bluuebunny/crossref_metadata_2025 huggingface dataset:
Trajectory of migraine-related disability following long-term treatment with lasmiditan: results of the GLADIATOR study
Authors: Lipton Richard B. , Lombard Louise , Ruff Dustin D. , Krege John H. , Loo Li Shen , Buchanan Andrew , Melby Thomas E. , Buse Dawn C.
Published: February 2020

Background

Migraine is recognized as the second leading cause of disability globally. Lasmiditan is a novel, selective serotonin 5-HT1F receptor agonist developed for acute treatment of migraine. Here we analyzed effects of lasmiditan on migraine disability assessed with the Migraine Disability Assessment (MIDAS) scale for interim data from a long-term safety study.

Methods

Completers of two single-attack parent studies were offered participation in the 1 year GLADIATOR study, that randomized participants to treatment with lasmiditan 100 mg or 200 mg taken as needed for migraine attacks of at least moderate severity. Changes in MIDAS were modeled using a mixed model repeated measures analysis.

Results

The sample included 1978 patients who received ≥1 lasmiditan dose and were followed for a median of 288 days. Baseline mean MIDAS scores for the lasmiditan 100-mg and 200-mg groups were 29.4 and 28.9, respectively, indicating severe migraine-related disability. Relative to baseline, MIDAS total scores were significantly lower at 3, 6, 9, and 12 months for both dose groups. At 12 months, changes in MIDAS scores were − 12.5 and − 12.2 for lasmiditan 100 mg and 200 mg, respectively, with 49% and 53% of patients, respectively, achieving at least a 50% decrease in MIDAS total score. Statistically significant improvements were also seen for work and/or school absenteeism and presenteeism, monthly headache days, and mean headache pain intensity at all time points up to 1 year. Findings for patients who completed all visits versus those dropping out early were similar. Responses were generally similar for the lasmiditan 100 mg or 200 mg doses, between subgroups defined based on the number of baseline monthly migraine attacks (≤5 vs. >5), and also between subgroups defined by pain-free response (yes/no) during initial attacks.

Conclusions

Long-term treatment with lasmiditan was associated with significant reductions in migraine-related disability, including both work or school absenteeism and presenteeism. The similarity of responses in completers and those who dropped out suggests that selective attrition does not account for the improvements. Benefits were significant at 3 months and maintained through 12 months.

Trial registration

clinicaltrials.govNCT02565186; first posted October 1, 2015.
The effects of vitamin D supplementation on interictal serum levels of calcitonin gene-related peptide (CGRP) in episodic migraine patients: post hoc analysis of a randomized double-blind placebo-controlled trial
Authors: Ghorbani Zeinab , Rafiee Pegah , Fotouhi Akbar , Haghighi Samane , Rasekh Magham Reyhaneh , Ahmadi Zeynab Sadat , Djalali Mahmoud , Zareei Mahnaz , Razeghi Jahromi Soodeh , Shahemi Sahar , Mahmoudi Maryam , Togha Mansoureh
Published: February 2020

Background

Emerging evidence showed promising effects of vitamin D on headaches characteristics. Thus, it seems there is still a need for more researches to clarify the mechanisms by which this vitamin exerts anti-migraine effects.

Methods

The present study was conducted as a 16-week randomized double-blind placebo-controlled trial on 80 episodic migraine patients allocated in 2 parallel groups each consisted of 40 patients who received vitamin D 2000 IU/d or placebo. At baseline and after the intervention completion, headache diaries and migraine disability assessment questionnaire (MIDAS) were used to assess migraine related variables in patients. Also, interictal serum concentration of calcitonin gene-related peptide (CGRP) (as the dominant mediator of migraine pain pathogenesis) was evaluated using ELISA method.

Results

The mean (SD) of age in the vitamin D and placebo groups was 37 (8) and 38 (12) years, respectively. ANCOVA test adjusted for baseline values, and confounders showed vitamin D supplementation resulted in a significant improvement in MIDAS score after 12 weeks in the intervention group (21.49 (16.22–26.77)) compared to placebo (31.16 (25.51–36.82) P value: 0.016). Moreover, after controlling for baseline levels, and other variables using ANCOVA, CGRP level was appeared to be significantly lower following vitamin D supplementation (153.26 (133.03–173.49) ng/L) than the patients in the placebo arm (188.35 (167.15–209.54) ng/L) (P value = 0.022).

Conclusion

According to the current findings, vitamin D supplementation in episodic migraineurs, particularly in those with migraine with aura, may potentially improve migraine headache characteristics and disability probably through attenuating CGRP levels. Therefore, these results could provide a new insight into anti-nociceptive effects of vitamin D; however, more studies are required to confirm our findings.

Trial registration

The trial is registered in the Iranian registry of clinical trials (IRCT) at 11 July 2018, with IRCT code: IRCT20151128025267N6.
Deep learning versus parametric and ensemble methods for genomic prediction of complex phenotypes
Authors: Abdollahi-Arpanahi Rostam , Gianola Daniel , Peñagaricano Francisco
Published: February 2020

Background

Transforming large amounts of genomic data into valuable knowledge for predicting complex traits has been an important challenge for animal and plant breeders. Prediction of complex traits has not escaped the current excitement on machine-learning, including interest indeep learningalgorithms such as multilayer perceptrons (MLP) and convolutional neural networks (CNN). The aim of this study was to compare the predictive performance of two deep learning methods (MLP and CNN), two ensemble learning methods [random forests (RF) and gradient boosting (GB)], and two parametric methods [genomic best linear unbiased prediction (GBLUP) and Bayes B] using real and simulated datasets.

Methods

The real dataset consisted of 11,790 Holstein bulls with sire conception rate (SCR) records and genotyped for 58k single nucleotide polymorphisms (SNPs). To support the evaluation of deep learning methods, various simulation studies were conducted using the observed genotype data as template, assuming a heritability of 0.30 with either additive or non-additive gene effects, and two different numbers of quantitative trait nucleotides (100 and 1000).

Results

In the bull dataset, the best predictive correlation was obtained with GB (0.36), followed by Bayes B (0.34), GBLUP (0.33), RF (0.32), CNN (0.29) and MLP (0.26). The same trend was observed when using mean squared error of prediction. The simulation indicated that when gene action was purely additive, parametric methods outperformed other methods. When the gene action was a combination of additive, dominance and of two-locus epistasis, the best predictive ability was obtained with gradient boosting, and the superiority of deep learning over the parametric methods depended on the number of loci controlling the trait and on sample size. In fact, with a large dataset including 80k individuals, the predictive performance of deep learning methods was similar or slightly better than that of parametric methods for traits with non-additive gene action.

Conclusions

For prediction of traits with non-additive gene action, gradient boosting was a robust method. Deep learning approaches were not better for genomic prediction unless non-additive variance was sizable.
An eQTL in the cystathionine beta synthase gene is linked to osteoporosis in laying hens
Authors: De Koning Dirk-Jan , Dominguez-Gasca Nazaret , Fleming Robert H. , Gill Andrew , Kurian Dominic , Law Andrew , McCormack Heather A. , Morrice David , Sanchez-Rodriguez Estefania , Rodriguez-Navarro Alejandro B. , Preisinger Rudolf , Schmutz Matthias , Šmídová Veronica , Turner Frances , Wilson Peter W. , Zhou Rongyan , Dunn Ian C.
Published: February 2020

Background

Skeletal damage is a challenge for laying hens because the physiological adaptations required for egg laying make them susceptible to osteoporosis. Previously, we showed that genetic factors explain 40% of the variation in end of lay bone quality and we detected a quantitative trait locus (QTL) of large effect on chicken chromosome 1. The aim of this study was to combine data from the commercial founder White Leghorn population and the F2 mapping population to fine-map this QTL and understand its function in terms of gene expression and physiology.

Results

Several single nucleotide polymorphisms on chromosome 1 between 104 and 110 Mb (galGal6) had highly significant associations with tibial breaking strength. The alternative genotypes of markers of large effect that flanked the region had tibial breaking strengths of 200.4 vs. 218.1 Newton (P < 0.002) and, in a subsequent founder generation, the higher breaking strength genotype was again associated with higher breaking strength. In a subsequent generation, cortical bone density and volume were increased in individuals with the better bone genotype but with significantly reduced medullary bone quality. The effects on cortical bone density were confirmed in a further generation and was accompanied by increased mineral maturity of the cortical bone as measured by infrared spectrometry and there was evidence of better collagen cross-linking in the cortical bone. Comparing the transcriptome of the tibia from individuals with good or poor bone quality genotypes indicated four differentially-expressed genes at the locus, one gene,cystathionine beta synthase(CBS), having a nine-fold higher expression in the genotype for low bone quality. The mechanism wascis-acting and although there was an amino-acid difference in the CBS protein between the genotypes, there was no difference in the activity of the enzyme. Plasma homocysteine concentration, the substrate of CBS, was higher in the poor bone quality genotype.

Conclusions

Validated markers that predict bone strength have been defined for selective breeding and a gene was identified that may suggest alternative ways to improve bone health in addition to genetic selection. The identification of how genetic variants affect different aspects of bone turnover shows potential for translational medicine.
Late viral or bacterial respiratory infections in lung transplanted patients: impact on respiratory function
Authors: Dubert Marie , Visseaux Benoit , Birgy André , Mordant Pierre , Metivier Anne-Cécile , Dauriat Gaelle , Fidouh Nadhira , Yazdanpanah Yazdan , Grall Nathalie , Castier Yves , Mal Hervé , Thabut Gabriel , Lescure François-Xavier
Published: February 2020

Background

Respiratory infections are a major threat for lung recipients. We aimed to compare with a monocentric study the impact of late viral and bacterial respiratory infections on the graft function.

Methods

Patients, who survived 6 months or more following lung transplantation that took place between 2009 and 2014, were classified into three groups: a viral infection group (VIG) (without any respiratory bacteria), a bacterial infection group (BIG) (with or without any respiratory viruses), and a control group (CG) (no documented infection). Chronic lung allograft dysfunction (CLAD) and acute rejection were analysed 6 months after the inclusion in the study.

Results

Among 99 included lung recipients, 57 (58%) had at least one positive virological respiratory sample during the study period. Patients were classified as follows: 38 in the VIG, 25 in the BIG (among which 19 co-infections with a virus) and 36 in the CG. The BIG presented a higher initial deterioration in lung function (p = 0.05) than the VIG. But 6 months after the infection, only the VIG presented a median decrease of forced expiratory volume in 1 s; − 35 mL (IQR; − 340; + 80) in the VIG, + 140 mL (+ 60;+ 330) in the BIG and + 10 (− 84;+ 160) in the CG, p < 0.01. Acute rejection was more frequent in the VIG (n = 12 (32%)), than the BIG (n = 6 (24%)) and CG (n = 3 (8%)), p < 0.05, despite presenting no more CLAD (p = 0.21).

Conclusions

Despite a less severe initial presentation, single viral respiratory infections seem to lead to a greater deterioration in lung function, and to more acute rejection, than bacterial infections.
How shoulder immobilization influences daily physical activity – an accelerometer based preliminary study
Authors: Rickert Carolin , Grabowski Monika , Gosheger Georg , Schorn Dominik , Schneider Kristian Nikolaus , Klingebiel Sebastian , Liem Dennis
Published: February 2020

Background

To investigate the influence of shoulder immobilization on daily physical activity.

Introduction

The harmful effect of sedentary behavior does not receive much attention in orthopedic surgery even though immobilization, especially of the lower extremity, has been associated with reduced physical activity. Immobilization of the shoulder is common after reconstructive shoulder surgery and could also potentially lead to reduced physical activity and have a negative effect on a patient’s general health.

Method

Twenty-one healthy volunteers were immobilized in an orthosis (DJO Ultrasling III) for 10 h on two consecutive days. In the following week, activity was measured on the same days without the orthosis. Activity including gait cycles per minute and total gait cycles per day was measured by accelerometer based step count StepWatchTMActivity Monitor. Average age was 26 +/− 3 years. A questionnaire was administered to evaluate subjective activity.

Results

Participants wearing the shoulder orthosis were significantly less active than without immobilization by 2227.5 gait cycles/day (5501.2 with SO, 7728.7 without SO). Also, significantly more time in sedentary behavior occurred (< 400 steps/h) when the shoulder was immobilized. Patients were significantly more active without shoulder orthosis in medium level activities (800–999 steps/h). Differences for low (400–799 steps/h) and high activity levels (> 1000 steps/h) were not statistically significant. Subjective limitations while wearing the orthosis were graded at 2.343 on a scale of 0–4.

Conclusion

Results of this study show that even in young, healthy volunteers immobilization of the shoulder in an orthosis for 2 days leads to significantly reduced activity levels. A negative influence on general health, especially in older patients who are immobilized for up to 6 weeks, can potentially occur. Promoting physical activity during the immobilization period should be part of rehabilitation after injuries/surgery of the shoulder.

Trial registration

Retrospectively registered in DRKS (DRKS00017636).
Intraoperative injection of absorbable gelatin sponge (AGS) mixed with cement followed by spinal decompression to treat elderly with vertebral hemangiomas
Authors: Xu Weihong , Lan Zhibin , Huang Yuming
Published: February 2020

Background

Elderly patients with vertebral hemangiomas are rare and might require surgery. Thus, the choice of surgery for these lesions remains controversial because of the rarity of these lesions. This study aimed to analyze the clinical efficacy of the intraoperative injection of absorbable gelatin sponge mixed with cement followed by spinal decompression to treat the elderly with typical vertebral hemangiomas. The risk factors for hemangioma recurrence were investigated through a literature review.

Methods

We retrospectively analyzed 13 patients with typical aggressive hemangiomas between January 2009 and January 2016. Of these patients, 7 were treated with spinal decompression combined with intraoperative vertebroplasty (Group A), and 6 patients were treated with decompression with intraoperative vertebroplasty and absorbable gelatin sponge (Group B). The general data and perioperative data of the patients were compared. Patients were followed up for at least 3 years, and postoperative complications and recurrence rates were recorded and compared.

Results

All patients had typical aggressive hemangiomas. The average age of all patients was 64.4 ± 3.3 years. The preoperative data did not differ significantly between the two groups (P > 0.05). The blood loss of groups A and B was 707.1 ± 109.7 ml and 416.7 ± 103.3 ml, respectively (P = 0.003) (P = 0.003), and the average surgery durations were 222 ± 47.8 min and 162 ± 30.2 min, respectively (P = 0.022). The average follow-up duration was 62 ± 19 months, and no cases of recurrence were found at the final follow-up assessment.

Conclusions

Multimodal treatment significantly alleviated the clinical symptoms of elderly patients with typical aggressive vertebral hemangiomas. Intraoperative absorbable gelatin sponge injection is a safe and effective way to reduce blood loss and surgery duration.
Influences of health facility type for delivery and experience of cesarean section on maternal and newborn postnatal care between birth and facility discharge in Malawi
Authors: Kim Eunsoo Timothy , Singh Kavita , Speizer Ilene S. , Lemani Clara
Published: February 2020

Background

A number of studies in the past have looked at determinants of postnatal care. However, many of them do not distinguish between postnatal care (PNC) before discharge and after discharge for women delivering at health facilities. Conceptually and practically, factors associated with PNC before discharge and after discharge should be different. This study examines key factors for maternal and newborn PNC before discharge.

Methods

Data from the 2015–16 Malawi Demographic and Health Survey were used for the study. Three categorical endogenous variables examined in the study were whether or not mothers received a postnatal check between birth and facility discharge, whether or not newborns received a postnatal check between birth and facility discharge and whether or not women delivered by cesarean section. Delivery by cesarean section was considered as a mediator in the model. The main predictor of interest was type of health facility where women delivered. Other exogenous variables included were women’s age at most recent birth, number of antenatal visits, women’s education, household wealth, parity, newborn size, region of the country and residence. Simultaneous equation modeling was used to examine the associations of interest.

Results

47% of the mothers and 68% of the newborns had PNC before facility discharge. The total and direct effects of delivering in private hospitals on maternal and newborn PNC before facility discharge were significantly higher than the effects of delivering in government hospitals. The total effects of delivering in government health centers or health posts on maternal and newborn PNC before facility discharge were significantly lower than the effects of delivering in government hospitals. Delivering by cesarean section compared to delivering vaginally was positively associated with maternal and newborn PNC before facility discharge.

Conclusion

It is important that all women and newborns receive PNC before they are discharged from the facility regardless of whether or not they had a complication. The same standard of quality PNC should be provided equitably across all types and affiliations of health facilities.
Understanding in the Australian aged care sector of reablement interventions for people living with dementia: a qualitative content analysis
Authors: O’Connor Claire M. C. , Gresham Meredith , Poulos Roslyn G. , Clemson Lindy , McGilton Katherine S. , Cameron Ian D. , Hudson Wendy , Radoslovich Helen , Jackman Joan , Poulos Christopher J.
Published: February 2020

Background

Reablement has potential for enhancing function and independence in people with dementia. In order to enhance the use of evidence-based reablement in this population, this study sought to understand the current practices and needs of the sector around these interventions.

Methods

A purposive sample of 22 Australian aged and community-care providers participated in a semi-structured interview. Qualitative content analysis was applied to the data, with key themes interpreted within the context of the study aims: to explore (1) what reablement interventions are currently being offered to people living with dementia in Australia, and (2) what are key factors that will contribute to enhanced uptake of reablement interventions in dementia practice.

Results

Four themes emerged: (1) ‘what reablement interventions are being offered’, outlined a range of exercise and cognitive/social interventions, with only a proportion generated from a clear evidence-base, (2) ‘what’s in a name’, illustrated the range of terms used to describe reablement, (3) ‘whose role is it’, highlighted the confusion around the range of health professionals involved in providing reablement interventions, and (4) ‘perceived barriers and enablers to providing reablement to people living with dementia’, described a range of factors that both hinder and support current reablement practice.

Conclusions

Reablement interventions currently provided for people living with dementia in Australia are variable, with confusion around the definition of reablement, and apparently limited use of evidence-informed interventions. A multifaceted approach involving an evidence-informed and freely-accessible resource, and taking into account the varied levels of influence within the aged care sector would support uptake and implementation of reablement interventions for people living with dementia.
Sharing responsibility: municipal health professionals’ approaches to goal setting with older patients with multi-morbidity – a grounded theory study
Authors: Oksavik Jannike Dyb , Kirchhoff Ralf , Sogstad Maren Kristine Raknes , Solbjør Marit
Published: February 2020

Background

Recent health policy promoting integrated care emphasizes to increase patients’ health, experience of quality of care and reduce care utilization. Thus, health service delivery should be co-produced by health professionals and individual patients with multiple diseases and complex needs. Collaborative goal setting is a new procedure for older patients with multi-morbidity. The aim is to explore municipal health professionals’ experiences of collaborative goal setting with patients with multi-morbidity aged 80 and above.

Methods

A qualitative study with a constructivist grounded theory approach. In total twenty-four health professionals from several health care services in four municipalities, participated in four focus group discussions.

Results

Health professionals took four approaches to goal setting with older patients with multi-morbidity: motivating for goals, vicariously setting goals, negotiating goals, and specifying goals. When ‘motivating for goals’, they educated reluctant patients to set goals. Patients’ capacity or willingness to set goals could be reduced, due to old age, illness or less knowledge about the health system. Health professionals were ‘vicariously setting goals’ when patients did not express or take responsibility for goals due to adaptation processes to disease, or symptoms as cognitive impairment or exhaustion. By ‘Negotiating goals’, health professionals handled disagreements with patients, and often relatives, who expected to receive more services than usual care. They perceived some patients as passive or having unrealistic goals to improve health. ‘Specifying goals’ was a collaboration. Patients currently treated for one condition, set sub-goals to increase health. Patients with complex diseases prioritized one goal to maintain health. These approaches constitute a conceptual model of how health professionals, to varying extents, share responsibility for goal setting with patients.

Conclusions

Goal setting for patients with multi-morbidity were carried out in an interplay between patients’ varying levels of engagement and health professionals’ attitudes regarding to what extents patients should be responsible for pursuing the integrated health services’ objectives. Even though goal setting seeks to involve patients in co-production of their health service delivery, the health services´ aims and context could restrict this co-production.
Clinical and histologic tissue responses of skin incisions closed with glycomer 631 and lactomer 9–1 using a subcuticular technique in pigs
Authors: Plavec Tanja , Švara Tanja , Zdovc Irena , Gombač Mitja , Damjanovska Marija , Stopar Pintarič Tatjana , Cvetko Erika , Seliškar Alenka
Published: February 2020

Background

Glycomer 631 and lactomer 9–1 are absorbable suture materials indicated for soft tissue approximation in non-infected wounds. Pigs are often used as surgical models in translational research; however, reports of tissue reactions to both suture materials in pigs are limited. The aim of this study was to assess clinical and histologic responses of skin incisions closed with a subcuticular technique using glycomer 631 and lactomer 9–1 in pigs.

Results

Skin incisions on 17 pigs were closed with glycomer 631 and lactomer 9–1, and a clinical reactive score (CRS) including erythema, swelling, discharge and dehiscence was calculated on postoperative days 7 and 14. Subcuticular tissue reaction was assessed histologically on postoperative day 14 (the presence of extravascular neutrophils, macrophages, multinucleated giant cells, lymphocytes, fibroblasts, bacterial colonies and the overall severity of the inflammatory response to the suture material), and the cumulative score of the variables was calculated as an aggregate tissue irritation score (ATIS). Tissue samples were examined for suture extrusion and evaluated microbiologically. The clinical reactive score did not differ between the suture materials. Only one ATIS variable, namely the overall severity of the inflammatory response, was lower (p = 0.029) when glycomer 631 was used. Suture extrusion was found in 10/17 of the incisions closed by glycomer 631 and in 7/13 of the incisions closed by lactomer 9–1. Trueperella pyogenes was isolated from the skin and from the area of tissue reaction in six pigs.

Conclusions

No difference in CRS between the suture materials was observed, and thus both materials may be used for the subcuticular technique in pigs. Glycomer 631 induced less tissue reaction only in terms of the overall severity of the inflammatory response. Suture extrusion was observed in more than 50% of incisions regardless of the suture material, possibly due to a large amount of suture material in the wound. Trueperella pyogenes was the only pathogen isolated from the tissue surrounding the suture material.
Impact of mutations in DNA methylation modification genes on genome-wide methylation landscapes and downstream gene activations in pan-cancer
Authors: Lee Chai-Jin , Ahn Hongryul , Jeong Dabin , Pak Minwoo , Moon Ji Hwan , Kim Sun
Published: February 2020

Background

In cancer, mutations of DNA methylation modification genes have crucial roles for epigenetic modifications genome-wide, which lead to the activation or suppression of important genes including tumor suppressor genes. Mutations on the epigenetic modifiers could affect the enzyme activity, which would result in the difference in genome-wide methylation profiles and, activation of downstream genes. Therefore, we investigated the effect of mutations on DNA methylation modification genes such as DNMT1, DNMT3A, MBD1, MBD4, TET1, TET2 and TET3 through a pan-cancer analysis.

Methods

First, we investigated the effect of mutations in DNA methylation modification genes on genome-wide methylation profiles. We collected 3,644 samples that have both of mRNA and methylation data from 12 major cancer types in The Cancer Genome Atlas (TCGA). The samples were divided into two groups according to the mutational signature. Differentially methylated regions (DMR) that overlapped with the promoter region were selected using minfi and differentially expressed genes (DEG) were identified using EBSeq. By integrating the DMR and DEG results, we constructed a comprehensive DNA methylome profiles on a pan-cancer scale. Second, we investigated the effect of DNA methylations in the promoter regions on downstream genes by comparing the two groups of samples in 11 cancer types. To investigate the effects of promoter methylation on downstream gene activations, we performed clustering analysis of DEGs. Among the DEGs, we selected highly correlated gene set that had differentially methylated promoter regions using graph based sub-network clustering methods.

Results

We chose an up-regulated DEGs cluster where had hypomethylated promoter in acute myeloid leukemia (LAML) and another down-regulated DEGs cluster where had hypermethylated promoter in colon adenocarcinoma (COAD). To rule out effects of gene regulation by transcription factor (TF), if differentially expressed TFs bound to the promoter of DEGs, that DEGs did not included to the gene set that effected by DNA methylation modifiers. Consequently, we identified 54 hypomethylated promoter DMR up-regulated DEGs in LAML and 45 hypermethylated promoter DMR down-regulated DEGs in COAD.

Conclusions

Our study on DNA methylation modification genes in mutated vs. non-mutated groups could provide useful insight into the epigenetic regulation of DEGs in cancer.
Discovering weaker genetic associations guided by known associations
Authors: Wang Haohan , Vanyukov Michael M. , Xing Eric P. , Wu Wei
Published: February 2020

Background

The current understanding of the genetic basis of complex human diseases is that they are caused and affected by many common and rare genetic variants. A considerable number of the disease-associated variants have been identified by Genome Wide Association Studies, however, they can explain only a small proportion of heritability. One of the possible reasons for the missing heritability is that many undiscovered disease-causing variants are weakly associated with the disease. This can pose serious challenges to many statistical methods, which seems to be only capable of identifying disease-associated variants with relatively stronger coefficients.

Results

In order to help identify weaker variants, we propose a novel statistical method, Constrained Sparse multi-locus Linear Mixed Model (CS-LMM) that aims to uncover genetic variants of weaker associations by incorporating known associations as a prior knowledge in the model. Moreover, CS-LMM accounts for polygenic effects as well as corrects for complex relatednesses. Our simulation experiments show that CS-LMM outperforms other competing existing methods in various settings when the combinations of MAFs and coefficients reflect different scenarios in complex human diseases.

Conclusions

We also apply our method to the GWAS data of alcoholism and Alzheimer’s disease and exploratively discover several SNPs. Many of these discoveries are supported through literature survey. Furthermore, our association results strengthen the belief in genetic links between alcoholism and Alzheimer’s disease.
Analysis of trends of malaria from 2010 to 2017 in Boricha District, Southern Ethiopia
Authors: Dabaro Desalegn , Birhanu Zewdie , Yewhalaw Delenasaw
Published: February 2020

Background

Ethiopia has made a significant progress of malaria control. Currently, the country has adopted and is implementing the World Health Organization very ambitious, but achievable, malaria elimination plan through extensive efforts. The regular evaluation of its performance is vital for plausible improvement. Thus, the aim of this study was to determine the trends of malaria infection in Boricha district, Southern Ethiopia.

Methods

A retrospective study was conducted in all health facilities of the district. All malaria cases registered during 2010 to 2017 were reviewed to determine the trends of malaria morbidity. EpiData 3.1 was used for data entry and data were analysed using SPSS version 20.0.

Results

A total of 135,607 malaria suspects were diagnosed using microscopy and rapid diagnostic test over the last 8 years, of which 29,554 (21.8%) were confirmed positive cases. Plasmodium falciparum, Plasmodium vivax and mixed infections (both species) accounted for 56.3%, 38.4% and 5.2% of cases, respectively. Except in 2013 and 2014, Plasmodium falciparum was the dominant species over P. vivax. Of the total confirmed cases 51.6% were adults (≥ 15 years) followed by 24.5% of 5–14 years, and 23.9% of under 5 years. In general, malaria morbidity was significantly reduced over the last 8 years. The positivity rate declined from 54.6% to 5% during 2010 to 2017, and the case incidence rate per 1000 population at risk also declined from 18.9 to 2.2 during the same period. Malaria was reported in all months of the year, with peaks in November, followed by September and July. Malaria transmission has strong association with season (x2 = 303.955, df = 22, p < 0.0001).

Conclusion

In general, a significant reduction of malaria morbidity was observed over the past 8 years. However, further investigation using advanced diagnostic tools is vital to determine the level of sub-microscopic infections to guide the elimination plan. In addition, eco-epidemiological analysis at fine-scale level is essential to devise area-specific interventions.
The sensibility of the new blood lipid indicator——atherogenic index of plasma (AIP) in menopausal women with coronary artery disease
Authors: Guo Qianyun , Zhou Shu , Feng Xunxun , Yang Jiaqi , Qiao Jiaming , Zhao Yingxin , Shi Dongmei , Zhou Yujie
Published: February 2020

Background

Dyslipidemia is a key driver of coronary artery disease (CAD) development. This study aimed to determine whether the atherogenic index of plasma (AIP), a novel comprehensive lipid index, is an independent and reliable predictor of CAD risk in postmenopausal women.

Methods

A cohort of consecutive 4644 postmenopausal women (aged 50 or above) undergoing coronary angiography (CAG) in Anzhen Hospital (Beijing, China) from January–December 2014 was included in the analysis. Of them, 3039 women were CAD patients, and 1605 were non-CAD subjects.

Results

Relative to control subjects, TG levels in CAD patients were higher and HDL-C levels were lower. In CAD patients, non-traditional lipid profile values (TC/HDL-C, AI, and AIP) were significantly elevated relative to controls. AIP was positively correlated with TC (r = 0.157), TG (r = 0.835), LDL-C (r = 0.058), non-HDL-C (r = 0.337), TC/HDL-C (r = 0.683), LDL-C/HDL-C (r = 0.437), LCI (r = 0.662), and AI (r = 0.684), and negatively correlated with HDL-C (r = − 0.682) (all P < 0.001), but was independent of age (r = − 0.022; P = 0.130) and BMI (r = 0.020, P = 0.168). Aunivariate logistic regression analysis revealed AIP to be the measured lipid parameter most closely related to CAD, and its unadjusted odds ratio was 1.824 (95% CI: 1.467–2.267, P < 0.001). After adjusting for several CAD risk factors (age, BMI, smoking, drinking, EH, DM, hyperlipidemia, and family history of CVD, AIP was still found to represent a significant CAD risk factor (OR 1.553, 95% CI: 1.234–1.955, P < 0. 001).

Conclusion

AIP may be a powerful independent predictor of CAD risk in Chinese Han postmenopausal women, and may be superior to the traditional lipid indices.
TRAF1 suppresses antifungal immunity through CXCL1-mediated neutrophil recruitment during Candida albicans intradermal infection
Authors: Bai Wenjuan , Wang Qingqing , Deng Zihou , Li Tiantian , Xiao Hui , Wu Zhiyuan
Published: February 2020

Background

Candida albicansis the most common opportunistic human fungal pathogen. The chemokine ligand CXCL1 plays a protective role in fungal infection through the recruitment of neutrophils. TRAF1 (tumor necrosis factor-associated factor 1) can be highly induced by proinflammatory stimuli such as LPS and TNF and has been implicated in septic shock. However, the role of TRAF1 in infection, especially fungal infection, remains elusive. Herein, we reveal that TRAF1 suppresses the antifungal immune response toCandida albicansintradermal infection through the regulation of CXCL1 induction and neutrophil recruitment.

Methods

A mouse model ofC. albicansintradermal infection was established. TheTraf1−/−mice andTraf1−/−immortalized human keratinocytes were generated. The p65 inhibitor triptolide, STAT1 inhibitor fludarabine, neutrophil-depletion antibody Ly6G, and neutralizing antibody for CXCL1 were utilized. The expression of proinflammatory cytokines and chemokines was assessed by real-time PCR and ELISA, and the activation of signaling molecules was analyzed by Western blotting. Hematoxylin and eosin staining and periodic acid Schiff staining were used for histology or fungal detection, respectively. The immunofluorescence and flow cytometry analyses were employed in the assessment of immune cell infiltration. Bone marrow transplantation and adoptive transfer experiments were conducted to establish a role for TRAF1 in the macrophage compartment in fungal skin infection.

Results

TRAF1-deficient mice demonstrated improved control ofCandida albicansintradermal infection, and concomitant increase in neutrophil recruitment and reduction in fungal burden. The chemokine CXCL1 was upregulated in the TRAF1-deficient macrophages treated with heat-killedC. albicans. Mechanistically, TRAF1-deficient macrophages showed increased activation of transcription factor NFκB p65. The human CXCL8 was also highly induced in the TRAF1-deficient human keratinocytes upon TNF stimulation through decreasing the activation of transcription factor STAT1. TRAF1-deficient macrophages played a critical role in containing theC. albicansskin infection in vivo.

Conclusion

TRAF1-deficient mice can better control fungal infection in the skin, a process attributable to the CXCL-neutrophil axis. Mechanistically, TRAF1 likely regulates CXCL1 expression in both macrophages and keratinocytes through the transcriptional factor NFκB and STAT1, respectively. Our finding offers new insight into the understanding of the immune regulatory mechanisms in host defense againstC. albicansinfection.

Graphical abstract
CD4+CD38+ central memory T cells contribute to HIV persistence in HIV-infected individuals on long-term ART
Authors: Song Cheng-Bo , Zhang Le-Le , Wu Xian , Fu Ya-Jing , Jiang Yong-Jun , Shang Hong , Zhang Zi-Ning
Published: February 2020

Background

Despite the effective antiretroviral treatment (ART) of HIV-infected individuals, HIV persists in a small pool. Central memory CD4+T cells (Tcm) make a major contribution to HIV persistence. We found that unlike HLA-DR, CD38 is highly expressed on the Tcm of HIV-infected subjects receiving ART for > 5 years. It has been reported that the half-life of total and episomal HIV DNA in the CD4+CD38+T cell subset, exhibits lower decay rates at 12 weeks of ART. Whether CD38 contributes to HIV latency in HIV-infected individuals receiving long-term ART is yet to be addressed.

Methods

Peripheral blood mononuclear cells (PBMCs) were isolated from the whole blood of HIV-infected subjects receiving suppressive ART. The immunophenotyping, proliferation and apoptosis of CD4+T cell subpopulations were detected by flow cytometry, and the level of CD38 mRNA and total HIV DNA were measured using real-time PCR and digital droplet PCR, respectively. A negative binomial regression model was used to determine the correlation between CD4+CD38+Tcm and total HIV DNA in CD4+T cells.

Results

CD38 was highly expressed on CD4+Tcm cells from HIV infected individuals on long-term ART. Comparing with HLA-DR−Tcm and CD4+HLA-DR+T cells, CD4+CD38+Tcm cells displayed lower levels of activation (CD25 and CD69) and higher levels of CD127 expression. The proportion of CD38+Tcm, but not CD38−Tcm cells can predict the total HIV DNA in the CD4+T cells and the CD38+Tcm subset harbored higher total HIV DNA copy numbers than the CD38−Tcm subset. After transfected with CD38 si-RNA in CD4+T cells, the proliferation of CD4+T cells was inhibited.

Conclusion

The current date indicates that CD4+CD38+Tcm cells contribute to HIV persistence in HIV-infected individuals on long-term ART. Our study provides a potential target to resolve HIV persistence.
Transcriptional insights into the CD8+ T cell response in mono-HIV and HCV infection
Authors: Li Si-Yao , Zhang Zi-Ning , Jiang Yong‑Jun , Fu Ya‑Jing , Shang Hong
Published: February 2020

Background

Disease progression in the absence of therapy varies significantly in mono-HIV and HCV infected individuals. Virus-specific CD8+ T cells play an important role in restricting lentiviral replication and determining the rate of disease progression during HIV and HCV mono- and co-infection. Thus, understanding the similarities in the characteristics of CD8+ T cells in mono-HIV and HCV infection at the transcriptomic level contributes to the development of antiviral therapy. In this study, a meta-analysis of CD8+ T cell gene expression profiles derived from mono-HIV and HCV infected individuals at different stages of disease progression, was conducted to understand the common changes experienced by CD8+ T cells.

Methods

Five microarray datasets, reporting CD8+ T cell mRNA expression of the mono-HIV and HCV infected patients, were retrieved from Gene Expression Omnibus (GEO). Differentially expressed genes (DEGs) were identified via integrative meta-analysis of expression data (INMEX) program. Network analysis methods were used to assess protein–protein interaction (PPI) networks, Gene Ontology (GO) terms and pathway enrichment for DEGs. MirDIP and miRDB online prediction tools were used to predict potential microRNAs (miRNAs) targeting hub genes.

Results

First, we identified 625 and 154 DEGs in the CD8+ T cells originating from mono-HIV and HCV chronic progressor patients, respectively, compared to healthy individuals. Among them, interferon-stimulated genes (ISGs) including ISG15, IFIT3, ILI44L, CXCL8, FPR1 and TLR2, were upregulated after mono-HIV and HCV infection. Pathway enrichment analysis of DEGs showed that the “cytokine–cytokine receptor interaction” and “NF-kappa B” signaling pathways were upregulated after mono-HIV and HCV infection. In addition, we identified 92 and 50 DEGs in the CD8+ T cells of HIV non-progressor and HCV resolver patients, respectively, compared with corresponding chronic progressors. We observed attenuated mitosis and reduced ISG expression in HIV non-progressors and HCV resolvers compared with the corresponding chronic progressors. Finally, we identified miRNA-143-3p, predicted to target both IFIT3 in HIV and STAT5A in HCV infection.

Conclusions

We identified DEGs and transcriptional patterns in mono-HIV and HCV infected individuals at different stages of disease progression and identified miRNA-143-3p with potential to intervene disease progression, which provides a new strategy for developing targeted therapies.
ABAT and ALDH6A1, regulated by transcription factor HNF4A, suppress tumorigenic capability in clear cell renal cell carcinoma
Authors: Lu Jun , Chen Zhan , Zhao Hu , Dong Huiyue , Zhu Ling , Zhang Yi , Wang Jie , Zhu Hehuan , Cui Qiang , Qi Chuang , Wang Shuiliang , Chen Shushang , Shao Jichun
Published: February 2020

Background

Clear cell renal cell carcinoma (ccRCC) is a malignancy characterized by metabolic reprogramming. ABAT and ALDH6A1 are metabolic enzymes. In this study, we aim to investigate the associations of ABAT and ALDH6A1 with the malignancy of ccRCC cells.

Methods

The gene expression levels of ABAT and ALDH6A1 in ccRCC were analyzed from gene expression microarray datasets and RNA sequencing data. Clinical information was analyzed from The Cancer Genome Atlas (TCGA) data. The distributions of ABAT and ALDH6A1 in ccRCC clinical tissues were screened by reverse transcription-quantitative polymerase chain reaction (RT-QPCR) and immunohistochemical assays. The effect of overexpression of ABAT or ALDH6A1 was measured by detecting the cell viability, migration ability, and the ratio of lactate and nicotinamide adenine dinucleotide phosphate (NADPH). Chromatin immunoprecipitation (ChIP) and luciferase reporter assays were carried out to investigate the transcript regulation of HNF4A in ABAT and ALDH6A1.

Results

Remarkable downregulated ABAT and ALDH6A1 expression levels were observed in ccRCC patients and low expression of ABAT and ALDH6A1 was correlated with poor survival. Overexpression of ABAT or ALDH6A1 significantly attenuated cell proliferation and migration, and impaired lactate production. In ABAT increased ccRCC cells, the ratio of NADPH/NADP+ was reduced. Finally, we demonstrated that ABAT and ALDH6A1 were directly regulated by a tumor suppressor, HNF4A.

Conclusions

These observations identified HNF4A-regulated low-expressed ABAT and ALDH6A1 as promising diagnostic and prognostic biomarkers for ccRCC.
Systematic review and meta-analysis of the prevalence of chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME)
Authors: Lim Eun-Jin , Ahn Yo-Chan , Jang Eun-Su , Lee Si-Woo , Lee Su-Hwa , Son Chang-Gue
Published: February 2020

Background

Chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) has been emerging as a significant health issue worldwide. This study aimed to systemically assess the prevalence of CFS/ME in various aspects of analyses for precise assessment.

Methods

We systematically searched prevalence of CFS/ME from public databases from 1980 to December 2018. Data were extracted according to 7 categories for analysis: study participants, gender and age of the participants, case definition, diagnostic method, publication year, and country of the study conducted. Prevalence data were collected and counted individually for studies adopted various case definitions. We analyzed and estimated prevalence rates in various angles: average prevalence, pooled prevalence and meta-analysis of all studies.

Results

A total of 1291 articles were initially identified, and 45 articles (46 studies, 56 prevalence data) were selected for this study. Total 1085,976 participants were enrolled from community-based survey (540,901) and primary care sites (545,075). The total average prevalence was 1.40 ± 1.57%, pooled prevalence 0.39%, and meta-analysis 0.68% [95% CI 0.48–0.97]. The prevalence rates were varied by enrolled participants (gender, study participants, and population group), case definitions and diagnostic methods. For example, in the meta-analysis; women (1.36% [95% CI 0.48–0.97]) vs. men (0.86% [95% CI 0.48–0.97]), community-based samples (0.76% [95% CI 0.53–1.10]) vs. primary care sites (0.63% [95% CI 0.37–1.10]), adults ≥ 18 years (0.65% [95% CI 0.43–0.99]) vs. children and adolescents < 18 years (0.55% [95% CI 0.22–1.35]), CDC-1994 (0.89% [95% CI 0.60–1.33]) vs. Holmes (0.17% [95% CI 0.06–0.49]), and interviews (1.14% [95% CI 0.76–1.72]) vs. physician diagnosis (0.09% [95% CI 0.05–0.13]), respectively.

Conclusions

This study comprehensively estimated the prevalence of CFS/ME; 0.89% according to the most commonly used case definition CDC-1994, with women approximately 1.5 to 2 folds higher than men in all categories. However, we observed the prevalence rates are widely varied particularly by case definitions and diagnostic methods. An objective diagnostic tool is urgently required for rigorous assessment of the prevalence of CFS/ME.