in thinking about medication adherence, moving from “compliance” and historically paternalistic models of care, to seeking better ways of characterizing dynamic and complex relationships that determine medication adherence and diabetes control. This study sought to understand the relationship between patient’s attitudes and medication adherence for oral anti-diabetics in Thailand.

Methods

In-depth interviews of patients with type 2 diabetes mellitus, taking oral anti-diabetic drugs, at the out-patient clinic run by the Department of Family Medicine, Chiang Mai University between May and December 2016. Thematic analysis followed the WHO framework for medication adherence in chronic disease to explore patient’s attitudes and their influence on medication compliance.

Results

Of 24 patients, 9 were men. The mean age was 62 years (SD 8.9 years). 67% had high compliance. Four themes were identified as important factors related to medication adherence: attitudes toward disease, attitudes toward treatment, attitudes toward family support and attitudes toward health care team. Specifically, symptoms at diagnosis, understanding and acceptance in taking medication, the presence of family support and the perception of concern by the doctor relate to improved medication compliance.

Conclusions

Medication adherence in Thai patients with diabetes requires support from both the health care providers and the family. The patient’s perception of the doctor’s concern creates greater patient trust in the health care team. This trust, along with family support, helps deepen patients’ understanding of the disease, accept the chronic nature of their disease, and engenders a positive attitude towards taking medication that can improve medication adherence.
Effect of endometrial thickness and embryo quality on live-birth rate of fresh IVF/ICSI cycles: a retrospective cohort study
Authors: Lv Hong , Li Xiuzhu , Du Jiangbo , Ling Xiufeng , Diao Feiyang , Lu Qun , Tao Shiyao , Huang Lei , Chen Shiyao , Han Xiumei , Zhou Kun , Xu Bo , Liu Xiaoyu , Ma Hongxia , Xia Yankai , Shen Hongbing , Hu Zhibin , Jin Guangfu , Guan Yichun , Wang Xinru
Published: August 2020

Background

Successful implantation and delivery require both the functional embryo and receptive endometrium in assisted reproductive technology (ART) cycles. However, little is known about embryo-endometrial interaction on live-birth. We aimed to investigate the independent effect and interaction of endometrial thickness (EMT) and embryo quality on live-birth in fresh embryo transfer (ET) cycles.

Methods

We conducted a retrospective cohort study including 15,012 ART cycles between 2013 and 2016 in three centers in China. Poisson regression with generalized estimating equations was employed to calculate relative risks (RRs) and 95% confidence intervals (CIs). We estimated the interaction of embryo quality and EMT on live-birth rate (LBR).

Results

The LBR per cycle was 42.8% overall. LBR increased with increasing EMT and reached a plateau (50.6 to 54.2%) when EMT was 11 mm or thicker. Embryo quality represented by cumulative score was associated with LBR independently of number of embryos transferred and EMT. LBR was not increased with thicker EMT when only Q1 cleavage-stage embryo transferred (aRR 0.95, 95%CI 0.61–1.46). LBR was not increased significantly with thicker EMT with transfer of two good-quality cleavage-stage embryos and any blastocyst combination except Q1 group. There was significant interaction between EMT and embryo quality on LBR for cleavage-stage ETs (P=0.023).

Conclusions

This study demonstrated the nonlinear EMT-LBR association and the EMT cut-off value of 11 mm which may be of more clinical significance for predicting live-birth. Embryo quality is an independent prognostic tool for LBR. Our finding of significant embryo-endometrial interaction indicates combination of EMT and embryos quality might improve the prognostic value in clinical practice for live-birth in patients undergoing transfer of 1–2 fresh cleavage-stage embryos.
The prevalence of rheumatoid arthritis in middle-aged and elderly people living in Naqu City, Tibet, Autonomous Region of China
Authors: Zhang Qingxi , Liu Qiang , Lin Chutong , Baima Yangjin , Li Hu , Gong Hongqiang , Lin Jianhao
Published: August 2020

Objective

To estimate the prevalence of rheumatoid arthritis (RA) in the Tibet Autonomous Region (China).

Methods

A population-based cross-sectional survey was conducted on 1458 residents of Luoma Town, Tibet Autonomous Region, who were aged ≥ 40 years old. We interviewed participants using questionnaires, and rheumatoid factor (RF), anti-citrullinated protein antibodies (ACPA), and C-reactive protein (CRP) were determined. The identification of RA in this study was on the basis of criteria issued by the 2010 American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) guideline.

Results

Herein, 782 participants completed all items of RA. The overall prevalence of RA was 4.86%, and the prevalence was higher in women than that in men (7.14% vs. 2.56%, p = 0.005). The age-standardized prevalence of RA was 6.30% (95% confidence interval (CI) 4.20–8.64%), which was 2.46% (95% CI 1.04%, 4.10%) and 9.59% (95% CI 5.93%, 13.77%) in men and women, respectively.

Conclusion

The prevalence of RA is relatively higher in the Tibet than that in other areas of China.
Genetic deletion of microRNA-22 blunts the inflammatory transcriptional response to status epilepticus and exacerbates epilepsy in mice
Authors: Almeida Silva Luiz F. , Reschke Cristina R. , Nguyen Ngoc T. , Langa Elena , Sanz-Rodriguez Amaya , Gerbatin Rogerio R. , Temp Fernanda R. , de Freitas Mayara L. , Conroy Ronan M. , Brennan Gary P. , Engel Tobias , Henshall David C.
Published: August 2020

MicroRNAs perform important roles in the post-transcriptional regulation of gene expression. Sequencing as well as functional studies using antisense oligonucleotides indicate important roles for microRNAs during the development of epilepsy through targeting transcripts involved in neuronal structure, gliosis and inflammation. MicroRNA-22 (miR-22) has been reported to protect against the development of epileptogenic brain networks through suppression of neuroinflammatory signalling. Here, we used mice with a genetic deletion of miR-22 to extend these insights. Mice lacking miR-22 displayed normal behaviour and brain structure and developed similar status epilepticus after intraamygdala kainic acid compared to wildtype animals. Continuous EEG monitoring after status epilepticus revealed, however, an accelerated and exacerbated epilepsy phenotype whereby spontaneous seizures began sooner, occurred more frequently and were of longer duration in miR-22-deficient mice. RNA sequencing analysis of the hippocampus during the period of epileptogenesis revealed a specific suppression of inflammatory signalling in the hippocampus of miR-22-deficient mice. Taken together, these findings indicate a role for miR-22 in establishing early inflammatory responses to status epilepticus. Inflammatory signalling may serve anti-epileptogenic functions and cautions the timing of anti-inflammatory interventions for the treatment of status epilepticus.
Correction to: miR-3928v is induced by HBx via NF-κB/EGR1 and contributes to hepatocellular carcinoma malignancy by down-regulating VDAC3
Authors: Zhang Qiaoge , Song Ge , Yao Lili , Liu Yankun , Liu Min , Li Shengping , Tang Hua
Published: August 2020

An amendment to this paper has been published and can be accessed via the original article.
TOB-STOP-COP (TOBacco STOP in COPd trial): study protocol—a randomized open-label, superiority, multicenter, two-arm intervention study of the effect of “high-intensity” vs. “low-intensity” smoking cessation intervention in active smokers with chronic obstructive pulmonary disease
Authors: Saeed Mohamad Isam , Sivapalan Pradeesh , Eklöf Josefin , Ulrik Charlotte Suppli , Pisinger Charlotta , Lapperre Therese , Tønnesen Philip , Hoyer Nils , Janner Julie , Karlsson Marie Lavesen , Bech Charlotte Sandau , Marså Kristoffer , Godtfredsen Nina , Brøndum Eva , Munk Birgit , Raaschou Merete , Browatzski Andrea , Lütken Pernille , Jensen Jens-Ulrik Stæhr
Published: August 2020

Background

Cigarette smoking is the leading cause of chronic obstructive pulmonary disease (COPD), and it contributes to the development of many other serious diseases. Smoking cessation in COPD patients is known to improve survival and reduce the number of hospitalization-requiring acute exacerbations of COPD. However, smoking cessation interventions in these patients have only been successful for approximately 15–20% for consistent smoking abstinence in 12 months. Thus, more effective interventions are needed for this patient group. The aim of this study is to determine whether a high-intensity intervention compared to a low-intensity intervention can increase the proportion of persistent (> 12 months) anamnestic and biochemical smoking cessation in active smokers with COPD.

Methods

This study is a randomized controlled trial. A total of 600 active smokers with COPD will be randomly assigned 1:1 to either a standard treatment (guideline-based municipal smoking cessation program, “low intensity” group) or an intervention (“high-intensity” group) group, which consists of group sessions, telephone consultations, behavior design, hotline, and “buddy-matching” (smoker matched with COPD patient who has ceased smoking). Both groups will receive pharmacological smoking cessation. The primary endpoint is anamnestic and biochemical (cotinine analysis in urine) validated smoking cessation after 12 months.

Discussion

The potential benefit of this project is to improve smoking cessation rates and thereby reduce smoking-related exacerbations of COPD. In addition, the project can potentially benefit from increasing the quality of life and longevity of COPD patients and reducing the risk of other smoking-related diseases.

Trial registration

ClinicalTrials.gov NCT04088942. Registered on 13 September 2019
A population-based gene expression signature of molecular clock phase from a single epidermal sample
Authors: Wu Gang , Ruben Marc D. , Francey Lauren J. , Smith David F. , Sherrill Joseph D. , Oblong John E. , Mills Kevin J. , Hogenesch John B.
Published: August 2020

Background

For circadian medicine to influence health, such as when to take a drug or undergo a procedure, a biomarker of molecular clock phase is required––one that is easily measured and generalizable across a broad population. It is not clear that any circadian biomarker yet satisfies these criteria.

Methods

We analyzed 24-h molecular rhythms in human dermis and epidermis at three distinct body sites, leveraging both longitudinal (n = 20) and population (n = 154) data. We applied cyclic ordering by periodic structure (CYCLOPS) to order the population samples where biopsy time was not recorded. With CYCLOPS-predicted phases, we used ZeitZeiger to discover potential biomarkers of clock phase.

Results

Circadian clock function was strongest in the epidermis, regardless of body site. We identified a 12-gene expression signature that reported molecular clock phase to within 3 h (mean error = 2.5 h) from a single sample of epidermis––the skin’s most superficial layer. This set performed well across body sites, ages, sexes, and detection platforms.

Conclusions

This research shows that the clock in epidermis is more robust than dermis regardless of body site. To encourage ongoing validation of this putative biomarker in diverse populations, diseases, and experimental designs, we developed SkinPhaser––a user-friendly app to test biomarker performance in datasets (https://github.com/gangwug/SkinPhaser).
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

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

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

Periplasmic 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

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

Background

Arteriovenous (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.

Methods

We 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.

Discussion

There 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 registration

PROSPERO 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

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.
The Effect of a Paired Lab on Course Completion and Grades in Nonmajors Introductory Biology
Authors: DeFeo Dayna Jean , Bibler Andrew , Gerken Sarah
Published: August 2020

Students who take introductory biology labs have better lecture course outcomes than students who do not take a lab. However, this analysis finds that much of the difference in student performance is attributable to selection bias rather than the lab itself. The data challenge the misconception that labs serve as recitations for lecture content.
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

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

Neurodegenerative 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

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

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.