Novel SPEF2 variants cause male infertility and likely primary ciliary dyskinesia.

PURPOSE: This study aimed to identify the genetic causes of male infertility and primary ciliary dyskinesia (PCD)/PCD-like phenotypes in three unrelated Han Chinese families. METHODS: We conducted whole-exome sequencing of three patients with male infertility and PCD/PCD-like phenotypes from three unrelated Chinese families. Ultrastructural and immunostaining analyses of patient spermatozoa and respiratory cilia and in vitro analyses were performed to analyze the effects of SPEF2 variants. Intracytoplasmic sperm injection (ICSI) was administered to three affected patients. RESULTS: We identified four novel SPEF2 variants, including one novel homozygous splicing site variant [NC_000005.10(NM_024867.4): c.4447 + 1G > A] of the SPEF2 gene in family 1, novel compound heterozygous nonsense variants [NC_000005.10(NM_024867.4): c.1339C > T (p.R447*) and NC_000005.10(NM_024867.4): c.1645G > T (p.E549*)] in family 2, and one novel homozygous missense variant [NC_000005.10(NM_024867.4): c.2524G > A (p.D842N)] in family 3. All the patients presented with male infertility and PCD/likely PCD. All variants were present at very low levels in public databases, predicted to be deleterious in silico prediction tools, and were further confirmed deleterious by in vitro analyses. Ultrastructural analyses of the spermatozoa of the patients revealed the absence of the central pair complex in the sperm flagella. Immunostaining of the spermatozoa and respiratory cilia of the patients validated the pathogenicity of the SPEF2 variants. All patients carrying SPEF2 variants underwent one ICSI cycle and delivered healthy infants. CONCLUSION: Our study reported four novel pathogenic variants of SPEF2 in three male patients with infertility and PCD/PCD-like phenotypes, which not only extend the spectrum of SPEF2 mutations but also provide information for genetic counseling and treatment of such conditions.

ADGRE5-centered Tsurv model in T cells recognizes responders to neoadjuvant cancer immunotherapy.

Background: Neoadjuvant immunotherapy with anti-programmed death-1 (neo-antiPD1) has revolutionized perioperative methods for improvement of overall survival (OS), while approaches for major pathologic response patients' (MPR) recognition along with methods for overcoming non-MPR resistance are still in urgent need. Methods: We utilized and integrated publicly-available immune checkpoint inhibitors regimens (ICIs) single-cell (sc) data as the discovery datasets, and innovatively developed a cell-communication analysis pipeline, along with a VIPER-based-SCENIC process, to thoroughly dissect MPR-responding subsets. Besides, we further employed our own non-small cell lung cancer (NSCLC) ICIs cohort's sc data for validation in-silico. Afterward, we resorted to ICIs-resistant murine models developed by us with multimodal investigation, including bulk-RNA-sequencing, Chip-sequencing and high-dimensional cytometry by time of flight (CYTOF) to consolidate our findings in-vivo. To comprehensively explore mechanisms, we adopted 3D ex-vivo hydrogel models for analysis. Furthermore, we constructed an ADGRE5-centered Tsurv model from our discovery dataset by machine learning (ML) algorithms for a wide range of tumor types (NSCLC, melanoma, urothelial cancer, etc.) and verified it in peripheral blood mononuclear cells (PBMCs) sc datasets. Results: Through a meta-analysis of multimodal sequential sc sequencing data from pre-ICIs and post-ICIs, we identified an MPR-expanding T cells meta-cluster (MPR-E) in the tumor microenvironment (TME), characterized by a stem-like CD8+ T cluster (survT) with STAT5-ADGRE5 axis enhancement compared to non-MPR or pre-ICIs TME. Through multi-omics analysis of murine TME, we further confirmed the existence of survT with silenced function and immune checkpoints (ICs) in MPR-E. After verification of the STAT5-ADGRE5 axis of survT in independent ICIs cohorts, an ADGRE5-centered Tsurv model was then developed through ML for identification of MPR patients pre-ICIs and post-ICIs, both in TME and PBMCs, which was further verified in pan-cancer immunotherapy cohorts. Mechanistically, we unveiled ICIs stimulated ADGRE5 upregulation in a STAT5-IL32 dependent manner in a 3D ex-vivo system (3D-HYGTIC) developed by us previously, which marked Tsurv with better survival flexibility, enhanced stemness and potential cytotoxicity within TME. Conclusion: Our research provides insights into mechanisms underlying MPR in neo-antiPD1 and a well-performed model for the identification of non-MPR.

Association between Urinary Haloacetic Acid Concentrations and Liver Injury among Women: Results from the Tongji Reproductive and Environmental (TREE) Study.

BACKGROUND: Experimental studies have shown that disinfection byproducts (DBPs) including haloacetic acids (HAAs) can cause liver toxicity, but evidence linking this association in humans is sparse. OBJECTIVES: We aimed to explore the associations between HAA exposures and liver injury. METHODS: We included 922 women between December 2018 and January 2020 from the Tongji Reproductive and Environmental (TREE) cohort study in Wuhan, China. Urinary HAA concentrations including trichloroacetic acid (TCAA) and dichloroacetic acid (DCAA) and serum indicators of liver function, including alanine aminotransferase (ALT), aspartate aminotransferase (AST), and gamma-glutamyltransferase (GGT) were measured. Liver injury was defined as if any of serum indicator levels were above the 90th percentile. Multivariate logistic and linear regression models were fitted to assess the associations of urinary HAA concentrations with the risk of liver injury and liver function indicators. Stratified analyses by age, body mass index (BMI), alcohol use, and passive smoking were also applied to evaluate the potential effect modifiers. RESULTS: There is little evidence of associations of urinary TCAA concentrations with liver injury risk and liver function indicators. However, urinary DCAA concentrations were associated with a higher risk of liver injury [odds ratios (OR) for 1-interquartile range (IQR) increase in natural log (ln) transformed DCAA concentrations: 1.45; 95% confidence interval (CI): 1.07, 1.98]. This association was observed only among nondrinkers (pinteraction=0.058). We also found that a 1-IQR increase in ln-transformed DCAA concentrations was positively associated with ALT levels (percentage change=6.06%; 95% CI: 0.48%, 11.95%) and negatively associated with AST/ALT (percentage change=-4.48%; 95% CI: -7.80%, -1.04%). In addition, urinary DCAA concentrations in relation to higher GGT levels was observed only among passive smokers (pinteraction=0.040). CONCLUSION: Our findings suggest that exposure to DCAA but not TCAA is associated with liver injury among women undergoing assisted reproductive technology. https://doi.org/10.1289/EHP13386.

Detangling electrolyte chemical dynamics in lithium sulfur batteries by operando monitoring with optical resonance combs.

Challenges in enabling next-generation rechargeable batteries with lower cost, higher energy density, and longer cycling life stem not only from combining appropriate materials, but from optimally using cell components. One-size-fits-all approaches to operational cycling and monitoring are limited in improving sustainability if they cannot utilize and capture essential chemical dynamics and states of electrodes and electrolytes. Herein we describe and show how the use of tilted fiber Bragg grating (TFBG) sensors to track, via the monitoring of both temperature and refractive index metrics, electrolyte-electrode coupled changes that fundamentally control lithium sulfur batteries. Through quantitative sensing of the sulfur concentration in the electrolyte, we demonstrate that the nucleation pathway and crystallization of Li2S and sulfur govern the cycling performance. With this technique, a critical milestone is achieved, not only towards developing chemistry-wise cells (in terms of smart battery sensing leading to improved safety and health diagnostics), but further towards demonstrating that the coupling of sensing and cycling can revitalize known cell chemistries and break open new directions for their development.

Mitopherogenesis, a form of mitochondria-specific ectocytosis, regulates sperm mitochondrial quantity and fertility.

Mitochondrial export into the extracellular space is emerging as a fundamental cellular process implicated in diverse physiological activities. Although a few studies have shed light on the process of discarding damaged mitochondria, how mitochondria are exported and the functions of mitochondrial release remain largely unclear. Here we describe mitopherogenesis, a formerly unknown process that specifically secretes mitochondria through a unique extracellular vesicle termed a 'mitopher'. We observed that during sperm development in male Caenorhabditis elegans, healthy mitochondria are exported out of the spermatids through mitopherogenesis and each of the generated mitophers harbours only one mitochondrion. In mitopherogenesis, the plasma membrane first forms mitochondrion-embedding outward buds, which then promptly bud off and thereby result in the generation of mitophers. Mechanistically, extracellular protease signalling in the testis triggers mitopher formation from spermatids, which is partially mediated by the tyrosine kinase SPE-8. Moreover, mitopherogenesis requires normal microfilament dynamics, whereas myosin VI antagonizes mitopher generation. Strikingly, our three-dimensional electron microscopy analyses indicate that mitochondrial quantity requires precise modulation during sperm development, which is critically mediated by mitopherogenesis. Inhibition of mitopherogenesis causes accumulation of mitochondria in sperm, which may lead to sperm motility and fertility defects. Our findings identify mitopherogenesis as a previously undescribed process for mitochondria-specific ectocytosis, which may represent a fundamental branch of mechanisms underlying mitochondrial quantity control to regulate cell functions during development.

Associations between Urinary Concentrations of Disinfection Byproducts and in Vitro Fertilization Outcomes: A Prospective Cohort Study in China.

BACKGROUND: Experimental studies show that disinfection byproducts (DBPs) can inhibit oocyte maturation, decrease fertilization capacity, and impair embryo development, but human evidence is lacking. OBJECTIVES: We aimed to evaluate the associations between exposure to drinking water DBPs and in vitro fertilization (IVF) outcomes. METHODS: The study included 1,048 women undergoing assisted reproductive technology (ART) treatment between December 2018 and January 2020 from a prospective cohort study, the Tongji Reproductive and Environmental study in Wuhan, China. Exposure to DBPs was assessed by dichloroacetic acid (DCAA) and trichloroacetic acid (TCAA) in up to four urine samples, which were collected on the day of both enrollment and oocyte retrieval. Multivariable generalized linear mixed models, accounting for multiple IVF cycles per woman, were applied to evaluate the associations between urinary biomarkers of DBP exposures and IVF outcomes. Stratified analyses were used to explore the potential effect modifiers. RESULTS: The included 1,048 women underwent 1,136 IVF cycles, with 960 (91.6%), 84 (8.0%), and 4 (0.4%) women contributing one cycle, two cycles, and three cycles, respectively. We found that elevated quartiles of urinary DCAA and TCAA concentrations were associated with reduced numbers of total oocytes and metaphase II oocytes and that urinary DCAA concentrations with a lower proportion of best-quality embryos (all p for trends<0.05). Moreover, elevated quartiles of urinary DCAA concentrations were associated with decreased proportions of successful implantation, clinical pregnancy, and live birth (14%, 15%, and 15% decreases in adjusted means comparing the extreme quartiles, respectively; all p for trends<0.05). Stratification analyses showed that the inverse associations of urinary TCAA concentrations with multiple IVF outcomes were stronger among women ≥30 y of age (p for interactions<0.05). DISCUSSION: Exposure to drinking water DBPs was inversely associated with some IVF outcomes among women undergoing ART treatment. Further study is necessary to confirm our findings. https://doi.org/10.1289/EHP12447.

Individual and joint associations of urinary phthalate metabolites with polycystic ovary and polycystic ovary syndrome: Results from the TREE cohort.

Phthalates are widespread endocrine disrupting chemicals that adversely affect female reproductive health. We aimed to investigate the individual and joint associations of phthalate exposures measured by repeated urinary metabolites with polycystic ovary (PCO) and polycystic ovary syndrome (PCOS) (96 PCO cases, 96 PCOS cases and 370 controls). In single-pollutant analyses, mono-isobutyl phthalate (MiBP), monobenzyl phthalate (MBzP) and the sum of di(2-ethylhexyl) phthalate (∑DEHP) were associated with increased prevalence of PCO. Mono(2-ethylhexyl) phthalate (MEHP), MBzP and ∑DEHP were associated with elevated prevalence of PCOS. In multiple-pollutant analyses, one-quartile increase of weighted quantile sum index in phthalate metabolite mixtures was associated with increased prevalence of PCO and PCOS, and MBzP was the most major contributor. Our findings suggest a potential role for phthalate exposures, both individually and in mixtures, in the development of PCO and PCOS.

Oxidatively generated DNA damage mediates the associations of exposure to phthalates with uterine fibroids and endometriosis: Findings from TREE cohort.

BACKGROUND: Epidemiological studies on phthalate exposures in associations with uterine fibroids (UF) and endometriosis (EMT) are inconsistent. The underlying mechanisms are poorly understood. OBJECTIVES: To investigate the relationships of urinary phthalate metabolites with UF and EMT risks, and further to examine the mediating role of oxidative stress. METHODS: This study included 83 and 47 women separately diagnosed with UF and EMT, as well as 226 controls from the Tongji Reproductive and Environmental (TREE) cohort. Two spot urine samples from each woman were analyzed for two oxidative stress indicators and eight urinary phthalate metabolites. Unconditional logistic regression models or multivariate regression models were fitted to evaluate the associations among phthalate exposures, oxidative stress indicators, and the risks of UF and EMT. The potential mediating role of oxidative stress was estimated by the mediation analyses. RESULTS: We observed that each ln-unit increase in urinary mono-benzyl phthalate (MBzP) concentrations was associated with increased UF risk [adjusted OR (aOR): 1.56, 95% CI: 1.20, 2.02], and that each ln-unit increase in urinary MBzP (aOR: 1.48, 95% CI: 1.09, 1.99), mono-isobutyl phthalate (MiBP) (aOR: 1.83, 95% CI: 1.19, 2.82), and mono-2-ethylhexyl phthalate (MEHP) (aOR: 1.66, 95% CI: 1.19, 2.31) concentrations were associated with increased EMT risk (all FDR-adjusted P < 0.05). Moreover, we observed that all tested urinary phthalate metabolites were positively associated with two oxidative stress indicators [4-hydroxy-2-nonenal-mercapturic acid (4-HNE-MA) and 8-hydroxy-2-deoxyguanosine (8-OHdG)], in which 8-OHdG was associated with increased risks of UF and EMT (all FDR-adjusted P < 0.05). The mediation analyses showed that 8-OHdG mediated the positive relationships of MBzP with UF risk, and of MiBP, MBzP, and MEHP with EMT risk, with the estimated intermediary proportion ranging from 32.7% to 48.1%. CONCLUSIONS: Oxidatively generated DNA damage may mediate the positive associations of certain phthalate exposures with the risks of UF and EMT. However, further investigation is warranted to confirm these findings.

Impacts of disinfection byproduct exposures on male reproductive health: Current evidence, possible mechanisms and future needs.

Disinfection byproducts (DBPs) are a class of ubiquitous chemicals in drinking water and inevitably result in widespread human exposures. Potentially adverse health effects of DBP exposures, including reproductive and developmental outcomes, have been increasing public concerns. Several reviews have focused on the adverse pregnancy outcomes of DBPs. This review summarized current evidence on male reproduction health upon exposure to DBPs from toxicological and epidemiological literature. Based on existing experimental studies, there are sufficient evidence showing that haloacetic acids (HAAs) are male reproductive toxicants, including reduced epididymal weight, decreased semen parameters and sperm protein 22, and declined testosterone levels. However, epidemiological evidence remains insufficient to support a link of DBP exposures with adverse male reproductive outcomes, despite that blood and urinary DBP biomarkers are associated with decreased semen quality. Eight potential mechanisms, including germ/somatic cell dysfunction, oxidative stress, genotoxicity, inflammation, endocrine hormones, folate metabolism, epigenetic alterations, and gut microbiota, are likely involved in male reproductive toxicity of DBPs. We also identified knowledge gaps in toxicological and epidemiological studies to enhance future needs.

Synthesis, characterization, DFT studies, and adsorption properties of sulfonated starch synthesized in deep eutectic solvent.

In this study, sulfonated starch (SS) was successfully synthesized using sulfamic acid as a sulfonating agent in a deep eutectic solvent (DES). Four-factor and three-level orthogonal experiments were conducted to determine the optimal preparation conditions, which were found to be a molar ratio of starch to urea of 1:20, a reaction temperature of 90 °C, a reaction time of 5 h, and a stirring speed of 200 rpm. The sulfonation reaction mechanism was extensively studied using various techniques, including Fourier transform infrared spectroscopy, elemental analysis, X-ray diffraction, molecular weight, particle distribution, X-ray photoelectron spectroscopy, scanning electron microscopy, and DFT calculations. The results showed that the sulfonation reaction slightly damaged starch granules, occurred on the surface of starch granules, and on the O6 atoms of the glucose unit. SS exhibited a wide pH range of application (5-10), a fast adsorption rate (400 s to reach adsorption equilibrium), and a high adsorption capacity (118.3 mg/g) under optimal conditions. The adsorption process of SS for methylene blue followed the pseudo-first-order kinetic model and was consistent with the Langmuir model, which was endothermic and spontaneous. The adsorption process was attributed to hydrogen bonding and electrostatic interactions.

In-house fabrication of 1.3 to 7 mm MAS drive caps using desktop 3D printers.

The 3D-printing technology has emerged as a well-developed method to produce parts with considerably low cost and yet with high precision (<100 µm). Recent literature has shown that the 3D-printing technology can be exploited to fabricate a magic-angle spinning (MAS) system in solid-state nuclear magnetic resonance (NMR) spectroscopy. In particular, it was demonstrated that advanced industry-grade 3D printers could fabricate 3.2 mm MAS drive caps with intricate features, and the caps were shown to spin > 20 kHz. Here, we show that not only lab-affordable benchtop 3D printers can produce 3.2 mm drive caps with a similar quality as the commercialized version, but also smaller 2.5 mm and 1.3 mm MAS drive caps-despite a slight compromise in performance. All in-house fabricated drive caps (1.3 to 7 mm) can be consistently reproduced (>90 %) and achieve excellent spinning performances. In summary, the > 3.2 mm systems have similar performances as the commercial systems, while the 2.5- and 1.3-mm caps can spin up to 26 kHz ± 2 Hz, and 46 kHz ± 1 Hz, respectively. The low-cost and fast in-house fabrication of MAS drive caps allows easy prototyping of new MAS drive cap models and, possibly, new NMR applications. For instance, we have fabricated a 4 mm drive cap with a center hole that could allow better light penetration or sample insertion during MAS. Besides, an added groove design on the drive cap allows an airtight seal suitable for probing air- or moisture-sensitive materials. Moreover, the 3D-printed cap was shown to be robust for low-temperature MAS experiments at âˆ¼ 100 K, making it suitable for DNP experiments.

Maternal exposure to nitrosamines in drinking water during pregnancy and birth outcomes in a Chinese cohort.

Maternal exposure to regulated disinfection by-products (DBPs) during pregnancy has been linked with adverse birth outcomes. However, no human studies have focused on drinking water nitrosamines, a group of emerging unregulated nitrogenous DBPs that exhibits genotoxicity and developmental toxicity in experimental studies. This cohort study included 2457 mother-infant pairs from a single drinking water supply system in central China, and maternal trimester-specific and entire pregnancy exposure of drinking water nitrosamines were evaluated. Multivariable linear and Poisson regression models were used to estimate the associations between maternal exposure to nitrosamines in drinking water and birth outcomes [birth weight (BW), low birth weight (LBW), small for gestational age (SGA) and preterm delivery (PTD)]. Elevated maternal N-nitrosodimethylamine (NDMA) exposure in the second trimester and N-nitrosopiperidine (NPIP) exposure during the entire pregnancy were associated with decreased BW (e.g., ß = -88.6 g; 95% CI: -151.0, -26.1 for the highest vs. lowest tertile of NDMA; p for trend = 0.01) and increased risks of PTD [e.g., risk ratio (RR) = 2.16; 95% CI: 1.23, 3.79 for the highest vs. lowest tertile of NDMA; p for trend = 0.002]. Elevated maternal exposure of N-nitrosodiethylamine (NDEA) in the second trimester was associated with increased risk of SGA (RR = 1.80; 95% CI: 1.09, 2.98 for the highest vs. lowest tertile; p for trend = 0.01). Our study detected associations of maternal exposure to drinking water nitrosamines during pregnancy with decreased BW and increased risks of SGA and PTD. These findings are novel but require replication in other study populations.

Urinary concentrations of organophosphate esters in relation to semen quality: A cross-sectional study.

Organophosphate esters (OPEs) are widely used as flame retardants and plasticizers in consumer products. Toxicological studies have indicated that OPEs may affect male reproductive health, but human evidence is inconclusive. In this study, we explored associations of individual and mixtures of OPE exposure with semen quality among 1015 Chinese men from an infertility clinic. After adjusting for potential confounders, we observed that higher diphenyl phosphate (DPHP) and [Bis(2-methylphenyl) phosphate (BMPP)] exposure was associated with increased odds ratios (ORs) of having below-reference total sperm count. Higher bis (2-butoxyethyl) phosphate (BBOEP) exposure was associated with increased ORs of having below-reference progressive motility and total motility. For semen quality parameters modeled as continuous outcomes, inverse associations with individual OPE were still observed. In addition, urinary 1-hydroxy-2-propyl bis (1-chloro-2-propyl) phosphate (BCIPHIPP) concentrations were inversely associated with the percentage of normal morphology while positively associated with the percentage of abnormal heads. Quantile g-computation regression analyses showed that exposure to higher OPE mixtures was associated with lower total sperm motility and normal morphology. Our results indicated that both individual and mixtures of OPE exposure were associated with reduced semen quality.

Blood trihalomethane concentrations in relation to sperm mitochondrial DNA copy number and telomere length among 958 healthy men.

BACKGROUND: In animal and human studies, exposure to trihalomethanes (THMs) has been associated with reduced semen quality. However, the underlying mechanisms remain poorly understood. OBJECTIVE: To investigate the associations of blood THM concentrations with sperm mitochondrial DNA copy number (mtDNAcn) and telomere length (TL) among healthy men. METHODS: We recruited 958 men who volunteered as potential sperm donors. A single blood sample was collected from each participant at recruitment and measured for chloroform (TCM), bromodichloromethane (BDCM), dibromochloromethane (DBCM), and bromoform (TBM) concentrations. Within a 90-day follow-up, the last semen sample provided by each participant was quantified for sperm mtDNAcn and TL. We used multivariable linear regression models to assess the associations between blood THM concentrations and sperm mtDNAcn and TL. We also performed stratified analyses according to the time intervals between baseline blood THM determinations and semen collection (i.e., 0-9, 10-14, 15-69, or >69 days) to explore potential windows of susceptibility. RESULTS: After adjusting for potential confounders, we found inverse associations between quartiles (or categories) of blood TBM, brominated THM (Br-THM, the sum of BDCM, DBCM, and TBM), and total THM (TTHM, the sum of all four THMs) concentrations and sperm mtDNAcn (all P for trend≤0.03). Besides, we found inverse associations between quartiles of blood TCM, Br-THM, chlorinated THM (Cl-THM, the sum of TCM, BDCM, and DBCM), and TTHM concentrations and sperm TL (all P for trend<0.10). Stratified analyses showed stronger associations between Br-THM concentrations and sperm mtDNAcn determined 15-69 days since baseline exposure determinations, and between blood TCM and TTHM concentrations and sperm TL determined >69 days since baseline exposure determinations. CONCLUSION: Exposure to THMs may be associated with sperm mitochondrial and telomeric dysfunction.

Involvement of the oncogenic small nucleolar RNA SNORA24 in regulation of p53 stability in colorectal cancer.

Colorectal cancer (CRC) is a common malignant cancer worldwide. Although the molecular mechanism of CRC carcinogenesis has been studied extensively, the details remain unclear. Small nucleolar RNAs (snoRNAs) have recently been reported to have essential functions in carcinogenesis, although their roles in CRC pathogenesis are largely unknown. In this study, we found that the H/ACA snoRNA SNORA24 was upregulated in various cancers, including CRC. SNORA24 expression was significantly associated with age and history of colon polyps in CRC patient cohorts, with high expression associated with a decreased 5-year overall survival. Our results indicated that the oncogenic function of SNORA24 is mediated by promoting G1/S phase transformation, cell proliferation, colony formation, and growth of xenograft tumors. Furthermore, SNORA24 knockdown induced massive apoptosis. RNA-sequencing and gene ontology (GO) enrichment analyses were performed to explore its downstream targets. Finally, we confirmed that SNORA24 regulates p53 protein stability in a proteasomal degradation pathway. Our study clarifies the oncogenic role of SNORA24 in CRC and advance the current model of the role of the p53 pathway in this process.

Impact of the presence of private hospitals on the spatial equality of healthcare accessibility in Beijing, China.

Providing equal geographical access to hospitals, either in the public or private healthcare sector, is vital and will benefit public health in general. Against the background of the partial privatization of the healthcare sector, the impact of private hospitals on equal healthcare access has been a highly neglected issue. We have applied an assessment methodology to study this situation by comparing the status quo scenario with one without private hospitals, based on accessibility analysis and spatial equality measurements. The case study of Beijing, China revealed a double-sided impact. With the presence of private hospitals, the Gini coefficient of spatial accessibility in urban districts was reduced from 0.03391 to 0.03211, while it increased from 0.1734 to 0.1914 in suburban districts. Thus, private hospitals improved spatial equality in urban districts in Beijing but jeopardized it in suburban districts. These research findings should enlighten policymakers to promote healthcare equality but would also need to be repeated in some other big cities.

Study on the Influencing Factors of Osteoarthritis in Southern China.

Background: Osteoarthritis (OA) is a common chronic disease with numerous and interacting influencing factors, and current inadequate patient perceptions and behaviors in access to care contribute to the difficulties in the diagnosis, treatment, and management of osteoarthritis. Objective: The purpose of this study was to investigate the influencing factors of osteoarthritis (OA) in a southern Chinese population and to provide a scientific basis for the prevention and treatment of OA. Methods: A 1 : 2 matched case-control study was used to select 160 patients with OA from three hospitals in southern China as a case group. Three hundred and twenty cases of the same sex and similar age (within ± 2 years) were selected as the control group, and relevant data were collected for univariate and multivariate conditional logistic regression analysis. Results: There were no significant differences between the two groups of participants in terms of age, sex, and education (P > 0.05). Logistic regression statistical analysis showed that genetic factors (OR = 4.52, 95% CI = 1.56-7.83), body mass index (OR = 2.57, 95% CI = 1.16-5.84), alcohol consumption (OR = 3.81, 95% CI = 1.53-5.87), and a history of external joint limb injury (OR = 3.37, 95% CI = 1.67-5.24) would increase the risk of OA. In contrast, eating more fresh vegetables (OR = 0.08, 95% CI = 0.03-0.31), more fresh fruits (OR = 0.34, 95% CI = 0.12-0.96), more soy products (OR = 0.11, 95% CI = 0.04-0.45), and exposure to sunlight (OR = 0.31, 95% CI = 0.14-0.71) would reduce the OA risk of OA. Conclusion: Obesity, alcohol consumption, and a history of joint trauma all increase the risk of OA in a southern Chinese population, whereas a diet rich in fresh vegetables, fresh fruit, soy products, and sun exposure would reduce the risk of OA. In the future, we should focus on improving patients' awareness of medical care and developing their self-management skills, improving GPs' treatment skills, improving negative attitudes of both doctors and patients, and promoting positive patient care.

Urinary concentrations of polycyclic aromatic hydrocarbon and phthalate metabolite mixtures in relation to semen quality among men attending an infertility clinic.

Previous studies have reported that exposure to phthalates and polycyclic aromatic hydrocarbons (PAHs) is individually associated with altered semen quality, but no human studies have evaluated their joint effects of exposure mixtures, a more real-world scenario. We aimed to explore urinary metabolite mixtures of phthalates and PAHs in associations with semen quality. Repeated spot-urine samples gathered from 695 men attending a fertility clinic were analyzed for urinary metabolites of eight phthalates and ten monohydroxylated-PAHs (OH-PAHs). Principal component analysis (PCA)-multivariable linear regression (MLR) model, quantile g-computation (qg-comp), and Bayesian kernel machine regression (BKMR) were applied to estimate the associations of urinary mixtures of phthalate and OH-PAH metabolites with semen quality. The overall effects of urinary mixtures of phthalate and PAH metabolites on semen quality were not statistically significant. However, hydroxynaphthalene (OHNa) factor identified from PCA was monotonically associated with decreased total sperm count and sperm concentration, whereas di(2-ethylhexyl) phthalate (DEHP) factor was non-monotonically related to increased progressive sperm motility and total sperm motility. Qg-comp and BKMR models confirmed these findings and identified 2-OHNa and 2-OHFlu as the primary negative contributors, whereas MEOHP and MEHP as the primary positive contributors. Our findings suggest that exposure to mixtures of naphthalene and DEHP is associated with altered semen quality. The finding is warranted to confirm in further well-designed epidemiological studies.

SNORD15B and SNORA5C: Novel Diagnostic and Prognostic Biomarkers for Colorectal Cancer.

Colorectal cancer (CRC) is presenting a global public health problem with high incidence and mortality. Early diagnosis and treatment are the most important strategies to improve prognosis of this disease. Besides fecal occult blood test (FOBT) and colonoscopy, the most widely used methods for CRC screening currently, more effective methods for early diagnosis or prognostic prediction for CRC are needed. Small nucleolar RNAs (snoRNAs) is a class of noncoding RNAs (ncRNAs) playing crucial roles in carcinogenesis and considered to be promising tumor biomarker. In this study, we found that SNORD15B, SNORD48, and SNORA5C were significantly upregulated in CRC tissues. High levels of SNORD15B, SNORD48, or SNORA5C predicted poor clinical outcomes of CRC patients. Forced expression of SNORD15B or SNORA5C in CRC cells promoted proliferation and colony formation. In a further investigation, association between the level of SNORD15B/SNORA5C and clinicopathological parameters of CRC patient cohorts was analyzed based on data from The Cancer Genome Atlas (TCGA). We found that high expressions of SNORD15B and SNORA5C were significantly associated with age, lymphatic invasion, and history of colon polyps, and they were proved to be independent risk factors for survival of CRC patients. This study confirms that SNORD15B and SNORA5C have oncogenic effects in carcinogenesis of CRC. The findings suggest the two genes as potential diagnostic and prognostic biomarkers for CRC.

Environmental metal exposure, seminal plasma metabolome and semen quality: Evidence from Chinese reproductive-aged men.

Environmental metal exposure has been associated with decreasing semen quality, but the effects of multiple metal exposure on seminal plasma metabolome remain obscure. In this study, semen and repeated urine samples from 551 volunteers were collected in Wuhan City. Heavy metals and trace elements were measured using inductively coupled plasma mass spectrometer, and seminal plasma metabolomes were acquired using liquid chromatography coupled with high-resolution mass spectrometry. Weighted gene co-expression network analysis showed more than half of the seminal plasma metals were associated with specific metabolite modules, whereas only a few urine metals presented weak associations, indicating that seminal plasma may be an ideal biological sample for male reproductive biomarker discovery and exposure risk assessment. Seminal plasma zinc (Zn) and selenium (Se) concentrations were significantly associated with 22 metabolites (e.g., glycerophospholipids, acyl-carnitines and amino acid derivatives). Among these metabolites, acyl-carnitines were positively associated with semen quality and sperm concentration. Moreover, acyl-carnitines were associated with both Zn and Se exposure, indicating the potential role of carnitine pathway in their toxicity mechanism. Our findings suggest that seminal plasma metabolome connects Zn and Se exposure and sperm concentrations in Chinese men of reproductive age.