Search

Abstract Background Contrast-induced acute kidney injury (CI-AKI) is manifested by a rapid decline in renal function occurring within 48–72 h in patients exposed to iodinated contrast media (CM). Although intravenous hydration is currently the effective method confirmed to prevent CI-AKI, it has several drawbacks. Some investigations have demonstrated the nephroprotective effects of vagus nerve stimulation (VNS) against kidney ischemia-reperfusion injury, but no direct research has investigated the use of VNS for treating CI-AKI. Additionally, most current VNS treatment applies invasive electrical stimulator implantation, which is largely limited by the complications. Our recent publications introduce the magnetic vagus nerve stimulation (mVNS) system pioneered and successfully used for the treatment of myocardial infarction. However, it remains uncertain whether mVNS can mitigate CI-AKI and its specific underlying mechanisms. Therefore, we herein evaluate the potential therapeutic effects of mVNS on CM-induced nephropathy in rats and explore the underlying mechanisms. Results mVNS treatment was found to significantly improve the damaged renal function, including the reduction of elevated serum creatinine (Scr), blood urea nitrogen (BUN), and urinary N-acetyl-β-D-glucosaminidase (NAG) with increased urine output. Pathologically, mVNS treatment alleviated the renal tissue structure injury, and suppressed kidney injury molecule-1 (KIM-1) expression and apoptosis in renal tubular epithelial cells. Mechanistically, increased circulating plasma exosomal miR-365-3p after mVNS treatment enhanced the autophagy and reduced CM-induced apoptosis in renal tubular epithelial cells by targeting Ras homolog enriched in brain (Rheb). Conclusions In summary, we demonstrated that mVNS can improve CI-AKI through enhanced autophagy and apoptosis inhibition, which depended on plasma exosomal miR-365-3p. Our findings highlight the therapeutic potential of mVNS for CI-AKI in clinical practice. However, further research is needed to determine the optimal stimulation parameters to achieve the best therapeutic effects. Graphical abstract

Abstract Background Adverse atherogenic lipid profile is associated with an increased risk of major adverse cardiac events in patients after acute coronary syndrome (ACS). Knowledge regarding the impact of statins on lipid profile remains limited. Methods We retrospectively analysed multicenter, real-world data from the Chinese Cardiovascular Association Database-iHeart Project. Patients with a primary diagnosis of ACS from 2014 to 2021 during index hospitalisation and having at least one lipid panel record after discharge within 12 months were enrolled. We analysed target achievement of atherogenic lipid profile, including apolipoprotein B (

Abstract Background Medication-related osteonecrosis of the Jaw (MRONJ) is a rare but severe side effect in patients treated with medications such as Bisphosphonates (BPs). Its pathophysiological mechanism needs to be more precise. Establishing preventive measures and treatment standards is necessary. This study aimed to develop a composite hydrogel scaffold constituted by methacrylated gelatin (GelMA), methacrylated heparin (HepMA) and PRF, and investigate its potential application value in the prevention of MRONJ. Methods GelMA, HepMA, and PRF were prepared using specific ratios for hydrogel scaffolds. Through mechanical properties and biocompatibility analysis, the release rate of growth factors and the ability to promote bone differentiation in vitro were evaluated. To explore the healing-enhancing effects of hydrogels in vivo, the composite hydrogel scaffold was implanted to the MRONJ rat model. Micro-computed tomography (Micro-CT) and histological examination were conducted to evaluate the bone morphology and tissue regeneration. Results The Hep/GelMA-PRF hydrogel improved the degradation rate and swelling rate. It was also used to control the release rate of growth factors effectively. In vitro, the Hep/GelMA-PRF hydrogel was biocompatible and capable of reversing the inhibitory effect of zoledronic acid (ZOL) on the osteogenic differentiation of MC3T3-E1s. In vivo, the micro-CT analysis and histological evaluation demonstrated that the Hep/GelMA-PRF group exhibited the best tissue reconstruction. Moreover, compared to the ZOL group, the expression of osteogenesis proteins, including osteocalcin (OCN), type collagen I (Col I), and bone morphogenetic protein-2 (BMP-2) in the Hep/GelMA-PRF group were all significantly upregulated (P

Abstract Background The determining effect of facial hard tissues on soft tissue morphology in orthodontic patients has yet to be explained. The aim of this study was to clarify the hard-soft tissue relationships of the lower 1/3 of the face in skeletal Class II-hyperdivergent patients compared with those in Class I-normodivergent patients using network analysis. Methods Fifty-two adult patients (42 females, 10 males; age, 26.58 ± 5.80 years) were divided into two groups: Group 1, 25 subjects, skeletal Class I normodivergent pattern with straight profile; Group 2, 27 subjects, skeletal Class II hyperdivergent pattern with convex profile. Pretreatment cone-beam computed tomography and three-dimensional facial scans were taken and superimposed, on which landmarks were identified manually, and their coordinate values were used for network analysis. Results (1) In sagittal direction, Group 2 correlations were generally weaker than Group 1. In both the vertical and sagittal directions of Group 1, the most influential hard tissue landmarks to soft tissues were located between the level of cemento-enamel junction of upper teeth and root apex of lower teeth. In Group 2, the hard tissue landmarks with the greatest influence in vertical direction were distributed more forward and downward than in Group 1. (2) In Group 1, all the correlations for vertical-hard tissue to sagittal-soft tissue position and sagittal-hard tissue to vertical-soft tissue position were positive. However, Group 2 correlations between vertical-hard tissue and sagittal-soft tissue positions were mostly negative. Between sagittal-hard tissue and vertical-soft tissue positions, Group 2 correlations were negative for mandible, and were positive for maxilla and teeth. Conclusion Compared with Class I normodivergent patients with straight profile, Class II hyperdivergent patients with convex profile had more variations in soft tissue morphology in sagittal direction. In vertical direction, the most relevant hard tissue landmarks on which soft tissue predictions should be based were distributed more forward and downward in Class II hyperdivergent patients with convex profile. Class II hyperdivergent pattern with convex profile was an imbalanced phenotype concerning sagittal and vertical positions of maxillofacial hard and soft tissues.

Abstract Background This study quantitatively analyzed the anatomic structure of the alveolar bone in the maxillary molar region at three potential locations for Temporary Anchorage Device (TAD) placement. Additionally, the study compared the variability in this region across different age groups, sagittal skeletal patterns, vertical facial types, and sexes. Methods In this retrospective cone-beam computed tomography study, the buccal alveolar bone was analyzed in the posterior molar area of 200 patients, the measurement items include buccal alveolar bone height, alveolar bone thickness, interradicular distance, and maxillary retromolar space. Results Buccal alveolar height was greatest in the U56 region. The interradicular space was largest in the U56 region and increased from the alveolar crest to the sinus floor. Buccal alveolar bone thickness was highest in the U67 region and generally increased from the alveolar crest to the sinus floor. The maxillary retromolar space gradually increased from the alveolar crest to the root apex. Conclusions TADs are safest when placed in the buccal area between the maxillary second premolar and the first molar, particularly at the 9 mm plane. The U67 region is the optimal safe zone for TAD placement for maxillary dentition distalization. TADs placement in adolescents can be challenging. Maxillary third molar extraction can be considered for maxillary dentition distalization.

Abstract Background The potentially fatal attacks experienced by porphyria carriers are triggered by various porphyrinogenic drugs. However, determining the safety of particular drugs is challenging. Methods We retrospectively used the U.S. Food and Drug Administration’s Adverse Event Reporting System (FAERS) to identify drugs associated with porphyria as an adverse event (AE) extracted from data from January 2004 to March 2022. The associated search terms included “Porphyria,” “Porphyria screen,” “Porphyria non-acute,” “Porphyria acute,” “Acquired porphyria,” and “Pseudoporphyria.” Signal mining analysis was performed to identify the association between drugs and AEs by four algorithms, namely the reporting odds ratio, proportional reporting ratio, Bayesian confidence propagation neural network, and multi-item gamma Poisson shrinker. Results FAERS reported 1470 cases of porphyria-related AEs, and 406 drugs were screened after combining trade and generic names. All four algorithms identified 52 drugs with signals. The characteristics of all the reports and signaling drugs were analyzed. Conclusions This is the first report of drug-associated porphyria that provides critical information on drug porphyrogenicity, facilitating rational and evidence-based drug prescription and improving the accuracy of porphyrogenicity prediction based on model algorithms. Moreover, this study serves a reference for clinicians to ensure that porphyrinogenic drugs are not prescribed to carriers of porphyria genetic mutations.

Abstract Background Rash is one of common adverse drug reaction and which have been reported in typical and atypical antipsychotics. Reports of lurasidone induced skin reactions are sparse. In this study, we report a case of rash caused by lurasidone. Case presentation A 63-year-old man with bipolar disorder (BD) who is treated by lurasidone. However, the patient presents a rash all over after lurasidone dose increasing from 40 mg/day to 60 mg/day. With the diagnosis of drug induced rash, lurasidone was discontinued, and the rash complete disappears within 2 weeks. In addition, all case reports about antipsychotics associated rash were reviewed by searching English and Chinese database including Pubmed, Embase, Cochrane Library, CNKI and Wanfang database. A total of 139 articles contained 172 patients were included in our study. The literature review and our case suggest that the cutaneous adverse events caused by antipsychotic drugs should not be ignored, particularly for the patient who was first use or at dose increasing of antipsychotic. Conclusions In conclusion, we report a case of lurasidone related rash and review rash caused by antipsychotics. Psychiatrists should be alert to the possibility of the rash caused by antipsychotics, especially the patient was first use of antipsychotics or the antipsychotic dose was increasing.

Abstract Background Exercise has been identified as a promising non-pharmacological therapy for the management of depression, but there is still controversy over which type is most effective. We aimed to compare and rank the types of exercise that improve depression in postmenopausal women by quantifying information from randomized controlled trials (RCTs). Methods The PubMed, Web of Science, SPORTDiscus, CNKI, The Cochrane Library, PsycINFO, EMBASE, and CINAHL Plus databases were searched to identify articles published from inception to 1 March 2024 reporting RCTs that examined the effectiveness of exercise on depression in postmenopausal women. The risk of bias was assessed using the revised Cochrane risk-of-bias tool for RCTs. The quality of the evidence for each comparison was graded using the online confidence in network meta-analysis tool (CINeMA). Standardized mean differences (SMDs) were calculated using the mean and standard deviation of pre-to-post intervention changes and then pooled using a random effects model in a pairwise meta-analysis using Review Manager 5.4. Then, a frequentist network meta-analysis was conducted using a random effects model was conducted to evaluate the efficacy of different exercise types using the network package of Stata 15. Results This study included 26 studies involving 2,170 participants. The pairwise meta-analysis revealed that exercise had a significant positive effect on depression in postmenopausal women (SMD = -0.71, 95% confidence interval [CI] = -0.94 to -0.48; I 2 = 78%). The network meta-analysis revealed that mind-body exercise (SMD = -0.97, 95% CI = -1.28 to -0.67), aerobic exercise (SMD = -0.58, 95% CI = -0.88 to -0.27) and multicomponent exercise (SMD = -0.57, 95% CI = -1.15 to -0.002) significantly reduced depression compared to the control intervention. Mind-body exercise had the highest probability of being the most effective intervention. Exercise interventions also showed positive effects on anxiety. Most studies were judged to have some concerns regarding their risk of bias, and the confidence in evidence was often very low according to CINeMA. Conclusion For postmenopausal women, there is very low to moderate quality evidence that exercise interventions are an effective antidepressant therapy, with mind-body exercise most likely being the optimal type. Trial registration This meta-analysis was prospectively registered with PROSPERO (registration number: CRD42024505425).

Abstract Background Mediterranean diet rich in polyphenolic compounds holds great promise to prevent and alleviate multiple sclerosis (MS), a central nervous system autoimmune disease associated with gut microbiome dysbiosis. Health-promoting effects of natural polyphenols with low bioavailability could be attributed to gut microbiota reconstruction. However, its underlying mechanism of action remains elusive, resulting in rare therapies have proposed for polyphenol-targeted modulation of gut microbiota for the treatment of MS. Results We found that oral ellagic acid (EA), a natural polyphenol rich in the Mediterranean diet, effectively halted the progression of experimental autoimmune encephalomyelitis (EAE), the animal model of MS, via regulating a microbiota-metabolites-immunity axis. EA remodeled the gut microbiome composition and particularly increased the relative abundances of short-chain fatty acids -producing bacteria like Alloprevotella. Propionate (C3) was most significantly up-regulated by EA, and integrative modeling revealed a strong negative correlation between Alloprevotella or C3 and the pathological symptoms of EAE. Gut microbiota depletion negated the alleviating effects of EA on EAE, whereas oral administration of Alloprevotella rava mimicked the beneficial effects of EA on EAE. Moreover, EA directly promoted Alloprevotella rava (DSM 22548) growth and C3 production in vitro. The cell-free supernatants of Alloprevotella rava co-culture with EA suppressed Th17 differentiation by modulating acetylation in cell models. C3 can alleviate EAE development, and the mechanism may be through inhibiting HDAC activity and up-regulating acetylation thereby reducing inflammatory cytokines secreted by pathogenic Th17 cells. Conclusions Our study identifies EA as a novel and potentially effective prebiotic for improving MS and other autoimmune diseases via the microbiota-metabolites-immunity axis. Video Abstract

Abstract Background Cervical cancer is one of the most common gynecological malignancies. Previous studies have shown that the ethanol extract of Sophora moorcroftiana seeds (EESMS) possesses an antiproliferative effect on several tumors in vitro. Therefore, in this study, we assessed the impact of EESMS on human cervical carcinoma (HeLa) cell proliferation. Methods The proliferation and apoptotic effects of HeLa cells treated with EESMS were evaluated using 3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyl tetrazolium bromide assay, dual acridine orange/ethidium bromide double staining, flow cytometry, and western blotting. Single-cell level atomic force microscopy (AFM) was conducted to detect the mechanical properties of HeLa cells, and proteomics and bioinformatics methods were used to elucidate the molecular mechanisms of EESMS. Results EESMS treatment inhibited HeLa cell proliferation by blocking the G0/G1 phase, increasing the expression of Caspase-3 and affecting its mechanical properties, and the EESMS indicated no significant inhibitory effect on mouse fibroblasts L929 cell line. In total, 218 differentially expressed proteins were identified using two-dimensional electrophoresis, and eight differentially expressed proteins were successfully identified using matrix-assisted laser desorption/ionization-time-of-flight mass spectrometry. The differentially expressed proteins were involved in various cellular and biological processes. Conclusion This study provides a perspective on how cells change through biomechanics and a further theoretical foundation for the future application of Sophora moorcroftiana as a novel low-toxicity chemotherapy medication for treating human cervical cancer.

Abstract Background Palliative care and the integration of health and social care have gradually become the key direction of development to address the aging of the population and the growing burden of multimorbidity at the end of life in the elderly. Aims To explore the benefits/effectiveness of the availability and stability of palliative care for family members of terminally ill patients in an integrated institution for health and social care. Methods This prospective observational study was conducted at an integrated institution for health and social care. 230 patients with terminal illness who received palliative care and their family members were included. Questionnaires and scales were administered to the family members of patients during the palliative care process, including quality-of-life (SF-8), family burden (FBSD, CBI), anxiety (HAMA), and distress (DT). We used paired t-tests and correlation analyses to analyze the data pertaining to our research questions. Results In the integrated institution for health and social care, palliative care can effectively improve quality of life, reduce the family’s burden and relieve psychological impact for family members of terminally ill patients. Palliative care was an independent influencing factor on the quality of life, family burden, and psychosocial status. Independently of patient-related and family-related factors, the results are stable and widely applicable. Conclusion The findings underline the availability and stability of palliative care and the popularization of an integrated service model of health and social care for elder adults.

Abstract Background Pharmacist clinics offer professional pharmaceutical services that can improve public health outcomes. However, primary healthcare staff in China face various barriers and challenges in implementing such clinics. To identify existing problems and provide recommendations for the implementation of pharmacist clinics, this study aims to assess the knowledge, attitudes, and practices of pharmacist clinics among primary healthcare providers. Methods A cross-sectional survey based on the Knowledge-Attitude-Practice (KAP) model, was conducted in community health centers (CHCs) and private hospitals in Shanghai, China in May, 2023. Descriptive analytics and the Pareto principle were used to multiple-answer questions. Chi-square test, Fisher’s exact test, and binary logistic regression models were employed to identify factors associated with the knowledge, attitudes, and practices of pharmacist clinics. Results A total of 223 primary practitioners participated in the survey. Our study revealed that most of them had limited knowledge (60.1%, n = 134) but a positive attitude (82.9%, n = 185) towards pharmacist clinics, with only 17.0% (n = 38) having implemented them. The primary goal of pharmacist clinics was to provide comprehensive medication guidance (31.5%, n = 200), with medication education (26.3%, n = 202) being the primary service, and special populations (24.5%, n = 153) identified as key recipients. Logistic regression analysis revealed that education, age, occupation, position, work seniority, and institution significantly influenced their perceptions. Practitioners with bachelor’s degrees, for instance, were more likely than those with less education to recognize the importance of pharmacist clinics in medication guidance (aOR: 7.130, 95%CI: 1.809–28.099, p-value = 0.005) and prescription reviews (aOR: 4.675, 95% CI: 1.548–14.112, p-value = 0.006). Additionally, practitioners expressed positive attitudes but low confidence, with only 33.3% (n = 74) feeling confident in implementation. The confidence levels of male practitioners surpassed those of female practitioners (p-value = 0.037), and practitioners from community health centers (CHCs) exhibited higher confidence compared to their counterparts in private hospitals (p-value = 0.008). Joint physician-pharmacist clinics (36.8%, n = 82) through collaboration with medical institutions (52.0%, n = 116) emerged as the favored modality. Daily sessions were preferred (38.5%, n = 86), and both registration and pharmacy service fees were considered appropriate for payment (42.2%, n = 94). The primary challenge identified was high outpatient workload (30.9%, n = 69). Conclusions Although primary healthcare practitioners held positive attitudes towards pharmacist clinics, limited knowledge, low confidence, and high workload contributed to the scarcity of their implementation. Practitioners with diverse sociodemographic characteristics, such as education, age, and institution, showed varying perceptions and practices regarding pharmacist clinics.

Abstract Background The operation accuracy and efficiency of dynamic navigated endodontic surgery were evaluated through in vitro experiments. This study provides a reference for future clinical application of dynamic navigation systems in endodontic surgery. Materials and methods 3D-printed maxillary anterior teeth were used in the preparation of models for endodontic surgery. Endodontic surgery was performed with and without dynamic navigation by an operator who was proficient in dynamic navigation technology but had no experience in endodontic surgery. Optical scanning data were applied to evaluate the length and angle deviations of root-end resection. And the operation time was recorded. T tests were used to analyze the effect of dynamic navigation technology on the accuracy and duration of endodontic surgery. Results With dynamic navigation, the root-end resection length deviation was 0.46 ± 0.06 mm, the angle deviation was 2.45 ± 0.96°, and the operation time was 187 ± 22.97 s. Without dynamic navigation, the root-end resection length deviation was 1.20 ± 0.92 mm, the angle deviation was 16.20 ± 9.59°, and the operation time was 247 ± 61.47 s. Less deviation was achieved and less operation time was spent with than without dynamic navigation (P

Abstract Background Acute ischemic stroke is a common neurological disease with a significant financial burden but lacks effective drugs. Hypoxia-inducible factor (HIF) and prolyl hydroxylases (PHDs) participate in the pathophysiological process of ischemia. However, whether FG4592, the first clinically approved PHDs inhibitor, can alleviate ischemic brain injury remains unclear. Methods The infarct volumes and behaviour tests were first analyzed in mice after ischemic stroke with systemic administration of FG4592. The knockdown of HIF-1α and pretreatments of HIF-1/2α inhibitors were then used to verify whether the neuroprotection of FG4592 is HIF-dependent. The targets predicting and molecular docking methods were applied to find other targets of FG4592. Molecular, cell biological and gene knockdown methods were finally conducted to explore the potential neuroprotective mechanisms of FG4592. Results We found that the systemic administration of FG4592 decreased infarct volume and improved neurological defects of mice after transient or permanent ischemia. Meanwhile, FG4592 also activated autophagy and inhibited apoptosis in peri-infarct tissue of mice brains. However, in vitro and in vivo results suggested that the neuroprotection of FG4592 was not classical HIF-dependent. 2-oxoglutarate and iron-dependent oxygenase domain-containing protein 1 (OGFOD1) was found to be a novel target of FG4592 and regulated the Pro-62 hydroxylation in the small ribosomal protein s23 (Rps23) with the help of target predicting and molecular docking methods. Subsequently, the knockdown of OGFOD1 protected the cell against ischemia/reperfusion injury and activated unfolded protein response (UPR) and autophagy. Moreover, FG4592 was also found to activate UPR and autophagic flux in HIF-1α independent manner. Blocking UPR attenuated the neuroprotection, pro-autophagy effect and anti-apoptosis ability of FG4592. Conclusion This study demonstrated that FG4592 could be a candidate drug for treating ischemic stroke. The neuroprotection of FG4592 might be mediated by inhibiting alternative target OGFOD1, which activated the UPR and autophagy and inhibited apoptosis after ischemic injury. The inhibition of OGFOD1 is a novel therapy for ischemic stroke.

Abstract Background Toxoplasma gondii is an important protozoan pathogen with medical and veterinary importance worldwide. Drugs currently used for treatment of toxoplasmosis are less effective and sometimes cause serious side effects. There is an urgent need for the development of more effective drugs with relatively low toxicity. Methods The effect of tylosin on the viability of host cells was measured using CCK8 assays. To assess the inhibition of tylosin on T. gondii proliferation, a real-time PCR targeting the B1 gene was developed for T. gondii detection and quantification. Total RNA was extracted from parasites treated with tylosin and then subjected to transcriptome analysis by RNA sequencing (RNA-seq). Finally, murine infection models of toxoplasmosis were used to evaluate the protective efficacy of tylosin against T. gondii virulent RH strain or avirulent ME49 strain. Results We found that tylosin displayed low host toxicity, and its 50% inhibitory concentration was 175.3 μM. Tylsoin also inhibited intracellular T. gondii tachyzoite proliferation, with a 50% effective concentration of 9.759 μM. Transcriptome analysis showed that tylosin remarkably perturbed the gene expression of T. gondii, and genes involved in “ribosome biogenesis (GO:0042254)” and “ribosome (GO:0005840)” were significantly dys-regulated. In a murine model, tylosin treatment alone (100 mg/kg, i.p.) or in combination with sulfadiazine sodium (200 mg/kg, i.g.) significantly prolonged the survival time and raised the survival rate of animals infected with T. gondii virulent RH or avirulent ME49 strain. Meanwhile, treatment with tylosin significantly decreased the parasite burdens in multiple organs and decreased the spleen index of mice with acute toxoplasmosis. Conclusions Our findings suggest that tylosin exhibited potency against T. gondii both in vitro and in vivo, which offers promise for treatment of human toxoplasmosis. Graphical Abstract

Abstract Aim of this comparative cross-sectional study was to evaluate the effect of anterior teeth retraction and related hard and soft tissue change under physiologic anchorage control in patients with chief complain of protrusive teeth. 68 Class I or II orthodontic patients undergoing four-premolar extraction and requiring maximum or medium anchorage were included. Patients were treated with physiologic anchorage control technique (PASS group, n = 34, 18.6 ± 7.7 years, 10 male and 24 female) and self-ligation technique (Damon group, n = 34, 17.5 ± 5.4 years, 13 male and 21 female), respectively. TADs were used for anchorage reinforcement in Damon group. Pre- and post-treatment cephalograms were collected. Twenty-six skeletal, dental and soft tissue items were measured and analyzed using a blinded method. T test and paired rank-sum test were used for statistical analysis. The baseline characteristics were similar between groups (P > 0.05). After treatment, inter-group comparison showed statistically significant differences in the decrease of skeletal measurements ∠ANB (− 0.73 ± 1.05° in PASS group and − 0.25 ± 0.84° in the Damon group), Wits value (− 2.56 ± 2.29 mm in PASS group and − 0.47 ± 2.15 mm in Damon group) and soft tissue measurement UL-E (− 2.75 ± 1.36 mm in PASS group and − 2.03 ± 1.30 mm in Damon group) and the increase of FCA and Z angle, which was 2.03 ± 2.12°and 9.52 ± 4.78°in PASS group and 0.97 ± 2.12°and 6.96 ± 4.43°in Damon group, respectively (P

Abstract Purpose Benign skin lesions in zygomatic-infraorbital regions severely influence pediatric patients’ appearance as well as mental health. Treatments are difficult for the high requirements of patients’ guardians in both function and aesthetics. The present study aims to introduce a surgical method, Expanded Multi-Lobe Cervicofacial Flap, which combines the advantages of the classical cervicofacial advancement rotation flap and the tissue expansion technique. Methods A total of 21 pediatric patients were enrolled. The treatment process included 2 stages: implantation of the skin tissue expander and flap transfer. The excessive skin created by tissue expansion extended the coverage area of the multi-lobe flap. Results In this retrospective study, follow-up periods were all more than 12 months (20.8 ± 6.7). In the last follow-ups, the flaps were all in good condition, and No facial organ displacement was observed. The patients’ guardians were satisfied with the outcomes. Conclusions Using the expanded multi-lobe cervicofacial flap for the zygomatic-infraorbital benign skin lesion repair is effective, and this method is especially applicable to the pediatric population.

Abstract Background Eccentric muscle contraction can cause muscle damage, which reduces the efficiency of exercise. Previous evidence suggested that Sodium salicylate (SS) could improve the repair of aged muscle. This study intends to investigate whether SS can impact skeletal muscle damage caused by eccentric exercise. Methods Eccentric treadmill exercise was performed to induce muscle damage in mice. Plasma levels of muscle damage markers were estimated. RT-qPCR was employed for detecting mRNA levels of proinflammatory mediators in murine gastrocnemius muscle. Immunofluorescence staining of laminin/DAPI was utilized for quantifying centrally nucleated myofibers in the gastrocnemius muscle. Western blotting was implemented to examine protein levels of mitsugumin 53 (MG53), matrix metalloproteinase (MMP)-2/9, and NF-κB signaling-related markers. Results SS administration reduced muscle damage marker production in the plasma and decreased the levels of proinflammatory mediators, MG53 and MMP-2/9 in mice after exercise. SS alleviated the severity of muscle damage in the gastrocnemius of mice after eccentric exercise. SS blocked NF-κB signaling pathway in the gastrocnemius muscle. Conclusion SS administration ameliorates skeletal muscle damage caused by eccentric exercise in the mouse model.

Abstract Objectives This study aimed to investigate vertical changes in the maxillary central incisor and the maxillary first molar, along with alterations in the mandibular plane angle during space closure using miniscrew sliding mechanics. Methods Twenty adult patients treated at Peking University Hospital of Stomatology between 2008 and 2013 were included. Digital dental models and craniofacial cone-beam computed tomography (CBCT) scans were obtained at the start of treatment (T0) and immediately after space closure (T1). Stable miniscrews were used for superimposing maxillary digital dental models (T0 and T1), and vertical changes in the maxillary first molar and the maxillary central incisor were measured. Three-dimensional changes in the mandibular plane were assessed through CBCT superimposition. Results The maxillary central incisor exhibited an average extrusion of 2.56 ± 0.18 mm, while the maxillary first molar showed an average intrusion of 1.25 ± 1.11 mm with a distal movement of 0.97 ± 0.99 mm. Additionally, the mandibular plane angle decreased by an average of 0.83 ± 1.65°. All three indices exhibited statistically significant differences. Conclusion During space closure using the miniscrew sliding technique, significant changes occurred in both the sagittal and vertical dimensions of the upper dentition. This included extrusion of the maxillary central incisors, intrusion of the maxillary first molars, and a slight counterclockwise rotation of the mandibular plane.

Abstract Background Early detection of hepatocellular carcinoma (HCC) is important in order to improve patient prognosis and survival rate. Methylation sequencing combined with neural networks to identify cell-free DNA (cfDNA) carrying aberrant methylation offers an appealing and non-invasive approach for HCC detection. However, some limitations exist in traditional methylation detection technologies and models, which may impede their performance in the read-level detection of HCC. Methods We developed a low DNA damage and high-fidelity methylation detection method called No End-repair Enzymatic Methyl-seq (NEEM-seq). We further developed a read-level neural detection model called DeepTrace that can better identify HCC-derived sequencing reads through a pre-trained and fine-tuned neural network. After pre-training on 11 million reads from NEEM-seq, DeepTrace was fine-tuned using 1.2 million HCC-derived reads from tumor tissue DNA after noise reduction, and 2.7 million non-tumor reads from non-tumor cfDNA. We validated the model using data from 130 individuals with cfDNA whole-genome NEEM-seq at around 1.6X depth. Results NEEM-seq overcomes the drawbacks of traditional enzymatic methylation sequencing methods by avoiding the introduction of unmethylation errors in cfDNA. DeepTrace outperformed other models in identifying HCC-derived reads and detecting HCC individuals. Based on the whole-genome NEEM-seq data of cfDNA, our model showed high accuracy of 96.2%, sensitivity of 93.6%, and specificity of 98.5% in the validation cohort consisting of 62 HCC patients, 48 liver disease patients, and 20 healthy individuals. In the early stage of HCC (BCLC 0/A and TNM I), the sensitivity of DeepTrace was 89.6 and 89.5% respectively, outperforming Alpha Fetoprotein (AFP) which showed much lower sensitivity in both BCLC 0/A (50.5%) and TNM I (44.7%). Conclusions By combining high-fidelity methylation data from NEEM-seq with the DeepTrace model, our method has great potential for HCC early detection with high sensitivity and specificity, making it potentially suitable for clinical applications. DeepTrace: https://github.com/Bamrock/DeepTrace

Abstract Background Endostar is a strong angiogenesis inhibitor that is effective in treating non-small cell lung cancer (NSCLC), but the effect of Endostar in the treatment of patients with EGFR-TKI-resistant NSCLC remains unclear. We evaluated the clinical efficacy and safety of Endostar in EGFR-mutant NSCLC patients resistant to EGFR inhibition treatment. Methods From January 1, 2016 to June 30, 2018, 68 patients were selected from the 4 institutions for the study. Patients with NSCLC received Endostar plus chemotherapy every 21-day cycle. Chemotherapy types included platinum-containing dual drugs and platinum-free single drugs. Endostar was administered by intermittent intravenous infusion or continuous microinfusion pump infusion. The overall response rate (ORR), disease control rate (DCR) and adverse events were analyzed. Survival of patients was also evaluated. Results For all patients, the median progression-free survival (PFS) was 2.8 months, and the median overall survival (OS) was 14.2 months. PFS and OS in the Endostar pump continuous group were better than those in the Endostar intravenous infusion group. The disease control rate (DCR) was 79.4%. A total of 28 (41.2%) patients experienced varying grades of adverse events during treatment. No treatment-associated deaths were observed. The grade 3 treatment-emergent adverse events (TEAEs) were myelosuppression, weakness, and nausea/vomiting. Conclusions Endostar was effective and well tolerated in advanced NSCLC patients. Endostar treatment showed promising survival results in EGFR-mutant NSCLC patients.

Abstract Background Patinopecten yessoensis, a large and old molluscan group, has been one of the most important aquaculture shellfish in Asian countries because of its high economic value. However, the aquaculture of the species has recently been seriously affected by the frequent outbreaks of Polydora disease, causing great economic losses. Long non-coding RNAs (lncRNAs) exhibit exhibit crucial effects on diverse biological processes, but still remain poorly studied in scallops, limiting our understanding of the molecular regulatory mechanism of P. yessoensis in response to Polydora infestation. Results In this study, a high-throughput transcriptome analysis was conducted in the mantles of healthy and Polydora-infected P. yessoensis by RNA sequencing. A total of 19,133 lncRNAs with 2,203 known and 16,930 novel were identified. The genomic characterizations of lncRNAs showed shorter sequence and open reading frame (ORF) length, fewer number of exons and lower expression levels in comparison with mRNAs. There were separately 2280 and 1636 differentially expressed mRNAs and lncRNAs (DEGs and DELs) detected in diseased individuals. The target genes of DELs were determined by both co-location and co-expression analyses. Functional enrichment analysis revealed that DEGs involved in melanization and biomineralization were significantly upregulated; further, obviously increased melanin granules were observed in epithelial cells of the edge mantle in diseased scallops by histological and TEM study, indicating the crucial role of melanizaiton and biomineralization in P. yessoensis to resist against Polydora infestation. Moreover, many key genes, such as Tyrs, Frizzled, Wnts, calmodulins, Pifs, perlucin, laccase, shell matrix protein, mucins and chitins, were targeted by DELs. Finally, a core lncRNA-mRNA interactive network involved in melanization and biomineralization was constructed and validated by qRT-PCR. Conclusions This work provides valuable resources for studies of lncRNAs in scallops, and adds a new insight into the molecular regulatory mechanisms of P. yessoensis defending against Polydora infestation, which will contribute to Polydora disease control and breeding of disease-resistant varieties in molluscs.

Abstract Background Periodontitis triggers tooth loss and affects the health of population worldwide. Emerging evidence hints that circular RNAs (circRNAs) are involved in various diseases, including periodontitis. This study aimed to investigate the role of circ_0099630 in the progression of periodontitis. Methods Periodontitis cell model was constructed by treating human periodontal ligament cells (HPDLCs) with lipopolysaccharide (LPS). Quantitative real-time PCR was used to analyze the expression of circ_0099630, microRNA-409-3p (miR-409-3p) and toll-like receptor 4 (TLR4) mRNA. Western blot was used for detecting protein levels of TLR4, cleaved-caspase 3, Bcl-2, CyclinD1 and NF-κB signaling markers. For function analyses, cell proliferation was assessed by CCK-8 assay and EdU assay. The releases of pro-inflammation factors were monitored by ELISA kits. The potential relationship between miR-409-3p and circ_0099630 or TLR4 was verified by dual-luciferase reporter assay, RIP assay and pull-down assay. Results The expression of circ_0099630 and TLR4 was elevated in periodontitis patients and LPS-treated HPDLCs. LPS induced HPDLC proliferation inhibition, apoptosis and inflammatory responses, while circ_0099630 knockdown or TLR4 knockdown alleviated these injuries. Besides, TLR4 overexpression reversed the inhibitory effect of circ_0099630 knockdown on LPS-induced HPDLC injuries. Mechanism analysis showed that circ_0099630 positively regulated TLR4 expression by acting as miR-409-3p sponge. MiR-409-3p restoration largely ameliorated LPS-induced HPDLC injuries by depleting TLR4. Moreover, LPS activated the NF-κB signaling pathway, while circ_0099630 knockdown inhibited the activity of NF-κB signaling via the miR-409-3p/TLR4 axis. Conclusion Circ_0099630 knockdown relieved LPS-induced HPDLC injury by miR-409-3p/TLR4 axis, suggesting that circ_0099630 might be a potential target for periodontitis treatment.

Abstract Background Financial barriers in substance use disorder service systems have limited the widespread adoption—i.e., provider-level reach—of evidence-based practices (EBPs) for youth substance use disorders. Reach is essential to maximizing the population-level impact of EBPs. One promising, but rarely studied, type of implementation strategy for overcoming barriers to EBP reach is financing strategies, which direct financial resources in various ways to support implementation. We evaluated financing strategies for the Adolescent Community Reinforcement Approach (A-CRA) EBP by comparing two US federal grant mechanisms, organization-focused and state-focused grants, on organization-level A-CRA reach outcomes. Method A-CRA implementation took place through organization-focused and state-focused grantee cohorts from 2006 to 2021. We used a quasi-experimental, mixed-method design to compare reach between treatment organizations funded by organization-focused versus state-focused grants (164 organizations, 35 states). Using administrative training records, we calculated reach as the per-organization proportion of trained individuals who received certification in A-CRA clinical delivery and/or supervision by the end of grant funding. We tested differences in certification rate by grant type using multivariable linear regression models that controlled for key covariates (e.g., time), and tested threats to internal validity from our quasi-experimental design through a series of sensitivity analyses. We also drew on interviews and surveys collected from the treatment organizations and (when relevant) interviews with state administrators to identify factors that influenced reach. Results The overall certification rates were 27 percentage points lower in state-focused versus organization-focused grants (p = .01). Sensitivity analyses suggested these findings were not explained by confounding temporal trends nor by organizational or state characteristics. We did not identify significant quantitative moderators of reach outcomes, but qualitative findings suggested certain facilitating factors were more influential for organization-focused grants (e.g., strategic planning) and certain barrier factors were more impactful for state-focused grants (e.g., states finding it difficult to execute grant activities). Discussion As the first published comparison of EBP reach outcomes between financing strategies, our findings can help guide state and federal policy related to financing strategies for implementing EBPs that reduce youth substance use. Future work should explore contextual conditions under which different financing strategies can support the widespread implementation of EBPs for substance use disorder treatment.

Abstract Background Assessment of growth-related or treatment-related changes in the maxilla requires a reliable method of superimposition. Such methods are well established for two-dimensional (2D) cephalometric images but not yet for three-dimensions (3D). The aims of this study were to identify natural reference structures (NRS) for the maxilla in growing patients in 3D, opportunistically using orthodontic mini-screws as reference; and to test the applicability of the proposed NRS for maxillary superimposition by assessing the concordance of this approach with Björk’s ‘stable reference structures’ in lateral projection. Methods The stability of the mini-screws was tested on longitudinal pairs of pre- and post-orthodontic cone-beam computed tomography (CBCT) images by measuring the distance changes between screws. After verifying the stability of the mini-screws, rigid registration was performed for aligning the stable mini-screws. Then, non-rigid registration was used to establish the dense voxel-correspondence among CBCT images and calculate the displacement of each voxel belonging to the maxilla relative to the mini-screws. The displacement vectors were transformed to a standardized maxillary template to categorize the stability of the internal structures statistically. Those voxels that displaced less relative to the mini-screws were considered as the natural reference structures (NRS) for the maxilla. Test samples included another dataset of longitudinal CBCT scans. They were used to evaluate the applicability of the proposed NRS for maxillary superimposition. We assessed whether aligning the maxilla with proposed NRS is in concordance with the maxillary internal reference structures superimposition in the traditional 2D lateral view as suggested by Björk. This was quantitively assessed by comparing the mean sagittal and vertical tooth movements for both superimposition methods. Results The stability of the mini-screws was tested on 10 pairs of pre- and post-orthodontic cone-beam computed tomography (CBCT) images (T1: 12.9 ± 0.8 yrs, T2: 14.8 ± 0.7 yrs). Both the loaded and the unloaded mini-screws were shown to be stable during orthodontic treatment, which indicates that they can be used as reference points. By analyzing the deformation map of the maxilla, we confirmed that the infraorbital rims, maxilla around the piriform foramen, the infrazygomatic crest and the hard palate (palatal vault more than 1 cm distal to incisor foramen except the palatal suture) were stable during growth. Another dataset of longitudinal CBCT scans (T1: 12.2 ± 0.63 yrs, T2: 15.2 ± 0.96 yrs) was used to assess the concordance of this approach with Björk’s ‘stable reference structures’. The movement of the maxillary first molar and central incisor showed no statistically significant difference when superimposing the test images with the proposed NRS or with the classic Björk maxillary superimposition in the lateral view. Conclusions The infraorbital rims, maxilla around the piriform foramen, the infrazygomatic crest and the hard palate (palatal vault more than 1 cm posterior to incisal foramen except the palatal suture) were identified as stable regions in the maxilla. These stable structures can be used for maxillary superimposition in 3D and generate comparable results to Björk superimposition in the lateral view.

Abstract Background Breast cancer is the most common cancer affecting women across the world. Tumor endothelial cells (TECs) and malignant cells are the major constituents of the tumor microenvironment (TME), but their origin and role in shaping disease initiation, progression, and treatment responses remain unclear due to significant heterogeneity. Methods Tissue samples were collected from eight patients presenting with breast cancer. Single-cell RNA sequencing (scRNA-seq) analysis was employed to investigate the presence of distinct cell subsets in the tumor microenvironment. InferCNV was used to identify cancer cells. Pseudotime trajectory analysis revealed the dynamic process of breast cancer angiogenesis. We validated the function of small extracellular vesicles (sEVs)-derived protein phosphatase 1 regulatory inhibitor subunit 1B (PPP1R1B) in vitro experiments. Results We performed single-cell transcriptomics analysis of the factors associated with breast cancer angiogenesis and identified twelve subclusters of endothelial cells involved in the tumor microenvironment. We also identified the role of TECs in tumor angiogenesis and confirmed their participation in different stages of angiogenesis, including communication with other cell types via sEVs. Overall, the research uncovered the TECs heterogeneity and the expression levels of genes at different stages of tumor angiogenesis. Conclusions This study showed sEVs derived from breast cancer malignant cells promote blood vessel formation by activating endothelial cells through the transfer of PPP1R1B. This provides a new direction for the development of anti-angiogenic therapies for human breast cancer.

Abstract Objective The aim of this study was to systematically explore the inclination of the lower central incisor and symphysis in alveolar bone in severe skeletal class III patients. Materials and methods A total of 198 severe skeletal class III patients (ANB ≤ -4°) who underwent combined orthodontic and orthognathic treatment were divided into three groups based on the mandibular plane angle (MP-SN). Pretreatment lateral cephalograms were analysed and compared among the three groups. We also assessed cone-beam computed tomography (CBCT) images of 11 samples to investigate the reliability of the cephalometric analysis. Results ANOVA showed no statistically significant differences in the angle between the long axis of the mandibular symphysis and the long axis of the lower central incisor (MIA) among the low-angle, normal-angle and high-angle groups (P > 0.05), while significant differences were found in the angle between the axis of the lower incisor and the mandibular plane (IMPA) among the three groups (P 0.05). Conclusions In severe skeletal class III patients, the long axis of the lower central incisor was highly consistent with the long axis of the mandibular symphysis, which was more obvious in the high-angle subjects. The MIA reflects the physiological inclination of the lower central incisor better than the IMPA.

Abstract Background We aimed to investigate the differences of metabolic disorders between the general population and psychiatric patients, with an emphasis on the prevalence and influencing factors of liver fibrosis in psychiatric patients. Methods A total of 734 psychiatric patients and 734 general population matched for age, sex, and BMI were enrolled from Shanghai, China. All participants underwent blood pressure, glucose, lipid profile measurements, and anthropometric parameters including body weight, height and waist circumference. FibroScan examinations were also performed on psychiatric patients. Liver steatosis and fibrosis were diagnosed by controlled attenuation parameter (CAP) and liver stiffness measurement (LSM) by professional staff. Results Compared with the general population, psychiatric patients revealed significantly higher burden of metabolic disorders. The overall prevalence of liver steatosis (CAP ≥ 233 dB/m) and fibrosis (LSM ≥ 7.0 kPa) was 48.7% and 15.5% in psychiatric patients. Psychiatric patients with liver steatosis or fibrosis showed worse metabolic profile. Meanwhile, the prevalence of liver fibrosis was also significantly higher in patients with overweight, central obesity, diabetes, hypertension, metabolic syndrome, and liver steatosis. In logistic regression analyses, age, BMI and visceral adiposity index were independent risk factors for liver fibrosis in psychiatric patients. Additionally, antipsychotic medication was suggested to be associated with an increased risk of liver fibrosis in psychiatric patients with liver steatosis. Conclusions Prevalence of liver steatosis and fibrosis is high in Chinese psychiatric patients. Those with antipsychotic polypharmacy and obesity are at high risk, and may benefit from early liver assessment in preventing fibrosis progression.

Abstract Periodontitis is the sixth most prevalent chronic disease globally and places significant burdens on societies and economies worldwide. Behavioral modification, risk factor control, coupled with cause-related therapy have been the “gold standard” treatment for managing periodontitis. Given that host inflammatory and immunological responses play critical roles in the pathogenesis of periodontitis and impact treatment responses, several adjunctive strategies aimed at modulating host responses and improving the results of periodontal therapy and maintenance have been proposed. Of the many pharmacological host modulators, we focused on non-steroidal anti-inflammatory drugs (NSAIDs), due to their long history and extensive use in relieving inflammation and pain and reducing platelet aggregation. NSAIDs have been routinely indicated for treating rheumatic fever and osteoarthritis and utilized for the prevention of cardiovascular events. Although several efforts have been made to incorporate NSAIDs into the treatment of periodontitis, their effects on periodontal health remain poorly characterized, and concerns over the risk–benefit ratio were also raised. Moreover, there is emerging evidence highlighting the potential of NSAIDs, especially aspirin, for use in periodontal regeneration. This review summarizes and discusses the use of NSAIDs in various aspects of periodontal therapy and regeneration, demonstrating that the benefits of NSAIDs as adjuncts to conventional periodontal therapy remain controversial. More recent evidence suggests a promising role for NSAIDs in periodontal tissue engineering and regeneration.

Abstract Background Iron-overloaded patients are recognized as presenting an increased risk of osteoporosis. However, studies on the correlation between osteoporosis and organ iron overload are controversial or scarce. The aim of this study is to assess bone mineral density (BMD) and trabecular bone score (TBS) in correlation with hepatic and pancreatic iron overload. Methods Forty-one patients diagnosed with hemoglobinopathies, were studied. BMDs of the lumbar spine (LS), femoral neck (FN), and total hip (TH) were analyzed by Dual-energy X-ray absorptiometry (DXA) scan. LS bone quality was derived from each spine DXA examination using the TBS analysis. Hepatic and pancreatic iron overload were obtained with a multi-echo gradient echo T2* technique. Results Abnormal microarchitecture and abnormal bone mass were observed in 19/41 (46.3%) and 9/41 (22.0%) patients, respectively. For 26 males, BMD, T-score and Z-score of LS were significantly lower among subjects with moderate-severe hepatic iron-overload than their counterparts, as it is between no- and pancreatic iron-overload groups. For 15 females, patients with moderate-severe hepatic iron-overload had significantly lower BMD and T-score of FN and TH, and patients with pancreatic iron-overload had significantly lower BMD, T-score of FN, and lower BMD, T-score and Z-score of TH than their counterparts. Moreover, pancreatic T2*-value was positively correlated with BMD and T-score at all analyzed sites and Z-score at TH. Conclusion These data showed lower bone mass in patients with organ iron overload, particularly for LS in males, FN and TH in females. TBS may well represent a complementary tool for the evaluation of bone quality and the risk of fracture in iron-overloaded patients.

Abstract Background Both depression and anxiety are worldwide burden that is not being abated with our current knowledge and treatment of the condition. Numerous clinical trials have supported that physical activity (PA) can reduce the depression and anxiety in adolescents, but little is known about its mechanism of action. Therefore, the study objectives were to explore the potential relationship between physical activity and depression and anxiety from the perspective of body image and body mass index (BMI), and to provide an important reference for future self-esteem education and health promotion intervention. Methods The participants in this study were 251 Chinese college students between 17 and 22 years old. Participants completed the International Physical Activity Questionnaire-Short Form (IPAQ-SF), the Body Image Questionnaire (BIQ), the Self-rating Depression Scale (SDS) and the Self-rating Anxiety Scale (SAS). A descriptive and correlational approach was used, using the PROCESS macro for Statistical Package for the Social Sciences (SPSS). Results (1) Physical activity was significantly negatively correlated with both depression and anxiety (t = -0.216, p

Abstract Background Chronic kidney disease (CKD) is an important global public health issue. In China, CKD affects a large number of patients and causes a huge economic burden. This study provided a new way to predict the number of patients with CKD and estimate its economic burden in China based on the autoregressive integrated moving average (ARIMA) model. Methods Data of the number of patients with CKD in China from 2000 to 2019 were obtained from the Global Burden of Disease. The ARIMA model was used to fit and predict the number of patients with CKD. The direct and indirect economic burden of CKD were estimated by the bottom-up approach and the human capital approach respectively. Results The results of coefficient of determination (0.99), mean absolute percentage error (0.26%), mean absolute error (343,193.8) and root mean squared error (628,230.3) showed that the ARIMA (1,1,1) model fitted well. Akaike information criterion (543.13) and Bayesian information criterion (546.69) indicated the ARIMA (1,1,1) model was reliable when analyzing our data. The result of relative error of prediction (0.23%) also suggested that the model predicted well. The number of patients with CKD in 2020 to 2025 was predicted to be about 153 million, 155 million, 157 million, 160 million, 163 million and 165 million respectively, accounting for more than 10% of the Chinese population. The total economic burden of CKD from 2019 to 2025 was estimated to be $179 billion, $182 billion, $185 billion, $188 billion, $191 billion, $194 billion and $198 billion respectively. Conclusion The number of patients with CKD and the economic burden of CKD will continue to rise in China. The number of patients with CKD in China would increase by 2.6 million (1.6%) per year on average from 2020 to 2025. Meanwhile, the total economic burden of CKD in China would increase by an average of $3.1 billion per year. The ARIMA model is applicable to predict the number of patients with CKD. This study provides a new perspective for more comprehensive understanding of the future risk of CKD.

Abstract This study prospectively compared the efficacy and safety between matched related donor-hematopoietic stem cell transplantation (MRD-HSCT) (n = 108) and immunosuppressive therapy (IST) plus eltrombopag (EPAG) (IST + EPAG) (n = 104) to determine whether MRD-HSCT was still superior as a front-line treatment for patients with severe aplastic anemia (SAA). Compared with IST + EPAG group, patients in the MRD-HSCT achieved faster transfusion independence, absolute neutrophil count ≥ 1.0 × 109/L (P

Abstract Background Sustained, widespread availability of evidence-based practices (EBPs) is essential to address the public health and societal impacts of adolescent substance use disorders (SUD). There remains a particularly significant need to identify effective financing strategies, which secure and direct financial resources to support the costs associated with EBP implementation and sustainment. This protocol describes a new project comparing two types of U.S. federal grant mechanisms (i.e., a type of financing strategy), which supported the implementation of the Adolescent Community Reinforcement Approach (A-CRA) EBP for SUD, through either organization-focused or state-focused granting of funds. The Exploration-Preparation-Implementation-Sustainment (EPIS) framework will guide our study aims, hypotheses, and selection of measures. Method We will employ a longitudinal, mixed-method (i.e., web surveys, semi-structured interviews, document review, focus groups, administrative data), quasi-experimental design to compare the grant types’ outcomes and examine theoretically informed mediators and moderators. Aim 1 will examine the proportion of eligible clinicians certified in A-CRA with adequate fidelity levels (i.e., penetration outcomes) at the end of grant funding. Aim 2 will examine the sustainment of A-CRA up to 5 years post-funding, using a 10-element composite measure of treatment delivery and supervision activities. We will integrate the new data collected from state-focused grant recipients (~85 organizations in 19 states) with previously collected data from organization-focused grant recipients (Hunter et al., Implement Sci 9:104, 2014) (82 organizations in 26 states) for analysis. We will also use sensitivity analyses to characterize the effects of observed and unobserved secular trends in our quasi-experimental design. Finally, aim 3 will use comparative case study methods (integrating diverse quantitative and qualitative measures) to identify and disseminate policy implications about the roles of state- and organization-focused federal grants in efforts to promote adolescent SUD EBP implementation and sustainment. Discussion The proposed research will have direct, practical implications for behavioral health administrators, policymakers, implementation experts, and the public. It will offer new knowledge that can directly inform financing strategies to support large-scale, sustained EBP delivery in behavioral health—while advancing implementation science through the use of novel methods to study financing strategies and sustainment.

Abstract Background The combined application of immune cells and specific biomarkers related to the tumor immune microenvironment has a better predictive value for the prognosis of HCC. The purpose of this study is to construct a new prognostic model based on immune-related genes that regulate cross-talk between immune and tumor cells to assess the prognosis and explore possible mechanisms. Method The immune cell abundance ratio of 424 cases in the TCGA-LIHC database is obtained through the CIBERSORT algorithm. The differential gene analysis and cox regression analysis is used to screen IRGs. In addition, the function of IRGs was preliminarily explored through the co-culture of M2 macrophages and HCC cell lines. The clinical validation, nomogram establishment and performing tumor microenvironment score were validated. Results We identified 4 immune cells and 9 hub genes related to the prognosis. Further, we identified S100A9, CD79B, TNFRSF11B as an IRGs signature, which is verified in the ICGC and GSE76427 database. Importantly, IRGs signature is closely related to the prognosis, tumor microenvironment score, clinical characteristics and immunotherapy, and nomogram combined with clinical characteristics is more conducive to clinical promotion. In addition, after co-culture with M2 macrophages, the migration capacity and cell pseudopod of MHCC97H increased significantly. And CD79B and TNFRSF11B were significantly down-regulated in MHCC97H, Huh7 and LM3, while S100A9 was up-regulated. Conclusion We constructed an IRGs signature and discussed possible mechanisms. The nomogram established based on IRGs can accurately predict the prognosis of HCC patients. These findings may provide a suitable therapeutic target for HCC.

Abstract Background The Dong people mainly live in Hunan, Guangxi and Guizhou provinces, China, with a long history of glutinous rice cultivation, among which Kam Sweet Rice (KSR) is a group of rice landraces that has been domesticated for thousands of years by the Dong people. The core distribution area of KSR is Liping, Congjiang and Rongjiang County of southeast, Guizhou Province. Paddy fields, forests, livestock and cottages have formed a special artificial wetland ecosystem in local area, and the Dong people have also formed a set of traditional farming systems of KSR for variety breeding, field management, and soil and water conservation. However, this traditional agricultural management has not been reported at multiple levels based on landraces, species and ecosystems. Methods Fieldwork was conducted in ten villages in southeast Guizhou from 2019 to 2021. A total of 229 informants were interviewed from the villages. Semi-structured and key informant interviews were administered to collect ethnoecological data on the characteristics and traditional utilization of KSR, traditional farming systems and agricultural management of the Dong people. Results (1): A total of 57 KSR landraces were recorded as used by the Dong people in southeast Guizhou. We analyzed the cultural importance index (CII) of all KSRs. KSR with high CII often has a pleasant taste, special biological characteristics of cold resistance, disease and insect resistance and high utilization in the traditional culture of Dong people. (2) There is a clear division of labor between men and women in the breeding, seed retention, field management and grain storage management of different landraces of KSR in Dong communities. In order to resist natural disasters and insect pests, the cultivation of KSR is usually managed by multi-variety mixed planting. These agricultural management modes are the result of Dong people’s understanding and adaptation to the local natural geographical environment, as well as the experience and wisdom crystallization of Dong people’s long-term practice. (3) The traditional farmland of Dong People is a typical artificial wetland ecosystem that is planted with mixed KSR landraces with rich traditional wisdom. In addition, the economic benefit of the rice–fish–duck symbiotic system was 3.07 times that of hybrid rice alone; therefore, the rice–fish–duck system not only has the function of maintaining soil, water and ecological balance but also improves the income of Dong people. Conclusion KSR is a special kind of rice that has been domesticated and cultivated by Dong people for thousands of years. Dong people have also formed traditional agriculture dominated by KSR cultivation. The traditional agricultural management of Dong people provides suitable habitats for flora and fauna with biodiversity protection, and convenient conditions for rational utilization and distribution of water resources were also provided. This traditional management mode is of great significance for environmental protection, climate change response, community resource management, sustainable utilization and agricultural transformation in modern society. Therefore, we call for interdisciplinary research in natural and social sciences, in-depth study of the ecological culture of ethnic areas, and sort out treasures conducive to the development of all mankind.

Abstract Background Understanding the processes governing angiosperm seed growth and development is essential both for fundamental plant biology and for agronomic purposes. Master regulators of angiosperm seed development are expressed in a seed-specific manner. However, it is unclear how this seed specificity of transcription is established. In some vertebrates, DNA methylation valleys (DMVs) are highly conserved and strongly associated with key developmental genes, but comparable studies in plants are limited to Arabidopsis and soybean. Castor bean (Ricinus communis) is a valuable model system for the study of seed biology in dicots and source of economically important castor oil. Unlike other dicots such as Arabidopsis and soybean, castor bean seeds have a relatively large and persistent endosperm throughout seed development, representing substantial structural differences in mature seeds. Here, we performed an integrated analysis of RNA-seq, whole-genome bisulfite sequencing, and ChIP-seq for various histone marks in the castor bean. Results We present a gene expression atlas covering 16 representative tissues and identified 1162 seed-specific genes in castor bean (Ricinus communis), a valuable model for the study of seed biology in dicots. Upon whole-genome DNA methylation analyses, we detected 32,567 DMVs across five tissues, covering ~33% of the castor bean genome. These DMVs are highly hypomethylated during development and conserved across plant species. We found that DMVs have the potential to activate transcription, especially that of tissue-specific genes. Focusing on seed development, we found that many key developmental regulators of seed/endosperm development, including AGL61, AGL62, LEC1, LEC2, ABI3, and WRI1, were located within DMVs. ChIP-seq for five histone modifications in leaves and seeds clearly showed that the vast majority of histone modification peaks were enriched within DMVs, and their remodeling within DMVs has a critical role in the regulation of seed-specific gene expression. Importantly, further experiment analysis revealed that distal DMVs may act as cis-regulatory elements, like enhancers, to activate downstream gene expression. Conclusions Our results point to the importance of DMVs and special distal DMVs behaving like enhancers, in the regulation of seed-specific genes, via the reprogramming of histone modifications within DMVs. Furthermore, these results provide a comprehensive understanding of the epigenetic regulator roles in seed development in castor bean and other important crops.

Abstract Background ITPR1 is a key gene for autophagy, but its biological function is still unclear, and there are few studies on the correlation between ITPR1 gene expression and the occurrence and development of breast cancer. Methods Analyze the expression of ITPR1 through online databases such as Oncomine and TIMER. Kaplan–Meier plotter and other databases were used to evaluate the impact of ITPR1 on clinical prognosis. The expression of ITPR1 in analysis of 145 cases of breast cancer and 30 cases of adjacent normal tissue was detected by Immunohistochemistry. Statistical analysis was used to evaluate the clinical relevance and prognostic significance of abnormally expressed proteins. And the Western Blot was used to detect the expression of ITPR1 between breast cancer tissues and cells. The TIMER database studied the relationship between ITPR1 and cancer immune infiltration. And used the ROC plotter database to predict the response of ITPR1 to chemotherapy, endocrine therapy and anti-HER2 therapy in patients with breast cancer. Results Compared with normal breast samples, ITPR1 was significantly lower in patients with breast cancer. And the increased expression of ITPR1 mRNA was closely related to longer overall survival (OS), distant metastasis free survival (DMFS), disease specific survival (DSS) and relapse free survival (RFS) in breast cancer. And the expression level of ITPR1 was higher in patients treated with chemotherapy than untreated patients. In addition, the expression of ITPR1 was positively correlated with related gene markers of immune cells in different types of breast cancer, especially with BRCA basal tissue breast cancer. Conclusion ITPR1 was lower expressed in breast cancer. The higher expression of ITPR1 suggested favorable prognosis for patients. ITPR1 was related to the level of immune infiltration, especially in BRCA-Basal patients. All research results indicated that ITPR1 might affect breast cancer prognosis and participate in immune regulation. In short, ITPR1 might be a potential target for breast cancer therapy.

Abstract Background To establish the digital diagnostic templates by cluster analysis based on a set of cephalometric films and evaluate the outcome of the different treatment methods in the patients affiliated to the same cephalometric morphology template (CMT). These templates could be used for the automatic diagnosis of dentofacial deformities and prediction of treatment outcomes in the future. Methods In this study, we assessed the coordinates of 60 different landmarks on the cephalograms of 2249 patients (14.35 ± 4.99 years, range from 7 to 62) with dentofacial deformities. The cephalometric data were subjected to dentist for clustering without a priori pattern definitions to generate biologically informative CMTs. Three templates were selected to evaluate the treatment outcome of patients affiliated to the same CMT. Results The cluster analysis yielded 21 distinct groups. The total discriminant accuracy was 89.1%, while the cross-validation accuracy was 85.0%, showing that the clusters were robust. All CMTs were automatically created and drawn using a computer, based on the average coordinates of each cluster. Individuals affiliated to the same CMT showed similar dentofacial features. We also evaluated differences in the outcomes of patients affiliated to the same CMT. Conclusions Our results demonstrated the utility of clustering methods for grouping dentofacial deformities with similar dentofacial features. Clustering methods can be used to evaluate the differences in the outcomes of patients affiliated to the same CMT, which has good clinical application value.

Abstract Background When genes responsible for normal embryonic development are abnormally expressed in adults, it can lead to tumor development. This can suggest that the same mechanism that controls embryonic differentiation can also control tumor differentiation. We hypothesize that the malignant phenotype of lung cancer cells could acquire benign characteristics when in contact with an embryonic lung microenvironment. We cultured two lung cancer cell lines in embryonic lung mesenchyme-conditioned medium and evaluated morphological, functional and molecular changes. Methods The human embryonic mesenchymal lung-conditioned medium (hEML-CM) was obtained by culturing lung cells from embryos in the pseudoglandular stage of development. The NSCLC cell lines A549 and H1299 we cultured in the hEML-CM and in a tumor-conditioned medium. Morphological changes were analyzed with optical and transmission electron microscopy. To evaluate the functional effect of conditioned medium in tumor cells, we analyzed cell proliferation, migration, colony formation capacity in 2D and 3D and in vivo tumor growth capacity. The expression of the pluripotency genes OSKM, the adenocarcinoma marker NKX2-1, the lung surfactant proteins SFTP, the myofibroblast marker MYH and DNMT3A/3B was analyzed with qRT-PCR and the presence of the myofibroblast markers vimentin and α-SMA with immunofluorescence. Transcriptomic analysis was performed using Affymetrix arrays. Results The A549 and H1299 cells cultured in hEML-CM lost their epithelial morphology, acquired mesodermal characteristics, and decreased proliferation, migration, and colony formation capacity in 2D and 3D, as well as reduced its capacity to growth in vivo. The expression of OSKM, NKX2-1 and SFTP decreased, while that of DNMT3A/3B, vimentin, α-SMA and MYH increased. Distant matrix analysis based on transcriptomic profile showed that conditioned cells were closer to myoblast and human lung fibroblast than to normal epithelial immortalized lung cells. A total of 1631 for A549 and 866 for H1299 differentially expressed genes between control and conditioned cells were identified. Conclusions To the best of our knowledge, this is the first study to report that stimuli from the embryonic lung can modulate the malignant phenotype of lung cancer cells, control their growth capacity and activate their differentiation into myofibroblasts. These findings could lead to new strategies for lung cancer management.

Abstract Background SATB2-associated syndrome (SAS) is a multisystem disorder caused by mutation of human SATB2 gene. Tooth agenesis is one of the most common phenotypes observed in SAS. Our study aimed at identifying novel variant of SATB2 in a patient with SAS, and to investigate the cellular and molecular mechanism of tooth agenesis caused by SATB2 mutation. Methods We applied whole exome sequencing (WES) to identify the novel mutation of SATB2 in a Chinese patient with SAS. Construction and overexpression of wild-type and the mutant vector was performed, followed by functional analysis including flow cytometry assay, fluorescent immunocytochemistry, western blot, quantitative real-time PCR and Alizarin Red S staining to investigate its impact on hDPSCs and the underlying mechanisms. Results As a result, we identified a novel frameshift mutation of SATB2 (c. 376_378delinsTT) in a patient with SAS exhibiting tooth agenesis. Human DPSCs transfected with mutant SATB2 showed decreased cell proliferation and odontogenic differentiation capacity compared with hDPSCs transfected with wild-type SATB2 plasmid. Mechanistically, mutant SATB2 failed to translocate into nucleus and distributed in the cytoplasm, failing to activate Wnt/β-catenin signaling pathway, whereas the wild-type SATB2 translocated into the nucleus and upregulated the expression of active β-catenin. When we used Wnt inhibitor XAV939 to treat hDPSCs transfected with wild-type SATB2 plasmid, the increased odontogenic differentiation capacity was attenuated. Furthermore, we found that SATB2 mutation resulted in the upregulation of DKK1 and histone demethylase JHDM1D to inhibit Wnt/β-catenin signaling pathway. Conclusion We identified a novel frameshift mutation of SATB2 (c.376_378delinsTT, p.Leu126SerfsX6) in a Chinese patient with SATB2-associated syndrome (SAS) exhibiting tooth agenesis. Mechanistically, SATB2 regulated osteo/odontogenesis of human dental pulp stem cells through Wnt/β-catenin signaling pathway by regulating DKK1 and histone demethylase JHDM1D.

Abstract Background Pancreatoduodenectomy is a complex and challenging procedure that requires meticulous tissue dissection and proficient suturing skills. Minimally invasive surgery with the utilization of robotic platforms has demonstrated advantages in perioperative patient outcomes in retrospective studies. The development of robotic pancreatoduodenectomy (RPD) in specific has progressed significantly, since first reported in 2003, and high-volume centers in pancreatic surgery are reporting large patient series with improved pain management and reduced length of stay. However, prospective studies to assess objectively the feasibility and safety of RPD compared to open pancreatoduodenectomy (OPD) are currently lacking. Methods/design The PORTAL trial is a multicenter randomized controlled, patient-blinded, parallel-group, phase III non-inferiority trial performed in seven high-volume centers for pancreatic and robotic surgery in China (> 20 RPD and > 100 OPD annually in each participating center). The trial is designed to enroll and randomly assign 244 patients with an indication for elective pancreatoduodenectomy for malignant periampullary and pancreatic lesions, as well as premalignant and symptomatic benign periampullary and pancreatic disease. The primary outcome is time to functional recovery postoperatively, measured in days. Secondary outcomes include postoperative morbidity and mortality, as well as perioperative costs. A sub-cohort of 128 patients with pancreatic adenocarcinoma (PDAC) will also be compared to assess the percentage of patients who undergo postoperative adjuvant chemotherapy within 8 weeks, in each arm. Secondary outcomes in this cohort will include patterns of disease recurrence, recurrence-free survival, and overall survival. Discussion The PORTAL trial is designed to assess the feasibility and safety of RPD compared to OPD, in terms of functional recovery as described previously. Additionally, this trial will explore whether RPD allows increased access to postoperative adjuvant chemotherapy, in a sub-cohort of patients with PDAC. Trial registration ClinicalTrials.gov NCT04400357 . Registered on May 22, 2020

Abstract Background High morbidity and mortality due to carbapenem-resistant Gram-negative bacilli (CR-GNB) has led to the resurgence of polymyxin B (PMB) use in the last decade. The aim of our multicenter, real-world study was to evaluate the effectiveness and safety of PMB in the treatment of CR-GNB infections. Methods The real-world study included patients treated with intravenous PMB for at least 7 days during the period of October 2018 through June 2019. Associations between these clinical features and 28-day mortality or all-cause hospital mortality were explored through univariate analyses and multivariable logistic regression. Results The study included 100 patients. Many patients presented with combined chronic conditions, septic shock, mechanical ventilation, and the presence of Klebsiella pneumoniae. The mean duration of PMB therapy was 11 days (range 7–38 days). Temperature (38 °C vs 37.1 °C), white blood cells (14.13 × 109/l vs 9.28 × 109/l), C-reactive protein (103.55 ug/l vs 47.60 ug/l), procalcitonin (3.89 ng/ml vs 1.70 ng/ml) and APACHE II levels (17.75 ± 7.69 vs 15.98 ± 7.95) were significantly decreased after PMB treatment. The bacteria eradication rate was 77.65%. The overall mortality at discharge was 15%, and 28-day mortality was 40%. Major adverse reactions occurred in 16 patients. Nephrotoxicity was observed in 7 patients (7%). Conclusions Our results provide positive clinical and safety outcomes for PMB in the treatment of CR-GNB. Timely and appropriate use of PMB may be particularly useful in treating patients with sepsis in CR-GNB infections.

Abstract Background Liver cancer remains the leading cause of cancer death globally, and the treatment strategies are distinct for each type of malignant hepatic tumors. However, the differential diagnosis before surgery is challenging and subjective. This study aims to build an automatic diagnostic model for differentiating malignant hepatic tumors based on patients’ multimodal medical data including multi-phase contrast-enhanced computed tomography and clinical features. Methods Our study consisted of 723 patients from two centers, who were pathologically diagnosed with HCC, ICC or metastatic liver cancer. The training set and the test set consisted of 499 and 113 patients from center 1, respectively. The external test set consisted of 111 patients from center 2. We proposed a deep learning model with the modular design of SpatialExtractor-TemporalEncoder-Integration-Classifier (STIC), which take the advantage of deep CNN and gated RNN to effectively extract and integrate the diagnosis-related radiological and clinical features of patients. The code is publicly available at https://github.com/ruitian-olivia/STIC-model . Results The STIC model achieved an accuracy of 86.2% and AUC of 0.893 for classifying HCC and ICC on the test set. When extended to differential diagnosis of malignant hepatic tumors, the STIC model achieved an accuracy of 72.6% on the test set, comparable with the diagnostic level of doctors’ consensus (70.8%). With the assistance of the STIC model, doctors achieved better performance than doctors’ consensus diagnosis, with an increase of 8.3% in accuracy and 26.9% in sensitivity for ICC diagnosis on average. On the external test set from center 2, the STIC model achieved an accuracy of 82.9%, which verify the model’s generalization ability. Conclusions We incorporated deep CNN and gated RNN in the STIC model design for differentiating malignant hepatic tumors based on multi-phase CECT and clinical features. Our model can assist doctors to achieve better diagnostic performance, which is expected to serve as an AI assistance system and promote the precise treatment of liver cancer.

Abstract Backgroud To analyze the morphological changes of the anterior alveolar bone after the retraction of incisors in premolar extraction cases and the relationship between incisor retraction and remodeling of the alveolar base represented by points A and B displacements. Methods Pre- (T0) and post-treatment (T1) lateral cephalograms of 308 subjects in the maxilla and 154 subjects in the mandible who underwent the orthodontic treatment with extraction of 2 premolars in upper or lower arches were included. Alveolar bone width and height in both the maxillary and mandible incisor area were measured at T0 and T1 respectively. By superimposing the T0 and T1 cephalometric tracings, changes of points A and B, and the movement of the incisors were also measured. Then the correlation between incisor movement and the displacements of points A and B was analyzed. Results The alveolar bone width (ABW) showed a significant decrease in both maxilla and mandible (P 0.05). The alveolar bone height (ABH) showed a significant increase in the labial side of maxilla and a significant decrease in the lingual side of maxilla and mandible. A strong positive correlation was verified between incisor movement and position changes of points A and B in both horizontal and vertical directions. Conclusions Anterior alveolar bone width and height generally decreased after orthodontic treatment. Incisor retraction led to significant position changes of points A and B. The decrease of anterior alveolar bone due to significant incisor retraction should be taken into account in treatment planning.

Abstract Background Toxoplasma gondii is an obligate intracellular parasite that causes toxoplasmosis. Urine is an easily obtained clinical sample that has been widely applied for diagnostic purposes. However, changes in the urinary proteome during T. gondii infection have never been investigated. Methods Twenty four-hour urine samples were obtained from BALB/c mice with acute infection [11 days post infection (DPI)], mice with chronic infection (35 DPI) and healthy controls, and were analyzed using a label-free liquid chromatography tandem mass spectrometry analysis. Results We identified a total of 13,414 peptides on 1802 proteins, of which 169 and 47 proteins were significantly differentially expressed at acute and chronic infection phases, respectively. Clustering analysis revealed obvious differences in proteome profiles among all groups. Gene ontology analysis showed that a large number of differentially expressed proteins (DEPs) detected in acute infection were associated with biological binding activity and single-organism processes. KEGG pathway enrichment analysis showed that the majority of these DEPs were involved in disease-related and metabolic pathways. Conclusions Our findings revealed global reprogramming of the urine proteome following T. gondii infection, and data obtained in this study will enhance our understanding of the host responses to T. gondii infection and lead to the identification of new diagnostic biomarkers. Graphic Abstract

Abstract Background Castor bean (Ricinus communis L.) is an important oil crop, which belongs to the Euphorbiaceae family. The seed oil of castor bean is currently the only commercial source of ricinoleic acid that can be used for producing about 2000 industrial products. However, it remains largely unknown regarding the origin, domestication, and the genetic basis of key traits of castor bean. Results Here we perform a de novo chromosome-level genome assembly of the wild progenitor of castor bean. By resequencing and analyzing 505 worldwide accessions, we reveal that the accessions from East Africa are the extant wild progenitors of castor bean, and the domestication occurs ~ 3200 years ago. We demonstrate that significant genetic differentiation between wild populations in Kenya and Ethiopia is associated with past climate fluctuation in the Turkana depression ~ 7000 years ago. This dramatic change in climate may have caused the genetic bottleneck in wild castor bean populations. By a genome-wide association study, combined with quantitative trait locus analysis, we identify important candidate genes associated with plant architecture and seed size. Conclusions This study provides novel insights of domestication and genome evolution of castor bean, which facilitates genomics-based breeding of this important oilseed crop and potentially other tree-like crops in future.

Abstract Background Androgen insensitive syndrome (AIS) is a rare genetic disease resulting from androgen receptor (AR) mutations and one of the causes of 46, XY disorder of sexual development (DSD). This study aimed to describe the clinical features and molecular defects of 36 Chinese patients with AR variants and investigate the functional alterations of novel variants in vitro. Material and methods Subjects with AR variants were identified from 150 Chinese 46, XY DSD patients using targeted next-generation sequencing. In-silico and functional assays were performed to evaluate the transcriptional activity and nuclear localization of novel AR variants. Results Eight novel and fifteen reported AR variants were identified. 30.6% (11/36) of patients harbored additional variants other than AR. Mutations in the Arg841 residue were found in 7 unrelated patients. Postpubertal serum gonadotropin levels were significantly elevated in patients with complete AIS (CAIS) compared with those in patients with partial AIS (PAIS) (P

Abstract Background 3D facial scanning has changed the way facial aesthetic is evaluated and has numerous advantages for facial analysis. The specific relationship between lip vermilion morphological changes after orthodontic extraction treatment has not been fully explained. The objective of this study was to evaluate 3D morphological changes after orthodontic extraction treatment in lip vermilion of adult females with dentoalveolar protrusion using a structured light-based scanner. Methods Forty-two female subjects (25.2 ± 1.9 years) were recruited as the treatment group; these patients had undergone extraction treatment and achieved better sagittal profiles. Twenty female subjects (25.5 ± 2.1 years) were enrolled in the non-treatment group; these patients did not require any orthodontic treatment. The follow up time for the treatment group was more than 24 months and for the non-treatment group was more than 12 months. 3D facial scans were captured using 3D CaMega. Six landmarks (Ls, Li, R.Chp, L.Chp, R.Ch, and L.Ch), three linear measurements (mouth height, philtrum width, and mouth width), and three area measurements (upper, lower, and total vermilion area) were measured. The spatial deviations of three volumetric measurements (upper, lower, and total vermilion) were constructed for quantitative analysis. Color-coded displacement map were constructed for visualization of the soft-tissue displacement as qualitative evaluation. Results Mouth height and philtrum width decreased (-0.93 mm and − 1.08 mm, respectively) significantly (p = 0.008 and p = 0.027, respectively), and no significant (p = 0.488) change in mouth width was observed in the treatment group. The lower and total vermilion surface areas decreased (-51.00mm2 and − 69.82mm2, respectively) significantly (p = 0.003 and p = 0.031, respectively) in the treatment group, but no statistically significant (p = 0.752) change was detected in the upper vermilion. In the treatment group, significant retractions were observed in the color-coded displacement map, and three volumetric measurements of vermilion changed significantly (p = 0.012, p = 0.001 and p = 0.004, respectively). Significant differences were found between the treatment group and the non-treatment group in the linear, area and volumetric measurements. Conclusions This study established a method for qualitative and quantitative evaluation of the lip vermilion. Significant 3D retraction of the lip vermilion after the extraction treatment was found, with morphological variation between upper and lower vermilion.

Abstract Background Associations between trajectories of systolic blood pressure (SBP) during pregnancy and pregnant outcomes remain unclear and disparate. Methods Data of 20,353 mothers without chronic hypertension and who delivered live singletons between January, 2014 and November, 2019, was extracted from Taicang register-based cohort. Based on SBP measured during 10 to 40 weeks of gestation, SBP trajectories were explored using latent class growth mixture model, and their associations with maternal and neonatal outcomes were assessed by logistic regression analyses. Results Six heterogeneous SBP trajectories were identified: low delayed-increasing (7.47%), low reverse-increasing (21.88%), low-stable (19.13%), medium-stable (21.64%), medium reverse-increasing (16.47%), and high stable (13.41%) trajectories. The high-stable trajectory had SBP around 125 mmHg in the 10th gestational week, and increased slightly onwards. When compared with the low-stable trajectory, the high-stable trajectory had maximally adjusted odds ratio (95% confidence interval) of 5.28 (2.76–10.10), 1.30 (1.13–1.50), 1.53 (1.12–2.08), 1.32 (1.06–1.65) and 1.64 (1.08–2.48) for gestational hypertension (GH), early-term delivery (ETD), preterm delivery (PTD), small for gestational age and low birth weight (LBW), respectively. Besides, the medium reverse-increasing trajectory showed significantly increased risk of GH and ETD, while the medium-stable trajectory had significantly elevated risk of ETD and PTD. Notably, SBP trajectories slightly but significantly improved risk discrimination of GH, ETD and LBW, over traditional risk factors. Conclusion Women with different SBP trajectories were at varied risk of adverse maternal and fetal outcomes. Meanwhile, our study suggested that BP monitoring during pregnancy is necessary, especially for women with high SBP in early pregnancy or upward trajectory.