Psychometric properties and measurement invariance of the Chinese version of the cognitive emotion regulation questionnaire-short in patients with cancer.

OBJECTIVE: The study aimed to evaluate the psychometric properties and measurement invariance (MI) of the Chinese version of the cognitive emotion regulation questionnaire-short (CERQ-short) in cancer patients. METHODS: This cross-sectional study included 505 cancer patients from mainland China. In addition to sociodemographic and clinical characteristics, the CERQ-short and the distress thermometer were included in the study measures. RESULTS: Item analysis indicated a promising result. And the results of CFA indicated that the CERQ-short demonstrated satisfactory factorial validity in cancer patients. Cronbach's alpha coefficients were between 0.663 and 0.910, while McDonald's omega coefficients were between 0.664 and 0.910. The CERQ-short had sufficient convergent, discriminant and concurrent validity among cancer patients. Lastly, MI supported that the CERQ-short demonstrated strong measurement equivalence across gender, residence and age. CONCLUSIONS: This study shows that the Chinese version of the CERQ-short has convincing psychometric properties and MI, which supports its use in cancer patients.

Earliest evidence of avian primary feather moult.

Feather moulting is a crucial process in the avian life cycle, which evolved to maintain plumage functionality. However, moulting involves both energetic and functional costs. During moulting, plumage function temporarily decreases between the shedding of old feathers and the full growth of new ones. In flying taxa, a gradual and sequential replacement of flight feathers evolved to maintain aerodynamic capabilities during the moulting period. Little is known about the moult strategies of non-avian pennaraptoran dinosaurs and stem birds, before the emergence of crown lineage. Here, we report on two Early Cretaceous pygostylian birds from the Yixian Formation (125 mya), probably referable to Confuciusornithiformes, exhibiting morphological characteristics that suggest a gradual and sequential moult of wing flight feathers. Short primary feathers interpreted as immature are symmetrically present on both wings, as is typical among extant flying birds. Our survey of the enormous collection of the Tianyu Museum confirms previous findings that evidence of active moult in non-neornithine pennaraptorans is rare and likely indicates a moult cycle greater than one year. Documenting moult in Mesozoic feathered dinosaurs is critical for understanding their ecology, locomotor ability and the evolution of this important life-history process in birds.

Amyotrophic lateral sclerosis patients with various gene mutations show diverse motor phenotypes and survival in China.

BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disorder characterised by progressive degeneration of motor neurons. Genetic factors have a substantial impact on ALS. Therefore, this study aimed to explore the correlation between genotype (SOD1, TARDBP, FUS, C9orf72) and phenotype in ALS. METHODS: Genetic analysis was performed on 2038 patients with ALS, among which 1696 patients with sporadic ALS (SALS) as controls for genotype-phenotype analysis, and 1602 SALS as controls for survival analysis. Logistic regression and Cox proportional hazards models were used for statistical analysis. RESULTS: A total of 172 patients with ALS with the gene mutations were included in the statistical analysis (SOD1, n=65; FUS, n=43; TARDBP, n=27; C9orf72, n=37). SOD1 mutations were more frequent in flail leg phenotype (OR 7.317, p=0.001) and less in bulbar phenotype (OR 0.222, p=0.038). C9orf72 expansions exhibited higher frequency in bulbar phenotype (OR 2.770, p=0.008). SOD1 and FUS mutations were significantly associated with earlier age of onset (HR 2.039, p<0.001; HR 1.762, p=0.001). The patients with SOD1 mutations, C9orf72 expansions and those carrying pathogenic FUS mutations had significantly increased death risk (HR 2.217, p<0.001; HR 1.694, p=0.008; HR 1.652, p=0.036). The increased risk of death in ALS with C9orf72 expansions was significant in females (HR 2.419, p=0.014) but not in males (HR 1.442, p=0.128). CONCLUSION: Our study revealed distinct motor phenotypic tendencies in patients with ALS with different genotypes, indicating variations in the vulnerability of motor neurons during the disease's progression. Furthermore, we made novel discoveries regarding survival of different gene mutations, warranting further investigation.

The impact of maternal smoking during pregnancy and the age of smoking initiation on incident dementia: A prospective cohort study.

INTRODUCTION: The impact of early-life tobacco exposure on dementia has remained unknown. METHODS: Using the UK Biobank, the associations of maternal smoking during pregnancy (MSDP) and age of smoking initiation (ASI) with the onset time of all-cause dementia were estimated with accelerated failure time models. The effects of MSDP and ASI on brain structure and their genetic correlation to Alzheimer's disease (AD) were analyzed. A Mendelian randomization (MR) analysis was conducted. RESULTS: The time ratios for smokers starting in childhood, adolescence, and adulthood (vs never smokers) were 0.87 (0.76 to 0.99), 0.92 (0.88 to 0.96), and 0.95 (0.89 to 1.01). MSDP and smoking in adolescence altered many brain regions, including the hippocampus. In genetic analysis, MSDP was genetically and causally linked to AD, and a younger ASI was genetically correlated to a higher AD risk. DISCUSSION: Early-life smoking accelerated dementia onset and was genetically correlated to AD. MSDP demonstrated genetic and causal linkage to AD risks. HIGHLIGHTS: Unlike the commonly used Cox proportional hazards model, this article uses a parametric survival analysis method - the accelerated failure model - to explore the relationship between exposure to onset time. It can be used as an alternative method when the proportional hazards assumption is not met. Genetic analyses including genetic correlation study and MR analysis and brain structure analyses were conducted to support our findings and explore the potential mechanisms. The study reveals the relationship between different smoking initiation periods and the onset time of dementia and shows that earlier smoking exposure has a more significant impact on dementia. It emphasizes the importance of preventing early smoking. In the future, more research focusing on the relationship between early exposure and dementia is called for to provide more detailed prevention measures for dementia that cover all age groups.

Natural polysaccharides regulate intestinal microbiota for inhibiting colorectal cancer.

The gastrointestinal tract is an important part of the human immune system. The gut microbiome, which constitutes a major component of the gastrointestinal tract, plays a crucial role in maintaining normal physiological functions and influences the development, diagnosis, and immunotherapy of colorectal cancer (CRC). Natural polysaccharides can be extracted from animals, plants, and traditional Chinese medicines. They serve as an essential energy source for the gut microbiome, promoting probiotic proliferation and regulating the intestinal microecological balance. Moreover, polysaccharides exhibit anti-tumor effects due to their immune regulatory functions and low toxicity. This review focuses on discussing these anti-tumor effects in CRC, along with improving gut microbiome dysbiosis and regulating the tumor immune microenvironment, providing evidence for effective therapeutic strategies against CRC.

Predictors for survival in patients with Alzheimer's disease: a large comprehensive meta-analysis.

The prevalence of Alzheimer's disease (AD) is increasing as the population ages, and patients with AD have a poor prognosis. However, knowledge on factors for predicting the survival of AD remains sparse. Here, we aimed to systematically explore predictors of AD survival. We searched the PubMed, Embase and Cochrane databases for relevant literature from inception to December 2022. Cohort and case-control studies were selected, and multivariable adjusted relative risks (RRs) were pooled by random-effects models. A total of 40,784 reports were identified, among which 64 studies involving 297,279 AD patients were included in the meta-analysis after filtering based on predetermined criteria. Four aspects, including demographic features (n = 7), clinical features or comorbidities (n = 13), rating scales (n = 3) and biomarkers (n = 3), were explored and 26 probable prognostic factors were finally investigated for AD survival. We observed that AD patients who had hyperlipidaemia (RR: 0.69) were at a lower risk of death. In contrast, male sex (RR: 1.53), movement disorders (including extrapyramidal signs) (RR: 1.60) and cancer (RR: 2.07) were detrimental to AD patient survival. However, our results did not support the involvement of education, hypertension, APOE genotype, Aß42 and t-tau in AD survival. Our study comprehensively summarized risk factors affecting survival in patients with AD, provided a better understanding on the role of different factors in the survival of AD from four dimensions, and paved the way for further research.

Sleep characteristics and risk of Alzheimer's disease: a systematic review and meta-analysis of longitudinal studies.

BACKGROUND: Alzheimer's disease (AD) is on the rise in our aging society, making it crucial to identify additional risk factors to mitigate its increasing incidence. This systematic review and meta-analysis aimed to provide updated evidence regarding the association between sleep and AD. METHODS: We conducted a comprehensive search of MEDLINE, EMBASE, and Web of Science databases from inception to July 2023 to identify longitudinal studies. Adjusted relative risks were pooled for each sleep characteristic, and a dose-response analysis was performed specifically for sleep duration. RESULTS: A total of 15,278 records were initially retrieved, and after screening, 35 records were ultimately included in the final analysis. The results showed that insomnia (RR, 1.43; 95%CI, 1.17-1.74), sleep-disordered breathing (RR, 1.22; 95%CI, 1.07-1.39), as well as other sleep problems, including sleep fragmentation and sleep-related movement disorders, were associated with a higher risk of developing AD, while daytime napping or excessive daytime sleepiness (RR, 1.18; 95%CI, 1.00-1.40) only exhibited a trend toward a higher risk of AD development. Furthermore, our analysis revealed a significant association between self-reported sleep problems (RR, 1.34; 95%CI, 1.26-1.42) and the incidence of AD, whereas this association was not observed with sleep problems detected by objective measurements (RR, 1.14; 95%CI, 0.99-1.31). Moreover, both quite short sleep duration (< 4 h) and long duration (> 8 h) were identified as potential risk factors for AD. CONCLUSIONS: Our study found the association between various types of sleep problems and an increased risk of AD development. However, these findings should be further validated through additional objective device-based assessments. Additional investigation is required to establish a definitive causal connection between sleep problems and AD.

Synthetic analysis of trophic diversity and evolution in Enantiornithes with new insights from Bohaiornithidae.

Enantiornithines were the dominant birds of the Mesozoic, but understanding of their diet is still tenuous. We introduce new data on the enantiornithine family Bohaiornithidae, famous for their large size and powerfully built teeth and claws. In tandem with previously published data, we comment on the breadth of enantiornithine ecology and potential patterns in which it evolved. Body mass, jaw mechanical advantage, finite element analysis of the jaw, and traditional morphometrics of the claws and skull are compared between bohaiornithids and living birds. We find bohaiornithids to be more ecologically diverse than any other enantiornithine family: Bohaiornis and Parabohaiornis are similar to living plant-eating birds; Longusunguis resembles raptorial carnivores; Zhouornis is similar to both fruit-eating birds and generalist feeders; and Shenqiornis and Sulcavis plausibly ate fish, plants, or a mix of both. We predict the ancestral enantiornithine bird to have been a generalist which ate a wide variety of foods. However, more quantitative data from across the enantiornithine tree is needed to refine this prediction. By the Early Cretaceous, enantiornithine birds had diversified into a variety of ecological niches like crown birds after the K-Pg extinction, adding to the evidence that traits unique to crown birds cannot completely explain their ecological success.

The birds living in the world today are only a small part of the larger bird family tree. Around 120 to 65 million years ago, when dinosaurs and other large reptiles roamed the world, the ancestors of modern-day birds were actually rather rare. Instead, another now extinct group of birds called the Enantiornithes (meaning "opposite birds") were the most common birds. Many researchers believe that Enantiornithes may have filled similar roles in ancient ecosystems as living birds do today. For example, some may have hunted other birds or animals, while some may have eaten only plants. Some may have specialized at eating a few specific foods while others may have been 'generalists' that ate many different foods. However, some of the physical features of Enantiornithes set them apart from modern-day birds. For example, unlike living birds, Enantiornithes had teeth and their wings were also constructed very differently. Previous studies suggest that one group of these extinct birds most likely ate insects and another group most likely ate fish, but it remains unclear what variety of foods opposite birds as a whole may have consumed. Miller et al. compared the jaws, claws and various other physical features of fossils from six additional species of opposite birds with the skeletons of modern birds to infer what the diets of these opposite birds may have been. This approach revealed that Enantiornithes may have had a wide variety of different diets. The researchers found that two species probably ate plants, another species most likely ate meat, and another one likely ate a mixture of both. With a large sample across Enantiornithes, Miller et al. were able to predict the diet of their common ancestor. They found the common ancestor to most likely be a 'generalist' eating variety of foods and that some species subsequently evolved to have more specialist diets. Opposite birds probably played many different roles in ecosystems, like living birds do today. Therefore, a better understanding how Enantiornithes evolved may shed light on the factors that have influenced the evolution of modern-day birds. This may aid future conservation efforts to target birds whose descendants may be able to take up the ecological roles of other species that go extinct.

Safety evaluation of single-sperm cryopreservation technique applied in intracytoplasmic sperm injection.

Intracytoplasmic sperm injection (ICSI) is a technique that directly injects a single sperm into the cytoplasm of mature oocytes. Here, we explored the safety of single-sperm cryopreservation applied in ICSI. This retrospective study enrolled 186 couples undergoing ICSI-assisted pregnancy. Subjects were allocated to the fresh sperm (group A)/single-sperm cryopreservation (group B) groups based on sperm type, with their clinical baseline/pathological data documented. We used ICSI-compliant sperm for subsequent in vitro fertilization and followed up on all subjects. The recovery rate/cryosurvival rate/sperm motility of both groups, the pregnancy/outcome of women receiving embryo transfer, and the delivery mode/neonatal-related information of women with successful deliveries were recorded. The clinical pregnancy rate, cumulative clinical pregnancy rate, abortion rate, ectopic pregnancy rate, premature delivery rate, live birth delivery rate, neonatal birth defect rate, and average birth weight were analyzed. The two groups showed no significant differences in age, body mass index, ovulation induction regimen, sex hormone [anti-Müllerian hormone (AMH)/follicle-stimulating hormone (FSH)/luteinizing hormone (LH)] levels, or oocyte retrieval cycles. The sperm recovery rate (51.72%-100.00%) and resuscitation rate (62.09% ± 16.67%) in group B were higher; the sperm motility in the two groups demonstrated no significant difference and met the ICSI requirements. Group B exhibited an increased fertilization rate, decreased abortion rate, and increased safety versus group A. Compared with fresh sperm, the application of single-sperm cryopreservation in ICSI sensibly improved the fertilization rate and reduced the abortion rate, showing higher safety.

Transcriptomic profiling revealed immune-related signaling pathways in response to experimental infection of Leishmania donovani in two desert lizards from Northwest China.

Little is known about the immune response of lizards to Leishmania parasties. In this study, we conducted the first liver transcriptome analysis of two lizards (Phrynocephalus przewalskii and Eremias multiocellata) challenged with L. donovani, endemic to the steppe desert region of northwestern China. Our results revealed that multiple biological processes and immune-related signaling pathways are closely associated with the immune response to experimental L. donovani infection in the two lizards, and that both lizards show similar changes to mammals in terms of immunity to Leishmania. However, the interspecific divergence of the two lizards leads to different transcriptomic changes. In particular, in contrast to P. przewalskii, the challenged E. mutltiocellata was characterized by the induction of down-regulation of most DEGs. These findings will contribute to the scarce resources on lizard immunity and provide a reference for further research on immune mechanisms in reptiles.

Exploring aromatic components differences and composition regularity of 5 kinds of these 4 aroma types Phoenix Dancong tea based on GC-MS.

Different aromatic components do indeed give different tea flavors. There is still little research on whether there is a certain regularity in the combination and content of aromatic components in different aroma types of Phoenix Dancong (PDC) tea. This potential regularity may be a key factor in unraveling the relationship between reproduction and evolution in PDC tea. Here, the 5 kinds of these 4 aroma types PDC tea (Zhuye, Tuofu, Jianghuaxiang, Juduo, Yashixiang) were used as research materials in this study, the headspace solid-phase microextraction combined with gas chromatography-mass spectrometry was used to analyze the aromatic components of these PDC teas. The results showed a total of 36 aromatic components identified in this study. When conducting cluster analysis, it was found that similarity degree arrangement sequence of 5 PDC teas was Juduo, Tuofu, Yashixiang, Zhuye and Jianghuaxiang. Among these aromatic components, the 7,9-Di-tert-butyl-1-oxaspiro(4,5)deca-6,9-diene-2,8-dione, the 2-Cyclopenten-1-one, 3-methyl-2-(2-pentenyl)-,(Z)-, the 2,4-Di-tert-butylphenol, the 3,7-dimethyl-1,5,7-Octatrien-3-ol, and the 2-Furanmethanol,5-ethenyltetrahydro-.alpha.,.alpha.,5-trimethyl-,cis- are common to 5 PDC teas. This study aims to elucidate the similarities in the aromatic components of 5 PDC teas, revealing the major aroma-endowed substances of various aroma, and providing theoretical reference for further exploring the relationship between aroma type discrimination, variety selection, and evolution of PDC teas.

Systemic inflammation and risk of Parkinson's disease: A prospective cohort study and genetic analysis.

BACKGROUND: Multiple evidence has suggested the complex interplay between Parkinson's disease (PD) and systemic inflammation marked by C-reactive protein (CRP) and interleukin 6 (IL-6). Nevertheless, the findings across studies have shown inconsistency, and the direction of the effect remains controversial. Here, we aimed to explore the link between CRP and IL-6 and the risk of PD. METHODS: Based on data from the UK Biobank, we investigated the association between baseline CRP and IL-6 and the risk of incident PD with Cox proportional hazards regression analysis. We further performed extensive genetic analyses including genetic correlation, polygenic risk score (PRS), and pleiotropic enrichment based on summary statistics from previous genome-wide association studies. RESULTS: A higher level of CRP at baseline was associated with a lower risk of PD (HR = 0.85, 95 % CI: 0.79-0.90, P = 4.23E-07). The results remained consistent in the subgroup analyses stratified by sex, age and body mass index. From the genetic perspective, a significant negative genetic correlation was identified between CRP and PD risk (correlation: -0.14, P = 6.31E-05). Higher PRS of CRP was associated with a lower risk of PD (P = 0.015, beta = -0.04, SE = 0.017). Moreover, we observed significant pleiotropic enrichment for PD conditional on CRP, and identified 13 risk loci for PD, some of which are implicated in immune functionality and have been linked to PD, including CTSB, HNF4A, PPM1G, ACMSD, and NCOR1. In contrast, no significant association was identified between IL-6 and PD. CONCLUSIONS: Systemic inflammation at baseline measured by CRP level is associated with decreased future risk of PD. These discoveries contribute to a deeper comprehension of the role of inflammation in the risk of PD, and hold implications for the design of therapeutic interventions in clinical trials.

Fossil evidence sheds light on sexual selection during the early evolution of birds.

The impact of sexual selection on the evolution of birds has been widely acknowledged. Although sexual selection has been hypothesized as a driving force in the occurrences of numerous morphological features across theropod evolution, this hypothesis has yet to be comprehensively tested due to challenges in identifying the sex of fossils and by the limited sample size. Confuciusornis sanctus is arguably the best-known early avialan and is represented by thousands of well-preserved specimens from the Early Cretaceous Jehol lagerstätte, which provides us with a chance to decipher the strength of sexual selection on extinct vertebrates. Herein, we present a morphometric study of C. sanctus based on the largest sample size of this taxon collected up to now. Our results indicate that the characteristic elongated paired rectrices is a sexually dimorphic trait and statistically robust inferences of the sexual dimorphism in size, shape, and allometry that have been established, providing the earliest known sexual dimorphism in avian evolution. Our findings suggest that sexual selection, in conjunction with natural selection, does act upon body size and limb length ratio in early birds, thereby promoting a deeper understanding of the role of sexual selection in large-scale phylogenetic evolution.

The effects of hospice care education on first-year undergraduate nursing students in mainland China: A mixed-methods study.

BACKGROUND: With the rising number of people with end-stage chronic diseases, the demand for hospice care has increased dramatically. As the future health professionals for the implementation of hospice care, undergraduate nursing students in mainland China still lack knowledge and skills of hospice care, thus hospice care education plays a vital role in its development. OBJECTIVES: To understand the effects of hospice care education on nursing students' death attitudes, end-of-life attitudes, humanistic care qualities, and their learning experiences. DESIGN: This study used a mixed-methods design. SETTING: A University of Chinese Medicine in mainland China. PARTICIPANTS: The first-year undergraduate nursing students (n = 65). METHODS: A mixed-methods study was conducted to evaluate the impact of a hospice care course from March to June 2021. The quantitative part included a quasi-experimental study designed with pre- and post-intervention measurements and the qualitative part included a descriptive qualitative study with semi-structured individual interviews. RESULTS: The quantitative data revealed that after the course, nursing students experienced improvements in their death attitudes, end-of-life attitudes, and humanistic care qualities. Two categories were identified from the qualitative data. The category of "Gain from learning" included 4 themes (Confronting death and thinking about life; Understanding and agreeing with the idea of hospice care; Perceiving the humanistic spirit of medicine; Enhancing of the nursing discipline cognition and professional identity) and the category of "Course feedback" included 2 themes (Expressing recognition for the course arrangement; Making suggestions on the course optimization). CONCLUSIONS: Hospice care education had a positive influence on nursing students. Students expressed satisfaction with the course arrangement. However, future hospice care courses should further optimize the curriculum designs by increasing the discussion of death-related topics, sharing more real clinical cases, recruiting students from different majors, and providing clinical practice, to provide high-quality nursing education for the development of hospice care.

Rare DNAJC7 Variants May Play a Minor Role in Chinese Patients with ALS.

DnaJ heat shock protein family member C7 gene (DNAJC7) has been identified as a genetic risk factor for amyotrophic lateral sclerosis (ALS). In our study, we aimed to screen for rare variants in DNAJC7 in a large cohort of Chinese ALS patients, and investigate the genotype-phenotype correlation of DNAJC7 in ALS. Four (0.19%) variants of DNAJC7 with minor allele frequency (MAF) < 0.1% among 2124 patients were identified, including 1 protein-truncating variant and 3 missense variants, all of which were predicted to be damaging. The patients carrying variants of DNAJC7 in our cohort tented to have a limb onset and a relatively slow disease progression. However, burden analysis did not show an enrichment of rare damaging variants in ALS patients compared to controls. Further analysis involving diverse regions and larger sample size is necessary to elucidate the role of DNAJC7 in the pathogenicity of ALS.

Rare variant analysis of UQCRC1 in Chinese patients with early-onset Parkinson's disease.

Mitochondrial ubiquinol-cytochrome c reductase core protein 1 (UQCRC1) gene has been identified as a causative gene for autosomal dominant Parkinson's disease (PD), with the p.Y314S variant potentially associated with polyneuropathy in PD patients. The objectives of our study were to screen for UQCRC1 variants in Chinese patients with early-onset PD (EOPD) and explore the role of UQCRC1 in EOPD. We investigated the rare variants in 913 EOPD patients in our cohort using whole-exome sequencing, assessing their link to PD at both allele and gene levels. A total of 7 rare variants (minor allele frequency < 0.1%) of UQCRC1 were identified. However, no excessive burden of rare UQCRC1 variants was suggested in the EOPD patients. Further analysis with larger sample size and diverse regions is needed to determine the role of UQCRC1 in PD.

The impact of air pollution on outpatient medical service utilization and expenditure in a clean air city.

BACKGROUND: Although there's increasing research on the health effects of air pollution in China, its direct influence on health-related expenditures, particularly during less severe pollution episodes, is still not well-understood. This study aims to quantify impact of three air pollutants (sulfur dioxide, nitrogen dioxide, and particulate matter) on individual healthcare spending in a city with relatively clean air. METHODS: Using transaction-level medical social insurance data and temperature inversion as the instrumental variable, we estimate the current and cumulative effects of air pollutants on outpatient visits and medical expenses in an eastern city in China. RESULTS: We find a significantly positive effect on outpatient visits for 15-day moving average, and a significantly positive effect on outpatient expenditure for 25-day moving average. Therefore, the cumulative effect of pollutants on medical expenditure should not be ignored. The effects on total outpatient expenditure are larger for the elderly and men. The cumulative pollution exposure increases the visits to respiratory department but also increases the expenditure on non-respiratory diseases in the long term. CONCLUSION: Our findings provide empirical evidence that even for cities with good air quality, further improvements can improve patients' quality of life and lessen the expenditure burden on medical insurance.

Reproduction of a fossil rhinoceros from 18 mya and origin of litter size in perissodactyls.

Reproductive strategy is among the most important characteristics of organism. Here, we report reproductive strategy of singleton pregnancy of a fossil rhinoceros, Plesiaceratherium gracile, from 18 mya of the Shanwang Basin, China. Dental and body development data revealed that after birth, the calf of P. gracile is breastfed for 2-3 years; at approximately 5 years of age, when the M2 tooth is slightly worn, the female has already reached sexual maturity and attained a size close to that of an adult and could give birth to the first calf. Furthermore, given litter size is phylogenetically conservative and closely correlates with body size, we conclude that the litter size of perissodactyls is determined by the singleton pregnancy since the Eocene. By contrast, other reproductive traits are highly variable and have a different pace of evolution, and traits observed in living rhinoceroses have been evolving at least since 18 mya.

Genetic Modifiers of Age at Onset for Amyotrophic Lateral Sclerosis: A Genome-Wide Association Study.

OBJECTIVE: Age at onset (AAO) is an essential clinical feature associated with disease progression and mortality in amyotrophic lateral sclerosis (ALS). Identification of genetic variants and environmental risk factors influencing AAO of ALS could help better understand the disease's biological mechanism and provide clinical guidance. However, most genetic studies focused on the risk of ALS, while the genetic background of AAO is less explored. This study aimed to identify genetic and environmental determinants for AAO of ALS. METHODS: We performed a genome-wide association analysis using a Cox proportional hazards model on AAO of ALS in 10,068 patients. We further conducted colocalization analysis and in-vitro functional exploration for the target variants, as well as Mendelian randomization analysis to identify risk factors influencing AAO of ALS. RESULTS: The total heritability of AAO of ALS was ~0.16 (standard error [SE] = 0.03). One novel locus rs2046243 (CTIF) was significantly associated with earlier AAO by ~1.29 years (p = 1.68E-08, beta = 0.10, SE = 0.02). Functional exploration suggested this variant was associated with increased expression of CTIF in multiple tissues including the brain. Colocalization analysis detected a colocalization signal at the locus between AAO of ALS and expression of CTIF. Causal inference indicated higher education level was associated with later AAO. INTERPRETATION: These findings improve the current knowledge of the genetic and environmental etiology of AAO of ALS, and provide a novel target CTIF for further research on ALS pathogenesis and potential therapeutic options to delay the disease onset. ANN NEUROL 2023;94:933-941.