Pain, Function and Quality of Life in Temporomandibular Disorder Patients With Different Disc Positions.

BACKGROUND: Whether pain, jaw function and quality of life are correlated with disc positions is controversial, and similar studies evaluating disc positions by magnetic resonance imaging (MRI) are very limited. OBJECTIVE: This study evaluated the pain, mandibular function and quality of life of the temporomandibular disorders (TMDs) patients with different disc positions according to MRI, and the relationship among them. METHODS: Three hundred and thirty-five participants were included. Patients completed questionnaires included the Numeric Rating Scale (NRS), Jaw Functional Limitation Scale 8-item (JFLS-8), the Generalised Anxiety Disorder 7-item (GAD-7), Patient Health Questionnaire 9-item (PHQ-9) and Oral Health Impact Profile for TMD (OHIP-TMD). MRI was conducted to evaluate these diagnoses, resulting in the identification of three distinct categories: normal positioning (NP), disc displacement with reduction (DDwR) and disc displacement without reduction (DDwoR). RESULTS: Participants had the mean age of 28.55 ± 11.10 years (80.90% women). DDwR and DDwoR had a higher percentage of females compared with NP. Significant differences existed among patients in all questionnaires. The DDwoR group had significantly the highest pain, functional limitation and the worst quality of life. Moreover, they experienced the most difficulties in chewing tough foods, yawning, experiencing pain and psychological discomfort. Moreover, the multivariate regression showed that age, female gender, diagnosis as DDwoR, GAD-7 and PHQ-9 were significantly linked to higher functional limitation. Worse quality of life was associated with age, diagnosis as DDwoR, GAD-7 and PHQ-9. CONCLUSIONS: Among patients with different disc positions, DDwoR showed the highest pain, functional limitation and the worst quality of life. Also, NP showed a proportion of chronic pain. Physical pain, psychological discomfort and chewing tough food were regarded as the most impaired. Women who experience anxiety and depression tended to have a higher propotion of dysfunction and a lower quality of life.

Unveiling senescence-associated secretory phenotype in epidermal aging: insights from reversibly immortalized keratinocytes.

Aging of epidermal keratinocytes profoundly impacts skin health, contributing to changes in appearance, barrier function, and susceptibility to diseases. Despite its significance, the molecular mechanisms underlying epidermal aging remain elusive. In this study, a reversible immortalized cell line was established by expressing SV40T in keratinocytes using the Tet-Off lentiviral system. Inducing a senescent phenotype by terminating SV40T expression revealed a significant reduction in mitotic ability, as well as characteristics of cellular aging. RNA sequencing analysis revealed alterations in gene expression and signaling pathways including DNA repair dysfunction, notably senescence-associated secretory phenotype (SASP)-related genes, such as MMP1, SERPINB2 and VEGFA. Our study provides insights into the molecular mechanisms of epidermal aging, offering potential therapeutic targets and highlighting the role of SASP in the aging process.

Antihyperglycemic, Antiaging, and L. brevis Growth-Promoting Activities of an Exopolysaccharide from Agrobacterium sp. FN01 (Galacan) Evaluated in a Zebrafish (Danio rerio) Model.

Agrobacterium sp. are notable for their ability to produce substantial amounts of exopolysaccharides. Our study identified an exopolysaccharide (Galacan, 4982.327 kDa) from Agrobacterium sp. FN01. Galacan is a heteropolysaccharide primarily composed of glucose and galactose at a molar ratio of 25:1. The FT-IR results suggested that Galacan had typical absorption peaks of polysaccharide. The results of periodate oxidation, Smith degradation, and NMR confirmed the presence of structural units, such as ß-D-Galp(→, →3)ß-D-Galp(1→, →2,3)ß-D-Glcp(1→, ß-D-Glcp(1→, and →2)ß-D-Glcp(1→. Galacan demonstrated significant biological activities. In experiments conducted with zebrafish, it facilitated the proliferation of Lactobacillus brevis in the intestinal tract, suggesting potential prebiotic properties. Moreover, in vivo studies revealed its antihyperglycemic effects, as evidenced by significant reductions in blood glucose levels and enhanced fluorescence intensity of pancreatic ß cells in a streptozotocin (STZ)-induced hyperglycemic zebrafish model. Additionally, antiaging assays demonstrated Galacan's ability to inhibit ß-galactosidase activity and enhance telomerase activity in a hydrogen peroxide (HP)-induced aging zebrafish model. These findings emphasized the potential of Galacan as a natural prebiotic with promising applications in diabetes prevention and antiaging interventions.

Vision-Centric BEV Perception: A Survey.

In recent years, vision-centric Bird's Eye View (BEV) perception has garnered significant interest from both industry and academia due to its inherent advantages, such as providing an intuitive representation of the world and being conducive to data fusion. The rapid advancements in deep learning have led to the proposal of numerous methods for addressing vision-centric BEV perception challenges. However, there has been no recent survey encompassing this novel and burgeoning research field. To catalyze future research, this paper presents a comprehensive survey of the latest developments in vision-centric BEV perception and its extensions. It compiles and organizes up-to-date knowledge, offering a systematic review and summary of prevalent algorithms. Additionally, the paper provides in-depth analyses and comparative results on various BEV perception tasks, facilitating the evaluation of future works and sparking new research directions. Furthermore, the paper discusses and shares valuable empirical implementation details to aid in the advancement of related algorithms.

Revealing Gliding-Induced Structural Distortion in High-Nickel Layered Oxide Cathodes for Lithium-Ion Batteries.

After charging to a high state-of-charge (SoC), layered oxide cathodes exhibit high capacities but suffer from gliding-induced structural distortions caused by deep Li depletion within alkali metal (AM) layers, especially for high-nickel candidates. In this study, we identify the essential structure of the detrimental H3 phase formed at high SoC to be an intergrowth structure characterized by random sequences of the O3 and O1 slabs, where the O3 slabs represent Li-rich layers and the O1 slabs denote Li-depleted (or empty) layers that glide from the O3 slabs. Moreover, we adopt two doping strategies targeting different doping sites to eliminate the formation of Li-vacant O1 slabs. First, we introduce direct transition metal (TM) pillars between TMO2 slabs achieved through dopants (e.g., Nb) positioned within AM layers, significantly improving the cycling stability. Second, we introduce indirect Li pillars achieved through dopants located at TM layers to adjust the Li-O bond strength. While this strategy can regulate the uniformity of Li at the slab level, it results in an uneven Li distribution at the particle scale, ultimately failing to enhance the electrochemical performance. Our established research strategy facilitates the realization of diverse pillars between TMO2 slabs through doping, thereby offering guidance for stabilizing high-capacity layered oxide cathodes at high SoC.

Does "zero-strain" lithiated spinel serve as a strain retardant and an irreversible phase transition regulator for layered oxide cathodes?

Layered oxide cathodes encounter structural challenges during cycling, prompting the exploration of an ingenious heterostructure strategy, which incorporates stable components into the layered structure as strain regulators to enhance materials cycle stability. Despite considerable research efforts, identifying suitable, convenient, and cost-effective materials and methods remains elusive. Herein, focused on lithium cobalt oxide (LiCoO2), we utilized its low-temperature polymorph as a strain-retardant embedded within a cathode. Our findings reveal that the low-temperature component, exhibiting zero-strain characteristic, adopts a complex configuration with a predominant lithiated spinel structure, also featuring both cubic-layered and typical-layered configurations. But this composite cathode exhibits a sluggish lithium-ion transport rate, attributed to Co&Li dislocation at the dual structural boundaries and the formation of cobalt(iii) oxide. This investigation presents a pioneering endeavor in employing heterostructure strategies, underscoring the critical role of such strategies in component selection, which ultimately propels the advancement of layered oxide cathode candidates for Li-ion battery technology.

Subcellular localization and function analysis of PINK1 mitron in PD progression: mitron modulates mitochondrial morphology to regulate neuronal death.

Parkinson's disease (PD) is a multi-factorial neurodegenerative disorder. Loss or degeneration of the dopaminergic neurons in the substantia nigra and development of Lewy Bodies in dopaminergic neurons were the defining pathologic changes. MiRNAs fine-tune the protein levels by post-transcriptional gene regulation. MiR-7019-3p is encoded within the 5th intron of PD associated protein PINK1. In present study, we firstly demonstrated miR-7019-3p expression is significantly up regulated in PD mice model and neuron cell models, miR-7019-3p mainly existed in mitochondria, miR-7019-3p could regulate the structure and function of mitochondria in neuronal cells. We predicted and verified that mitochondria associated protein OPA1 and 12s rRNA, 16s rRNA and polycistronic RNA are target genes of miR-7019-3p. Finally, we proved that SP1 protein could independently regulate the expression of miR-7019-3p at the upstream. The evidences in the study suggest the role miR-7019-3p in the regulation of mitochondrial structure and function, and this kind of regulation could be implemented or promoted through the pathway of SP1-miR-7019-3p-OPA1/12s rRNA, 16s rRNA and polycistronic RNA. Our results have suggested a promising and potential therapeutic target for reversing mitochondria dysregulation in neuronal cells during Parkinson's disease process.

Self-sustained smouldering treatment technology for high-moisture sludge: Pilot-scaled tests with continuous operation.

Smouldering is a novel, low-energy, low-cost technology for disposing of sludge with high moisture. Currently, related researches focus on the lab-scale with batch disposal, but more reports about the pilot-scale with continuous process need to be done. Based on our previous research, this study further enlarged the pilot-scale smouldering reactor height from 1.2 m to 2.0 m and provides insight into the smouldering performance under long-term continuous operation and the influence of the discharging residue interval and Darcy velocity. The temperate evolution shows that the discharging residue interval significantly affects the reaction location stability due to the difference between the smouldering upward velocity and the feed-stock descent velocity. Furthermore, the unburnout content, heavy metal in the smouldering-derived residue, the non-condensable flue gas concentrations (O2, CO, NOx, VOCs, dioxin), and the components of the condensable liquid are deeply investigated. The pilot-scale measurements show that 30 s and 40 s for the discharging residue interval under the studied operating condition may be reasonable for the high (3.5 cm/s and 5.0 cm/s) and low (2.5 cm/s) Darcy velocity, respectively. Comprehensively, the condition with 30 s for the discharging residue interval and 3.5 cm/s for the Darcy velocity is suggested in the future actual application.

ß-Hydroxybutyrate dehydrogenase functionalized two-dimensional photonic crystals for quantitative and visual sensing of ketone bodies.

ß-Hydroxybutyrate (BHB) is a substantial physiological ketone body. Its elevated concentration causes ketoacidosis, which is a disorder with a high mortality rate. Therefore, there is an urgent need to develop a simple method for the in-situ monitoring of BHB in urine. In this study, a photonic crystal hydrogel (PCH) sensing material for the detection of urinary ketones was prepared by embedding a two-dimensional polystyrene photonic crystal array (PCA) in a hydrogel functionalized with ß-hydroxybutyrate dehydrogenase (BHBDH). BHBDH catalyzes the interconversion between ß-hydroxybutyrate and acetoacetic acid and relies on the cofactor nicotinamide adenine dinucleotide (NAD+) to participate in the reaction process. The catalytic cycle of converting ß-hydroxybutyrate to acetoacetate generates H+, which reduces the electrostatic repulsion between the carboxyl groups in the hydrogel network, ultimately leading to the shrinkage of the hydrogel volume. The hydrogel volume change was detected by measuring the diameter of the Debye diffraction ring, thus reflecting the concentration of BHB. When the concentration of BHB was increased from 0 to 10 mM, the reflection spectrum of PCH shifted for 117 nm within 60 min, consequently, the structural color of PCH changed from red to green and finally to blue. The material was used for quantitative detection of BHB with a detection limit of 48.94 µM. Then it was used for detection in artificial urine samples. While, this smart and reusable sensing material could provide a more convenient and efficient strategy for the ketone body detection in clinical diagnosis and point-of-care monitoring.

Study on the effect of conditioner on NOx precursor control behavior from sewage sludge pyrolysis: Focusing on conditioner assessments and in-situ fixation mechanism.

The nitrogen transformation during sludge pyrolysis is affected by the dewater conditioner. However, the comparative analysis of the conditioner under identical pyrolysis conditions has been previously absent. In this study, Ca-, Fe- and Al-based conditioners were selected as the representatives. A comprehensive evaluation considering the cost of the conditioners and the product characteristics was conducted. Additionally, the in-situ fixation mechanism of the conditioner on nitrogen-containing gas was concurrently revealed. Among the six conditioners, CaO and AlCl3 were identified as the top performers, ranking first and second, respectively. Furthermore, Fe/Ca-based conditioners reduced NH3 and HCN release by 1.5 âˆ¼ 5.53 % and 0 âˆ¼ 1.55 %, respectively, by facilitating the conversion of amine-N to a more stable form in condensable fraction. Fe promoted volatile amine-N cyclization, while Ca encouraged its dehydrogenation. Both Fe/Ca-based conditioners increased 7.5 âˆ¼ 14.8 % nitrogen retention in char, by inhibiting the decomposition of protein-N. Al-based conditioners had little effect on NH3 and HCN, but contributed to 2.3 âˆ¼ 2.8 % production of stabilized nitrogen in char. The introduction of Cl in Fe/Ca/Al chloride conditioners would promote the decomposition of inorganic ammonium salts to produce NH3 at 30 âˆ¼ 185 °C. And Cl also reacted with volatiles through electrophilic substitution reaction, leading to the formation of halogenated hydrocarbons in condensable fraction and the release of more NH3, HCN, and HNCO at 30 âˆ¼ 465 °C. The findings of this study provide a detailed comparative analysis of various conditioners under uniform conditions and reveal the in-situ fixation mechanism of nitrogen-containing gas. This will provide guidance for the sludge conditioning-dewatering-drying integrated treatment and disposal.

Revealing the Dynamic Evolution of Electrolyte Configuration on the Cathode-Electrolyte Interface by Visualizing (De)Solvation Processes.

Electrolyte engineering is crucial for improving cathode electrolyte interphase (CEI) to enhance the performance of lithium-ion batteries, especially at high charging cut-off voltages. However, typical electrolyte modification strategies always focus on the solvation structure in the bulk region, but consistently neglect the dynamic evolution of electrolyte solvation configuration at the cathode-electrolyte interface, which directly influences the CEI construction. Herein, we reveal an anti-synergy effect between Li+-solvation and interfacial electric field by visualizing the dynamic evolution of electrolyte solvation configuration at the cathode-electrolyte interface, which determines the concentration of interfacial solvated-Li+. The Li+ solvation in the charging process facilitates the construction of a concentrated (Li+-solvent/anion-rich) interface and anion-derived CEI, while the repulsive force derived from interfacial electric field induces the formation of a diluted (solvent-rich) interface and solvent-derived CEI. Modifying the electrochemical protocols and electrolyte formulation, we regulate the "inflection voltage" arising from the anti-synergy effect and prolong the lifetime of the concentrated interface, which further improves the functionality of CEI architecture.

SPL50 Regulates Cell Death and Resistance to Magnaporthe Oryzae in Rice.

BACKGROUND: The identification of spotted leaf 50 (spl50), a novel lesion mimic mutant (LMM) in rice, provides critical insights into the mechanisms underlying programmed cell death (PCD) and innate immunity in plants. RESULTS: Based on ethyl methane sulfonate (EMS)-induced mutagenesis, the spl50 mutant mimics hypersensitive responses in the absence of pathogen by displaying spontaneous necrotic lesions after the tillering phase. SPL50, an ARM repeat protein essential for controlling reactive oxygen species (ROS) metabolism and boosting resistance to blast disease, was identified by map-based cloning techniques. This work also demonstrates the detrimental effects of spl50 on photosynthetic efficiency and chloroplast development. The crucial significance of SPL50 in cellular signaling and stress response is shown by its localization to the cytoplasm and constitutive expression in various plant tissues. In light of growing concerns regarding global food security, this study highlights the pivotal role of SPL50 in regulating programmed cell death (PCD) and enhancing the immune response in plants, contributing to strategies for improving crop disease resistance. CONCLUSIONS: The novel identification of the SPL50 gene in rice, encoding an ARM repeat protein, reveals its pivotal role in regulating PCD and innate immune responses independently of pathogen attack.

Rescue of dead MnO2 for stable electrolytic Zn-Mn redox-flow battery: a metric of mediated and catalytic kinetics.

The virtues of electrolytic MnO2 aqueous batteries are high theoretical energy density, affordability and safety. However, the continuous dead MnO2 and unstable Mn2+/MnO2 electrolysis pose challenges to the practical output energy and lifespan. Herein, we demonstrate bifunctional cationic redox mediation and catalysis kinetics metrics to rescue dead MnO2 and construct a stable and fast electrolytic Zn-Mn redox-flow battery (eZMRFB). Spectroscopic characterizations and electrochemical evaluation reveal the superior mediation kinetics of a cationic Fe2+ redox mediator compared with the anionic ones (e.g. I- and Br-), thus eliminating dead MnO2 effectively. With intensified oxygen vacancies, density functional theory simulations of the reaction pathways further verify the concomitant Fe-catalysed Mn2+/MnO2 electrolysis kinetics via charge delocalization and activated O 2p electron states, boosting its rate capability. As a result, the elaborated eZMRFB achieves a coulombic efficiency of nearly 100%, ultra-high areal capacity of 80 mAh cm-2, rate capability of 20 C and a long lifespan of 2500 cycles. This work may advance high-energy aqueous batteries to next-generation scalable energy storage.

Organo-cation catalyzed enantioselective α-hydroxylation of pyridinone-fused lactones: asymmetric synthesis of SN-38 and irinotecan.

A catalytic asymmetric α-hydroxylation of pyridinone-fused lactones, containing the core structure of camptothecin, is described. Development of a novel spiropyrrolidine amide (SPA) derived triazolium bromide organo-cation catalyst is crucial for a highly enantioselective oxidation, which also accommodates a wide array of lactones with various substituents. The resulting tricyclic tertiary alcohol with an oxa-quaternary carbon center can be further applied in the synthesis of SN-38 and irinotecan, two anti-cancer drugs derived from camptothecin.

Profiling of circulating extracellular vesicle microRNAs reveals diagnostic potential and pathways in non-obstructive and obstructive azoospermia.

The accurate diagnosis of non-obstructive azoospermia (NOA) and obstructive azoospermia (OA) is crucial for selecting appropriate clinical treatments. This study aimed to investigate the pivotal role of miRNAs in circulating plasma extracellular vesicles (EVs) in distinguishing between NOA and OA, as well as uncovering the signaling pathways involved in azoospermia pathogenesis. In this study, differential expression of EV miR-513c-5p and miR-202-5p was observed between NOA and OA patients, while the selenocompound metabolism pathway could be affected in azoospermia through Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analysis. The predictive power of these microRNAs was evaluated using ROC-AUC analysis, demonstrating promising sensitivity, specificity, and area under the curve values. A binomial regression equation incorporating circulating plasma levels of EVs miR-202-5p and miR-513c-5p along with follicle-stimulating hormone was calculated to provide a clinically applicable method for diagnosing NOA and OA. This study presents a potentially non-invasive testing approach for distinguishing between NOA and OA, offering a possibly valuable tool for clinical practice.

Full-Dimensional Analysis of Gaseous Products to Unlocking In Depth Thermal Runaway Mechanism of Li-Ion Batteries.

In this study, state-of-the-art on-line pyrolysis MS (OP-MS) equipped with temperature-controlled cold trap and on-line pyrolysis GC/MS (OP-GC/MS) injected through high-vacuum negative-pressure gas sampling (HVNPGS) programming are originally designed/constructed to identify/quantify the dynamic change of common permanent gases and micromolecule organics from the anode/cathode-electrolyte reactions during thermal runaway (TR) process, and corresponding TR mechanisms are further perfected/complemented. On LiCx anode side, solid electrolyte interphase (SEI) would undergo continuous decomposition and regeneration, and the R-H+ (e.g., HF, ROH, etc.) species derived from electrolyte decomposition would continue to react with Li/LiCx to generate H2. Up to above 200 °C, the O2 would release from the charged NCM cathode and organic radicals would be consumed/oxidized by evolved O2 to form COx, H2O, and more corrosive HF. On the contrary, charged LFP cathode does not present obvious O2 evolution during heating process and the unreacted flammable/toxic organic species would exit in the form of high temperature/high-pressure (HT/HP) vapors within batteries, indicating higher potential safety risks. Additionally, the in depth understanding of the TR mechanism outlined above provides a clear direction for the design/modification of thermostable electrodes and non-flammable electrolytes for safer batteries.

Comparative Efficacy and Acceptability of Endoscopic Methods for Rectal Neuroendocrine Neoplasms with Low Malignant Potential: A Network Meta-analysis.

BACKGROUND/AIMS:  Although endoscopic resection is an effective treatment of rectal neuroendocrine neoplasms (R-NENs) with low malignant potential, there is no consensus on the most recommended endoscopic method. This study aimed to assess the efficacy and acceptability of different endoscopic treatments for R-NENs with low malignant potential. MATERIALS AND METHODS:  We searched databases for studies on treatments of R-NENs using endoscopic resection. These studies comprised techniques such as endoscopic mucosal resection (EMR), endoscopic submucosal dissection (ESD), modified endoscopic mucosal resection (EMRM), modified endoscopic submucosal dissection (ESDM), and transanal endoscopic microsurgery (TEM). The primary outcomes assessed were histological complete resection (HCR). RESULTS:  Overall, 38 retrospective studies (3040 R-NENs) were identified. Endoscopic mucosal resection with a cap (EMRC), endoscopic mucosal resection with ligation (EMRL), ESD, ESDM, and TEM demonstrated higher resectability than did EMR in achieving HCR. Endoscopic mucosal resection, EMRC, EMRL, EMRP, EMRD, and EMRU required shorter operation times than did ESD. Endoscopic mucosal resection, EMRC, ESDM, and TEM incurred lower risks than did ESD. CONCLUSION:  Regarding R-NENs <20 mm with low malignant potential, ESD could be used as the primary treatment. However, TEM may be more effective if supported by economic conditions and hospital facility. With respect to R-NENs <16 mm with low malignant potential, EMRL could be used as the primary treatment. In regard to R-NENs <10 mm with low malignant potential, EMRL, EMRC, and ESD could be used as the primary treatment. However, EMRL and EMRC might be better when operational difficulties and economic conditions were considered.

Unlocking the Na-Storage Behavior in Hard Carbon Anode by Mass Spectrometry.

Hard carbon (HC) is a promising anode candidate for Na-ion batteries (NIBs) because of its excellent Na-storage performance, abundance, and low cost. However, a precise understanding of its Na-storage behavior remains elusive. Herein, based on the D2O/H2SO4-based TMS results collected on charged/discharged state HC electrodes, detailed Na-storage mechanisms (the Na-storage states and active sites in different voltage regions), specific SEI dynamic evolution process (formation, rupture, regeneration and loss), and irreversible capacity contribution (dead Na0, NaH, etc.) were elucidated. Moreover, by employing the online electrochemical mass spectrometry (OEMS) to monitor the gassing behavior of HC-Na half-cell during the overdischarging process, a surprising rehydrogen evolution reaction (re-HER) process at around 0.02 V vs Na+/Na was identified, indicating the occurrence of Na-plating above 0 V vs Na+/Na. Additionally, the typical fluorine ethylene carbonate (FEC) additive was demonstrated to reduce the accumulation of dead Na0 and inhibit the re-HER process triggered by plated Na.

Association between loneliness and mental health among nurses: a cross-sectional research in China.

This study explored the association between loneliness and mental health among nurses in China during the COVID-19 pandemic. This cross-sectional study was conducted from March to April 2022. We enrolled 2,811 nurses from a tertiary hospital in China. Demographic characteristics, lifestyle factors, work-related factors, and psychological characteristics were collected from participants via a self-reported questionnaire. Loneliness was measured with the three-item short form of the Revised UCLA Loneliness Scale, and the Patient Health Questionnaire (PHQ-9) and the General Anxiety Disorder (GAD-7) scale were used to measure mental health. Adjusted odds ratios (ORs) and 95% confidence intervals (CI) were determined using binary logistic regression. Among participants in this study, 12.0% (337) experienced loneliness, and 7.8% (219) and 6.7% (189) reported depression and anxiety, respectively. The loneliness scores were categorized into three levels (3, 4-6, and 7-9). For depression, compared with the lowest reference, the ORs and 95% CI across the tertile were 1.31 (0.69-1.84) and 2.53 (1.11-5.76) after adjustment, respectively, and the P-value for trend was 0.045. For anxiety, compared with the lowest reference, the ORs and 95%CI across the tertile were 1.84 (1.28-2.63) and 2.52 (1.57-4.10) after adjustment, respectively; the P-value for trend was 0.004. This study showed that loneliness was significantly associated with poor mental health among nurses during the COVID-19 pandemic. These findings suggested that medical establishments should offer interventions for nurses to prevent mental health problems by targeting this modifiable risk factor.