bluuebunny/crossref_metadata_2025_split huggingface dataset:
Transcript isoforms of Reep6 have distinct functions in the retina
Authors: Liang Qingnan , Wu Nathaniel , Zaneveld Smriti , Liu Hehe , Fu Shangyi , Wang Keqing , Bertrand Renae , Wang Jun , Li Yumei , Chen Rui 
Published: June 2021

Abstract
Much of the complexity of the eukaryotic cell transcriptome is due to the alternative splicing of mRNA. However, knowledge on how transcriptome complexity is translated into functional complexity remains limited. For example, although different isoforms of a gene may show distinct temporal and spatial expression patterns, it is largely unknown whether these isoforms encode proteins with distinct functions matching their expression pattern. In this report, we investigated the function and relationship of the two isoforms of Reep6, namely Reep6.1 and Reep6.2, in rod photoreceptor cells. These two isoforms result from the alternative splicing of exon 5 and show mutually exclusive expression patterns. Reep6.2 is the canonical isoform that is expressed in non-retinal tissues, whereas Reep6.1 is the only expressed isoform in the adult retina. The Reep6.1 isoform-specific knockout mouse, Reep6E5/E5, is generated by deleting exon 5 and a homozygous deletion phenotypically displayed a rod degeneration phenotype comparable to a Reep6 full knockout mouse, indicating that the Reep6.1 isoform is essential for the rod photoreceptor cell survival. Consistent with the results obtained from a loss-of-function experiment, overexpression of Reep6.2 failed to rescue the rod degeneration phenotype of Reep6 knockout mice whereas overexpression of Reep6.1 does lead to rescue. These results demonstrate that, consistent with the expression pattern of the isoform, Reep6.1 has rod-specific functions that cannot be substituted by its canonical isoform. Our findings suggested that a strict regulation of splicing is required for the maintenance of photoreceptor cells.
Maternal stress and sex ratio at birth in Sweden over two and a half centuries: a retest of the Trivers–Willard hypothesis
Authors: Wu Hanbo 
Published: June 2021

AbstractSTUDY QUESTIONIs there a negative relationship, as predicted in the Trivers–Willard hypothesis (TWH), between the intensity of maternal stress and sex ratio at birth (SRB)?SUMMARY ANSWERUsing a comprehensive data set with multiple indicators of maternal stress, most measures of stress show no statistically significant association with SRB over a period spanning 243 years, indicating no support for the TWH.WHAT IS KNOWN ALREADYEvolutionary biologists have proposed a widely discussed hypothesis that women in poor and stressful conditions during pregnancy are more likely to give birth to girls, and exposure to stressful events may therefore lead to a reduction in sex (male-to-female) ratio at birth. The empirical evidence so far is mixed.STUDY DESIGN, SIZE, DURATIONAnnual time series data, spanning 243 years between 1749 and 1991 for Sweden at the national level, were drawn from multiple sources. The outcome is defined as the percentage of male births relative to all births in Sweden in a given year. The covariates include a set of economic and climatic variables as proxies for maternal stress.PARTICIPANTS/MATERIALS, SETTING, METHODSWe conduct a series of ARIMA (autoregressive integrated moving average) models to examine the relationship between maternal stress and SRB during three periods: 1749–1991, 1749–1861 and 1862–1991.MAIN RESULTS AND THE ROLE OF CHANCEIn 1749–1991, economic proxies for maternal stress showed no statistically significant association with SRB. In 1749–1861, two indicators were significantly associated with SRB, but the coefficients were opposite in direction to the TWH. In 1862–1991, five out of six covariates showed no significant association with SRB. An additional analysis found no significant correlation between sex ratio of stillbirths and all covariates in 1862–1991. Our results are incompatible with the TWH and suggest that previous findings in support of the TWH are not robust.LIMITATIONS, REASONS FOR CAUTIONThis study provides population-level evidence that may not necessarily reflect the nature of all individuals due to the ecological fallacy. The time series analysed in this study are annual data, and we cannot examine the potential seasonality due to the lack of disaggregated monthly data. Our findings may not be generalised to the contexts of extreme maternal stress conditions such as famine and war.WIDER IMPLICATIONS OF THE FINDINGSThe results from existing studies in this topic may be speculative, and additional research with more comprehensive design, data and covariates is needed to reconsider the robustness of previous findings.STUDY FUNDING/COMPETING INTEREST(S)The author receives no external funding and has no conflict of interest to declare.TRIAL REGISTRATION NUMBERN/A.
Toxic oil syndrome: health-related quality-of-life assessment using the SF-36 Health Survey
Authors: Posada de la Paz Manuel , Díaz-Guerra Enrique , Alonso-Ferreira Verónica , Villaverde-Hueso Ana , Arias-Merino Greta , Garrido-Estepa Macarena 
Published: June 2021

Abstract

Background
Toxic oil syndrome (TOS) is a multisystemic disease due to a massive intoxication that occurred in Spain in 1981 affecting &gt;20 000 persons. This study aims to evaluate the quality of life of the survivors’ cohort after 38 years of follow-up using the Short Form 36 (SF-36) Health Survey.

Methods
One thousand patients were selected among the 14 084 alive TOS cohort members in 2018 using a stratified random sampling method. Stratification was performed by the 2017 self-rated health status reported by patients. SF-36 results were compared directly and as standardized (T scores) with the Spanish-population reference values. Relationship between self-rated health status and SF-36 results was assessed.

Results
Overall, 900 cohort members participated and 895 valid responses were included in the study. Participants’ average age was 65.2 (standard deviation: 13.8) years and 563 (62.9%) participants were women. Participants’ distribution by self-rated health status was: 219 (24.5%) good/very good, 415 (46.4%) fair and 261 (29.1%) poor/very poor. Quality of life was below the Spanish-population reference in 84% of the TOS patients (87.2% for women and 78.6% for men) for the Physical Component Summary (PCS) and in 75.4% (81.7% for women and 64.8% for men) for the Mental Component Summary (MCS). PCS and MCS scores decreased similarly for both sexes with worse self-rated health.

Conclusions
Very low quality of life and self-rated health, especially for women, were found in the total TOS participants that can be extrapolated to the TOS survivors’ cohort. The TOS cohort still requires standardization of care with integral plans around the country.
Exploring the Effects of Pharmacological, Psychosocial, and Alternative/Complementary Interventions in Children and Adolescents With Attention-Deficit/Hyperactivity Disorder: Meta-Regression Approach
Authors: Yang Kung-Han , Lane Hsien-Yuan , Chang Yue-Cune , Tzang Ruu-Fen 
Published: June 2021

Abstract

Background
There have been various therapies for attention-deficit/hyperactivity disorder (ADHD), but the previous meta-analysis of ADHD efficacy remains unclear. This study aims to systemically meta-regress the effect sizes (ES) of psychostimulant pharmacotherapy (methylphenidate and lisdexamfetamine), non-stimulant pharmacotherapy (atomoxetine and alpha-2 agonists), psychosocial therapy (parental behavioral therapy [PBT]), combination therapy (psychostimulant plus PBT), and alternative/complementary interventions to determine the right treatment for ADHD.

Methods
We searched various ADHD interventions from the MEDLINE and PubMed databases (National Center for Biotechnology Information) between January 1, 1980, and July 30, 2018. Following the meta-analysis of random effects, the meta-regression analyses were used to explore factors potentially influencing treatment efficacy. The confounding variables included type of treatment, type of study, age, type of symptom scale used, and year of publication.

Results
A total of 107 trials (n = 9883 participants) were included. After adjustment, compared with the psychostimulant therapy (28 trial, 2134 participants), non-stimulant pharmacotherapy (28 trials, 4991 participants) and alternative/complement intervention (25 trials, 1195 participants) were less effective by the ES of −0.384 (P = .004) and −0.419 (P = .028), respectively. However, compared with psychostimulant, PBT (19 trials, 1122 participants; ES = −0.308, P = .095) and the combination of psychostimulant and PBT (7 trials, 441participants; ES = −0.196, P = .209) did not differ significantly.

Conclusions
Psychostimulant therapy surpassed non-stimulant pharmacotherapy and alternative/complement intervention. Psychostimulant therapy, PBT, and the combination of psychostimulant therapy and PBT appear to be similar in efficacy according to this meta-regression.
Mobility-related inequality in healthcare utilization between floating and native populations and its influencing factors: evidence from China
Authors: Tang Daisheng , Bu Tao , Liu Yahong 
Published: June 2021

Abstract
Our goal was to examine inequality in healthcare utilization and the factors that contribute to inequality between China's floating and native populations. Based on the China Labor-force Dynamics Surveys from 2014 to 2018, which used three rounds of data, we utilized a panel probit model that included fixed effects for time and province to estimate the probability of healthcare utilization for floating and native populations. In addition, we calculated the degree of inequality in healthcare utilization by using the method of mobility-related inequality and a decomposition approach was used to explain the contribution of each factor to the inequality. The floating population utilized healthcare at a lower rate, with a 10.5% probability of visiting a hospital and a 20.9% probability of receiving hospitalized treatment. The concentration index of mobility-related inequality in healthcare utilization shows a negative coefficient of −0.137 for hospital visits and −0.356 for hospitalized treatment. Contribution decomposition shows that self-assessed health, job category and household registration account for the largest contribution to the inequality in hospital visits, contributing −0.038, 0.021 and −0.017, respectively. Age, household registration and insurance account for the largest contribution to the inequality in hospitalized treatment, contributing −0.053, 0.024 and −0.023, respectively. The floating population was less likely to use health services and faced an inequality in treatment compared with the native population.
Tracking immunization coverage, dropout and equity gaps among children ages 12–23 months in Malawi – bottleneck analysis of the Malawi Demographic and Health Survey
Authors: Mmanga Kondwani , Mwenyenkulu Tisungane E , Nkoka Owen , Ntenda Peter A M 
Published: June 2021

Abstract

Background
Between 2010 and 2016, the proportion of children 12–23 months of age who received full immunization in Malawi decreased from 81% to 76%. Most studies on immunization have mainly focused on the risk factors of vaccination coverage while data on dropouts and equity gaps is very scanty. Thus the aim of the present study was to describe the trend in immunization coverage, dropout rates and effective immunization coverage (EIC) among children ages 12–23 months in Malawi.

Methods
Secondary analyses of the cross-sectional data obtained from the three waves of the Demographic and Health Surveys (2004, 2010 and 2015–16) were conducted. Using bottleneck analysis, outputs were generated based on service coverage, demand/equity (service utilization) and quality (full immunization). The World Health Organization benchmarks were used to assess gaps in the immunization coverage indicators.

Results
The coverage was &gt;90.0% in most of the antigens while full immunization status was estimated at 65%, 84% and 73% in 2004, 2010 and 2015, respectively. The highest coverage was observed in Bacillus Calmette–Guérin (BCG) and lowest in oral polio vaccine 1 (OPV1). OPV1 coverage was &lt;90% in the 2004 cohort year, while pentavalent 3 (Penta3) and measles-containing vaccine 1 (MCV1) coverages were &lt;90% in 2004. Dropout rates of Penta3 and MCV1 were significantly &gt;10% in 2004. The logistic regression analyses showed that children were significantly less likely to be immunized with Penta3 and MCV1 in all cohort years compared with Penta1.

Conclusions
Although immunization coverage was in line with the national and district targets for various antigens, full vaccination coverage (FVC) is still lagging behind. Furthermore, the dropout rates for Penta3 and MCV1 showed upside U-shaped patterns. Thus health education, supervision and orientation of service providers are urgently needed to address disparities that are existing in FVC.
Blockade of checkpoint ILT3/LILRB4/gp49B binding to fibronectin ameliorates autoimmune disease in BXSB/Yaa mice
Authors: Su Mei-Tzu , Inui Masanori , Wong Yi Li , Takahashi Maika , Sugahara-Tobinai Akiko , Ono Karin , Miyamoto Shotaro , Murakami Keiichi , Itoh-Nakadai Ari , Kezuka Dai , Itoi So , Endo Shota , Hirayasu Kouyuki , Arase Hisashi , Takai Toshiyuki 
Published: June 2021

Abstract
The extracellular matrix (ECM) is the basis for virtually all cellular processes and is also related to tumor metastasis. Fibronectin (FN), a major ECM macromolecule expressed by different cell types and also present in plasma, consists of multiple functional modules that bind to ECM-associated, plasma, and cell-surface proteins such as integrins and FN itself, thus ensuring its cell-adhesive and modulatory role. Here we show that FN constitutes an immune checkpoint. Thus, FN was identified as a physiological ligand for a tumor/leukemia/lymphoma- as well as autoimmune-associated checkpoint, ILT3/LILRB4 (B4, CD85k). Human B4 and the murine ortholog, gp49B, bound FN with sub-micromolar affinities as assessed by bio-layer interferometry. The major B4-binding site in FN was located at the N-terminal 30-kDa module (FN30), which is apart from the major integrin-binding site present at the middle of the molecule. Blockade of B4–FN binding such as with B4 antibodies or a recombinant FN30-Fc fusion protein paradoxically ameliorated autoimmune disease in lupus-prone BXSB/Yaa mice. The unexpected nature of the B4–FN checkpoint in autoimmunity is discussed, referring to its potential role in tumor immunity.
Efficacy assessment of lysin CF-296 in addition to daptomycin or vancomycin against Staphylococcus aureus in the murine thigh infection model
Authors: Asempa Tomefa E , DeRosa Nicole A , Cassino Cara , Lehoux Dario , Schuch Raymond , Nicolau David P 
Published: June 2021

Abstract

Objectives
CF-296 is a lysin in pre-clinical development for the treatment of MSSA and MRSA infections, used in addition to standard-of-care (SOC) antibiotics. We evaluated the efficacy of CF-296 alone and in addition to daptomycin or vancomycin against Staphylococcus aureus in the neutropenic mouse thigh infection model.

Methods
Eight isolates (one MSSA and seven MRSA) were studied. Mice were administered five CF-296 monotherapy doses ranging from 0.5 to 50 mg/kg intravenously. To assess adjunctive therapy, mice received sub-therapeutic daptomycin alone, sub-therapeutic vancomycin alone, or the five CF-296 doses in addition to either daptomycin or vancomycin.

Results
Relative to starting inoculum (5.80 ± 0.31 log10 cfu/thigh), bacterial density in vehicle controls increased by +2.49 ± 0.98 across all eight strains. Relative to 24 h controls, a dose–response in bacterial killing (range −0.22 ± 0.87 to −2.01 ± 1.71 log10 cfu/thigh) was observed with increasing CF-296 monotherapy against the eight isolates. Daptomycin and vancomycin resulted in −1.36 ± 0.77 and −1.37 ± 1.01 log10 cfu/thigh bacteria reduction, respectively, relative to 24 h controls. Escalating CF-296 exposures (0.5–50 mg/kg) in addition to daptomycin resulted in an enhanced dose–response, ranging from bacterial killing of −0.69 to −2.13 log10 cfu/thigh, relative to daptomycin alone. Similarly, in addition to vancomycin, escalating CF-296 exposures resulted in bacterial reduction ranging from −1.37 to −2.29 log10 cfu/thigh, relative to vancomycin alone.

Conclusions
Relative to SOC antibiotics (daptomycin or vancomycin), addition of CF-296 resulted in robust and enhanced antibacterial dose–response, achieving ≥1 log10 cfu/thigh decrease across most doses, highlighting a potential role for CF-296 adjunctive therapy against MSSA and MRSA isolates.
Impact of implementing electronic prior authorization on medication filling in an electronic health record system in a large healthcare system
Authors: Lauffenburger Julie C , Stults Cheryl D , Mudiganti Satish , Yan Xiaowei , Dean-Gilley Lisa M , He Mengdong , Tong Angela , Fischer Michael A 
Published: June 2021

Abstract

Objective
Medications frequently require prior authorization from payers before filling is authorized. Obtaining prior authorization can create delays in filling prescriptions and ultimately reduce patient adherence to medication. Electronic prior authorization (ePA), embedded in the electronic health record (EHR), could remove some barriers but has not been rigorously evaluated. We sought to evaluate the impact of implementing an ePA system on prescription filling.

Materials and Methods
ePA was implemented in 2 phases in September and November 2018 in a large US healthcare system. This staggered implementation enabled the later-implementing sites to be controls. Using EHR data from all prescriptions written and linked information on whether prescriptions were filled at pharmacies, we 1:1 matched ePA prescriptions with non-ePA prescriptions for the same insurance plan, medication, and site, before and after ePA implementation, to evaluate primary adherence, or the proportion of prescriptions filled within 30 days, using generalized estimating equations. We also conducted concurrent analyses across sites during the peri-implementation period (Sept–Oct 2018).

Results
Of 74 546 eligible ePA prescriptions, 38 851 were matched with preimplementation controls. In total, 24 930 (64.2%) ePA prescriptions were filled compared with 26 731 (68.8%) control prescriptions (Adjusted Relative Risk [aRR]: 0.92, 95%CI: 0.91–0.93). Concurrent analyses revealed similar findings (64.7% for ePA vs 62.3% control prescriptions, aRR: 1.03, 95%CI: 0.98–1.09).

Discussion
Challenges with implementation, such as misfiring and insurance fragmentation, could have undermined its effectiveness, providing implications for other health informatics interventions deployed in outpatient care.

Conclusion
Despite increasing interest in implementing ePA to improve prescription filling, adoption did not change medication adherence.
Programming of postnatal phenotype caused by exposure of cultured embryos from Brahman cattle to colony-stimulating factor 2 and serum
Authors: Estrada-Cortés Eliab , Jannaman Elizabeth A , Block Jeremy , Amaral Thiago F , Hansen Peter J 
Published: June 2021

AbstractAlterations in the environment of the preimplantation embryo can affect competence to establish pregnancy and phenotype of resultant calves. In this study, the bovine embryo produced in vitro was used to evaluate postnatal programming actions of the embryokine colony-stimulating factor 2 (CSF2) and serum, which is a common additive of culture media. Oocytes were collected by ovum pick up from Brahman donors and fertilized with semen from Brahman bulls. Embryos were randomly assigned to one of the three treatments: vehicle, CSF2 10 ng/mL, or 1% (v/v) serum. Treatments were added to the culture medium from day 5 to 7 after fertilization. Blastocysts were harvested on day 7 and transferred into crossbred recipients. Postnatal body growth and Longissimus dorsi muscle characteristics of the resultant calves were measured. The percent of cleaved embryos becoming blastocysts was increased by serum and, to a lesser extent, CSF2. Treatment did not affect survival after embryo transfer but gestation length was shortest for pregnancies established with serum-treated embryos. Treatment did not significantly affect postnatal body weight or growth. At 3 mo of age, CSF2 calves had lower fat content in the Longissimus dorsi muscle and less subcutaneous fat over the muscle than vehicle calves. There was a tendency for cross-sectional area of the muscle to be smaller for serum calves than vehicle calves. Results confirm the importance of the preimplantation period as a window to modulate postnatal phenotype of resultant calves. In particular, CSF2 exerted actions during the preimplantation period to program characteristics of accumulation of intramuscular and subcutaneous fat of resultant calves. The use of a low serum concentration in culture medium from day 5 to 7 of development can increase the yield of transferrable embryos without causing serious negative consequences for the offspring.
Congestion in highways when tolls and railroads matter: evidence from European cities
Authors: Garcia-López Miquel-Àngel , Pasidis Ilias , Viladecans-Marsal Elisabet 
Published: June 2021

Abstract
Using data from the 545 largest European cities, we study whether the expansion of their highway capacity provides a solution to the problem of traffic congestion. Our results confirm that in the long run, and in line with the ‘fundamental law of highway congestion’, the expansion in cities of lane kilometres causes an increase in vehicle traffic that does not solve urban congestion. We disentangle the increase in traffic due to the increases in coverage and in capacity. We further introduce road pricing and public transit policies in order to test whether they moderate congestion. Our findings confirm that the induced demand is considerably smaller in cities with road pricing schemes, and that congestion decreases with the expansion of public transportation.
Genetic Background of the Polish Primitive Horse (Konik) Coat Color Variation—New Insight into Dun Dilution Phenotypic Effect
Authors: Cieslak Jakub , Brooks Samantha Ann , Wodas Lukasz , Mantaj Weronika , Borowska Alicja , Sliwowska Joanna Helena , Ziarniak Kamil , Mackowski Mariusz 
Published: June 2021

Abstract
Only the blue dun coat color, produced by the action of the dun allele on the background of a black base coat, is officially permitted in the Polish primitive horse (PPH, Konik) breed, yet the population is not visually homogenous and various coat color shades occur. Herein, the molecular background of PPH coat color was studied based on genotyping of known causative variants in equine coat color-related genes (ASIP, MC1R, TBX3, SLC36A1, SLC45A2, PMEL17, and RALY). Additionally, screening for the new polymorphisms was conducted for the ASIP gene coding sequence and the TBX3 1.6-kb insert (associated with the dun dilution). We did not observe the champagne, silver, or cream color dilution variants in the PPH breed. A significant association (P &lt; 0.01) was recorded for the genotype in TBX3 gene 1.6 kb in/del and the degree of dun coat dilution, demonstrating that the dominant action of the dun mutation is not fully penetrant. In addition to the effect of the 1.6 kb in/del zygosity, variants within the TBX3 insert were significantly associated with PPH coat color variability (P &lt; 0.01), suggesting the presence of an additional allele at this locus. Finally, we identified a high frequency (35%) of genetically bay dun-colored PPH individuals that are officially recorded as blue (black base coat) duns. We propose that the difficulty in distinguishing these 2 phenotypes visually is due to an independent locus upstream of the ASIP gene, which was recently described as darkening the typical bay pigmentation shade.