bluuebunny/crossref_metadata_2025_split huggingface dataset:
Prioritized polycystic kidney disease drug targets and repurposing candidates from pre-cystic and cystic mouse Pkd2 model gene expression reversion
Authors: Wilk Elizabeth J. , Howton Timothy C. , Fisher Jennifer L. , Oza Vishal H. , Brownlee Ryan T. , McPherson Kasi C. , Cleary Hannah L. , Yoder Bradley K. , George James F. , Mrug Michal , Lasseigne Brittany N. 
Published: May 2023

Abstract
Background
Autosomal dominant polycystic kidney disease (ADPKD) is one of the most prevalent monogenic human diseases. It is mostly caused by pathogenic variants in PKD1 or PKD2 genes that encode interacting transmembrane proteins polycystin-1 (PC1) and polycystin-2 (PC2). Among many pathogenic processes described in ADPKD, those associated with cAMP signaling, inflammation, and metabolic reprogramming appear to regulate the disease manifestations. Tolvaptan, a vasopressin receptor-2 antagonist that regulates cAMP pathway, is the only FDA-approved ADPKD therapeutic. Tolvaptan reduces renal cyst growth and kidney function loss, but it is not tolerated by many patients and is associated with idiosyncratic liver toxicity. Therefore, additional therapeutic options for ADPKD treatment are needed.

Methods
As drug repurposing of FDA-approved drug candidates can significantly decrease the time and cost associated with traditional drug discovery, we used the computational approach signature reversion to detect inversely related drug response gene expression signatures from the Library of Integrated Network-Based Cellular Signatures (LINCS) database and identified compounds predicted to reverse disease-associated transcriptomic signatures in three publicly available Pkd2 kidney transcriptomic data sets of mouse ADPKD models. We focused on a pre-cystic model for signature reversion, as it was less impacted by confounding secondary disease mechanisms in ADPKD, and then compared the resulting candidates’ target differential expression in the two cystic mouse models. We further prioritized these drug candidates based on their known mechanism of action, FDA status, targets, and by functional enrichment analysis.

Results
With this in-silico approach, we prioritized 29 unique drug targets differentially expressed in Pkd2 ADPKD cystic models and 16 prioritized drug repurposing candidates that target them, including bromocriptine and mirtazapine, which can be further tested in-vitro and in-vivo.

Conclusion
Collectively, these results indicate drug targets and repurposing candidates that may effectively treat pre-cystic as well as cystic ADPKD.

Graphical Abstract
Verification of a clinical decision support system for the diagnosis of headache disorders based on patient–computer interactions: a multi-center study
Authors: Han Xun , Wan Dongjun , Zhang Shuhua , Yin Ziming , Huang Siyang , Xie Fengbo , Guo Junhong , Qu Hongli , Yao Yuanrong , Xu Huifang , Li Dongfang , Chen Sufen , Wang Faming , Wang Hebo , Chen Chunfu , He Qiu , Dong Ming , Wan Qi , Xu Yanmei , Chen Min , Yan Fanhong , Wang Xiaolin , Wang Rongfei , Zhang Mingjie , Ran Ye , Jia Zhihua , Liu Yinglu , Chen Xiaoyan , Hou Lei , Zhao Dengfa , Dong Zhao , Yu Shengyuan 
Published: May 2023

Abstract
Background
Although headache disorders are common, the current diagnostic approach is unsatisfactory. Previously, we designed a guideline-based clinical decision support system (CDSS 1.0) for diagnosing headache disorders. However, the system requires doctors to enter electronic information, which may limit widespread use.

Methods
In this study, we developed the updated CDSS 2.0, which handles clinical information acquisition via human–computer conversations conducted on personal mobile devices in an outpatient setting. We tested CDSS 2.0 at headache clinics in 16 hospitals in 14 provinces of China.

Results
Of the 653 patients recruited, 18.68% (122/652) were suspected by specialists to have secondary headaches. According to “red-flag” responses, all these participants were warned of potential secondary risks by CDSS 2.0. For the remaining 531 patients, we compared the diagnostic accuracy of assessments made using only electronic data firstly. In Comparison A, the system correctly recognized 115/129 (89.15%) cases of migraine without aura (MO), 32/32 (100%) cases of migraine with aura (MA), 10/10 (100%) cases of chronic migraine (CM), 77/95 (81.05%) cases of probable migraine (PM), 11/11 (100%) cases of infrequent episodic tension-type headache (iETTH), 36/45 (80.00%) cases of frequent episodic tension-type headache (fETTH), 23/25 (92.00%) cases of chronic tension-type headache (CTTH), 53/60 (88.33%) cases of probable tension-type headache (PTTH), 8/9 (88.89%) cases of cluster headache (CH), 5/5 (100%) cases of new daily persistent headache (NDPH), and 28/29 (96.55%) cases of medication overuse headache (MOH). In Comparison B, after combining outpatient medical records, the correct recognition rates of MO (76.03%), MA (96.15%), CM (90%), PM (75.29%), iETTH (88.89%), fETTH (72.73%), CTTH (95.65%), PTTH (79.66%), CH (77.78%), NDPH (80%), and MOH (84.85%) were still satisfactory. A patient satisfaction survey indicated that the conversational questionnaire was very well accepted, with high levels of satisfaction reported by 852 patients.

Conclusions
The CDSS 2.0 achieved high diagnostic accuracy for most primary and some secondary headaches. Human–computer conversation data were well integrated into the diagnostic process, and the system was well accepted by patients. The follow-up process and doctor–client interactions will be future areas of research for the development of CDSS for headaches.
Current management of classic bladder exstrophy in the modern era
Authors: Morrill Christian C. , Haffar Ahmad , Harris Thomas G. W. , Crigger Chad , Gearhart John P. 
Published: May 2023

Abstract
Background
Classic bladder exstrophy is a complex, multi-system congenital malformation affecting formation of the genitourinary system, pelvis, and abdominal wall.

Main body
Historically children with this abnormality were consigned to poor outcomes and quality of life. Modern advancements in the diagnosis and management of this disorder have resulted in low mortality rates and shifted clinical focus toward optimizing quality of life.

Conclusion
Modern techniques in addition to recent discoveries in the diagnosis and delayed management of this disorder have enabled high rates of urinary continence, genital cosmesis, and an improved quality of life. This is an updated overview of the pathology, diagnosis, and management of this rare disorder.
A comparative evaluation of the safety performance of bus priority route configurations
Authors: Gitelman Victoria , Doveh Etti 
Published: May 2023

AbstractOne way to promote public transport use in cities lies in establishing bus priority routes (BPRs) on main traffic arterials, to reduce bus travel times. But, BPRs require infrastructure changes in road layouts, creating more complex traffic settings that may have safety implications. Previous research indicated that design features affect BPRs' safety, but findings regarding the impacts of various BPR configurations are scarce. In this study, we examined the safety performance of three BPR configurations: barrier-separated central, open centre-lane and curbside BPRs, in Israel. Multivariate regression models were fitted to identify design features affecting accident occurrences on urban arterials with BPRs, using a database on all BPRs in operation. The comparative evaluations showed that barrier-separated BPRs were characterised by lower accident rates on road sections but by substantially higher accident numbers at junctions, relative to other BPR types, and particularly when bus-overtaking was possible. Hence, the use of barrier-separated bus routes should be reduced and bus-overtaking settings should be avoided, when implementing BPRs. In the comparison of curbside and center-lane BPRs none of them demonstrated a superior safety performance: the centre-lane BPRs were safer on sections while at junctions both types had advantages for certain accident types, thus, both forms are applicable in future BPR designs.
Whole genome sequencing and analysis of Armillaria gallica Jzi34 symbiotic with Gastrodia elata
Authors: Cai Jinlong , Muhammad Ikram , Chen Bilian , Xu Peng , Li Yiguo , Xu Huini , Li Kunzhi 
Published: May 2023

Abstract
Background
Armillaria species are plant pathogens, but a few Armillaria species can establish a symbiotic relationship with Gastrodia elata, a rootless and leafless orchid, that is used as a Chinese herbal medicine. Armillaria is a nutrient source for the growth of G. elata. However, there are few reports on the molecular mechanism of symbiosis between Armillaria species and G. elata. The genome sequencing and analysis of Armillaria symbiotic with G. elata would provide genomic information for further studying the molecular mechanism of symbiosis.

Results
The de novo genome assembly was performed with the PacBio Sequel platform and Illumina NovaSeq PE150 for the A. gallica Jzi34 strain, which was symbiotic with G. elata. Its genome assembly contained ~ 79.9 Mbp and consisted of 60 contigs with an N50 of 2,535,910 bp. There were only 4.1% repetitive sequences in the genome assembly. Functional annotation analysis revealed a total of 16,280 protein coding genes. Compared with the other five genomes of Armillaria, the carbohydrate enzyme gene family of the genome was significantly contracted, while it had the largest set of glycosyl transferase (GT) genes. It also had an expansion of auxiliary activity enzymes AA3-2 gene subfamily and cytochrome P450 genes. The synteny analysis result of P450 genes reveals that the evolutionary relationship of P450 proteins between A. gallica Jzi34 and other four Armillaria was complex.

Conclusions
These characteristics may be beneficial for establishing a symbiotic relationship with G. elata. These results explore the characteristics of A. gallica Jzi34 from a genomic perspective and provide an important genomic resource for further detailed study of Armillaria. This will help to further study the symbiotic mechanism between A. gallica and G. elata.
Is OPRM1 genotype a valuable predictor of VAS in patients undergoing laparoscopic radical resection of colorectal cancer with fentanyl?
Authors: Zhou Yan , Cao Lei , Yang Yihui , Gao Yaoyi , Li Yihao , Wang Beili , Pan Baishen , Huang Jian , Guo Wei 
Published: May 2023

Abstract
Objective
This study was conducted to examine the association between the A118G polymorphism of the OPRM1 gene and the risk of increased VAS scores in patients with colorectal cancer who underwent laparoscopic radical resection for which fentanyl was used.

Methods
The OPRM1 A118G genotype in subjects were detected. The relationship between the A118G polymorphism of the OPRM1 gene and increased Visual Analogue Scale (VAS) scores throughout the perioperative period was explored. A total of 101 patients receiving fentanyl anesthesia undergoing laparoscopic radical resection of colon tumors at Zhongshan Hospital, Fudan University between July 2018 and December 2020 were investigated in the present study. The relative risk between the A118G polymorphism of the OPRM1 gene and VAS ≥ 4 in the PACU was estimated using the adjusted effect relationship diagram, baseline characteristic analysis, and multiple logistic regression analysis. The relationship between the A118G polymorphism of the OPRM1 gene and VAS in the PACU, as well as perioperative fentanyl usage, was examined after confounders were adjusted.

Results
Subjects with OPRM1 A118G wild gene A were less sensitive to fentanyl, which was a risk factor for PACU VAS ≥ 4. Before the model was adjusted, the odds ratio (OR) was 14.73 (P = 0.001). After adjusting for age, sex, weight, height, and the duration of surgery, the OR increased to 16.55 (P = 0.001). When adjusting for age, sex, weight, height, surgery duration, COMT Val158Met gene polymorphism, CYP3A4 *1G gene polymorphism, and CYP3A5 *3gene polymorphism, the OR was 19.94 (P = 0.002). Moreover, OPRM1 A118G wild type gene A was found to be a risk factor for increased dosage of fentanyl in the PACU. Before the model was adjusted, the OR reached 16.90 (P = 0.0132). After adjusting for age, sex, body weight, intraoperative fentanyl dosage, surgery duration, and height, the OR was 13.81, (P = 0.0438). When adjusting for age, sex, weight, height, intraoperative fentanyl dosage, surgery duration, COMT Val158Met gene polymorphism, CYP3A4 *1G gene polymorphism, and CYP3A5 *3 gene polymorphism, the OR reached 15.23, (P = 0.0205).

Conclusion
The A118G polymorphism of the OPRM1 gene carrying wild gene A was a risk factor for VAS ≥ 4 in the PACU. Moreover, it is a risk factor for increased dosage of fentanyl in the PACU.
Frameworks for estimating causal effects in observational settings: comparing confounder adjustment and instrumental variables
Authors: Zawadzki Roy S. , Grill Joshua D. , Gillen Daniel L. ,   and for the Alzheimer’s Disease Neuroimaging Initiative
Published: May 2023

AbstractTo estimate causal effects, analysts performing observational studies in health settings utilize several strategies to mitigate bias due to confounding by indication. There are two broad classes of approaches for these purposes: use of confounders and instrumental variables (IVs). Because such approaches are largely characterized by untestable assumptions, analysts must operate under an indefinite paradigm that these methods will work imperfectly. In this tutorial, we formalize a set of general principles and heuristics for estimating causal effects in the two approaches when the assumptions are potentially violated. This crucially requires reframing the process of observational studies as hypothesizing potential scenarios where the estimates from one approach are less inconsistent than the other. While most of our discussion of methodology centers around the linear setting, we touch upon complexities in non-linear settings and flexible procedures such as target minimum loss-based estimation and double machine learning. To demonstrate the application of our principles, we investigate the use of donepezil off-label for mild cognitive impairment. We compare and contrast results from confounder and IV methods, traditional and flexible, within our analysis and to a similar observational study and clinical trial.
Phosphodiesterase 5 (PDE-5) inhibitors (sildenafil, tadalafil, and vardenafil) effects on esophageal motility: a systematic review
Authors: Shafiee Arman , Bahri Razman Arabzadeh , Teymouri Athar Mohammad Mobin , Afsharrezaei Fatemeh , Gholami Mostafa 
Published: May 2023

Abstract
Background
Esophageal motility disorders are a group of disorders associated with dysfunctional swallowing resulting from impaired neuromuscular coordination. Phosphodiesterase 5 (PDE-5) inhibitors induce smooth relaxation and are proposed as a treatment option for esophageal motility disorders such as achalasia.

Methods
This study is conducted based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). We systematically searched MEDLINE/ PubMed, Scopus, EMBASE, and Web of Science databases for esophageal outcomes of individuals treated with PDE5 inhibitors. A random effect meta-analysis was conducted.

Results
A total of 14 studies were included. They were conducted in different countries, with Korea and Italy having the highest number of articles. The main drug assessed was sildenafil. PDE-5 inhibitors resulted in a significant reduction in lower esophageal sphincter pressure (SMD − 1.69, 95% CI: -2.39 to -0.99) and the amplitude of contractions (SMD − 2.04, 95% CI: -2.97 to -1.11). Residual pressure was not significantly different between the placebo and sildenafil groups (SMD − 0.24, 95% CI: -1.20 to 0.72). Furthermore, a recent study reported contractile integral, stating that ingestion of sildenafil leads to a significant reduction in distal contractile integral and a significant increase in proximal contractile integral.

Conclusion
PDE-5 inhibitors significantly reduce LES resting pressure and esophageal peristaltic vigor, decreasing esophageal body contractility and contraction reserve. Therefore, using these drugs in patients affected by esophageal motility disorders may potentially improve their condition regarding symptom relief and prevention of further associated complications. Future reports investigating larger sample size is necessary in order to establish definite evidence regarding the efficacy of these drugs.
Chronic health conditions and mortality among older adults with complex care needs in Aotearoa New Zealand
Authors: Abey-Nesbit Rebecca , Jamieson Hamish A , Bergler Hans Ulrich , Kerse Ngaire , Pickering John W , Teh Ruth 
Published: May 2023

Abstract
Background
Older people have more comorbidities than younger groups and multimorbidity will increase. Often chronic conditions affect quality of life, functional ability and social participation. Our study aim was to quantify the prevalence of chronic conditions over a three-year period and their association with mortality after accounting for demographics.

Methods
We conducted a retrospective cohort study using routinely collected health data including community-dwelling older adults in New Zealand who had an interRAI Home Care assessment between 1 January 2017 and 31 December 2017. Descriptive statistics and differences between variables of interest among ethnic groups were reported. Cumulative density plots of mortality were developed. Logistic regression models adjusted for age and sex to estimate mortality were created independently for each combination of ethnicity and disease diagnosis.

Results
The study cohort consisted of 31,704 people with a mean (SD) age of 82.3 years (8.0), and of whom 18,997 (59.9%) were female. Participants were followed for a median 1.1 (range 0 to 3) years. By the end of the follow-up period 15,678 (49.5%) people had died. Nearly 62% of Māori and Pacific older adults and 57% of other ethnicities had cognitive impairment. Diabetes the next most prevalent amongst Māori and Pacific peoples, and coronary heart disease amongst Non-Māori/Non-Pacific individuals. Of the 5,184 (16.3%) who had congestive heart failure (CHF), 3,450 (66.6%) died. This was the highest mortality rate of any of the diseases. There was a decrease in mortality rate with age for both sexes and all ethnicities for those with cancer.

Conclusions
Cognitive impairment was the most common condition in community dwelling older adults who had an interRAI assessment. Cardiovascular disease (CVD) has the highest mortality risk for all ethnic groups, and in non-Māori/non-Pacific group of advanced age, risk of mortality with cognitive impairment is as high as CVD risk. We observed an inverse for cancer mortality risk with age. Important differences between ethnic groups are reported.
The mediating effect of leisure activities in the relationship between depression and cognitive decline in middle age and older adults in Taiwan
Authors: Hung Yu-Chan , Lao Wai-Lam , Yeh Chih-Jung , Lee Meng-Chih 
Published: May 2023

Abstract
Background
Depression can affect the development of cognitive functions, and there are many people with depressive symptoms and cognitive decline in the aging population. The role of mediators between depressive symptoms and the subsequent cognitive decline remains unclear. We aimed to investigate whether depressive symptoms can slow down cognitive decline through a mediator.

Methods
A total of 3,135 samples were collected in 2003, 2007, and 2011. This study used the CES-D10 and SPMSQ (Short Portable Mental State Questionnaire) to measure depression and cognitive functions. The effect of depression trajectory on the subsequent cognitive dysfunction was analyzed using multivariable logistic regression, and the mediating effect was analyzed using the Sobel test.

Results
The results of the multivariable linear regression analysis showed that after including different variables in each model, such as leisure activities and mobility in 2003 and 2007, women had a higher percentage of depressive symptoms in each model, compared to men. The effect of depression in 2003 on cognitive decline in 2011 was mediated by intellectual leisure activities in 2007 in men (Z=-2.01) and physical activity limitation in 2007 in women (Z=-3.02).

Conclusions
The mediation effect of this study shows that people with depressive symptoms will reduce their participation in leisure activities, which will lead to the degeneration of cognitive function. We suggest that if depressive symptoms are addressed as early as possible, people will have the ability and motivation to delay the decline of cognitive function through participation in leisure activities.
Migration status, physical limitations and associated self-rated health: a study of older Indian adults
Authors: Mandal Bittu , Pradhan Kalandi Charan , Mohanty Parimala , Muhammad T. 
Published: May 2023

Abstract
Background
Migrant status with mobility impairment becomes a double burden for health and wellbeing of older adults. This study examined the independent relationships and multitude effects between migrant status, functional and mobility impairments and poor self-rated health (SRH) among older Indian adults.

Methods
This study utilised nationally representative Longitudinal Ageing Study in India wave-1 (LASI) data, including a sample of 30,736 individuals aged 60 years and above. The main explanatory variables were migrant status, difficulty in activities of daily living (ADL), difficulty in instrumental activities of daily living (IADL) and mobility impairments; and the outcome variable was poor-SRH. Multivariable logistic regression and stratified analyses were used to fulfil the study objectives.

Results
Overall, about 23% of older adults reported poor-SRH. Reporting poor-SRH was more prevalent (28.03%) among recent migrants (less than ten years). The prevalence of reporting poor-SRH was significantly higher among older adults who had mobility impairment (28.65%), difficulty in ADL or IADL (40.82% & 32.57%). Migrant older adults (regardless of duration) who had mobility impairment had significantly greater odds of reporting poor-SRH compared with non-migrant older adults who did not have mobility impairment. Similarly, older respondents who had problems in ADL and IADL with migration status had higher odds of reporting poor-SRH than their non-migrant counterparts with no such problems.

Conclusions
The study revealed the vulnerability of migrant older adults with functional and mobility disability, as well as those with limited socioeconomic resources and suffering from multimorbidity on rating their perceived health. The findings can be utilised to target outreach programmes and provision of services for migrating older individuals with mobility impairments and enhance their perceived health and ensure active ageing.