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The emergence of multidrug-resistant microorganisms has been termed one of the most common global health threats, emphasizing the discovery of new antibacterial agents. To address this issue, we engineered peptides harboring "RWWWR" as a central motif plus arginine (R) end-tagging and then tested them

Background. This meta-analysis was performed to compare the efficacy and safety of direct oral anticoagulants (DOACs) with vitamin K antagonists (VKAs) for stroke prevention in real-world patients with diabetes and nonvalvular atrial fibrillation (NVAF) through observational studies. Methods. PubMed, Embase, and Web of Science databases were searched up to August 2020 for eligible studies. Outputs were presented as risk ratios (RRs) and corresponding 95% confidence intervals (CIs) by using a random-effect model. Results. Seven observational studies involving 249,794 diabetic NVAF patients were selected. Compared with VKAs, the use of DOACs was associated with significantly reduced risks of stroke ( RR = 0.56 , 95% CI 0.45-0.70; p < 0.00001 ), ischemic stroke ( RR = 0.61 , 95% CI 0.48-0.78; p < 0.0001 ), stroke or systemic embolism (SSE) ( RR = 0.81 , 95% CI 0.68-0.95; p = 0.01 ), myocardial infarction ( RR = 0.69 , 95% CI 0.55-0.88; p = 0.002 ), major bleeding ( RR = 0.75 , 95% CI 0.63-0.90; p = 0.002 ), intracranial hemorrhage ( RR = 0.50 , 95% CI 0.44-0.56; p < 0.00001 ), and major gastrointestinal bleeding ( RR = 0.77 , 95% CI 0.62-0.95; p = 0.02 ), and a borderline significant decrease in major adverse cardiac events ( RR = 0.87 , 95% CI 0.75-1.00; p = 0.05 ) in NVAF patients with diabetes. Conclusion. For patients with NVAF and diabetes in real-world clinical settings, DOACs showed superior efficacy and safety profile over VKAs and significantly reduced risks of stroke, ischemic stroke, SSE, myocardial infarction, major bleeding, intracranial hemorrhage, and major gastrointestinal bleeding.

Talker sex and spatial cues can facilitate segregation of competing speech. However, the spectrotemporal degradation associated with cochlear implants (CIs) can limit the benefit of talker sex and spatial cues. Acoustic hearing in the nonimplanted ear can improve access to talker sex cues in CI users. However, it's unclear whether the CI can improve segregation of competing speech when maskers are symmetrically placed around the target (i.e., when spatial cues are available), compared with acoustic hearing alone. The aim of this study was to investigate whether a CI can improve segregation of competing speech by individuals with unilateral hearing loss.Speech recognition thresholds (SRTs) for competing speech were measured in 16 normal-hearing (NH) adults and 16 unilaterally deaf CI users. All participants were native speakers of Mandarin Chinese. CI users were divided into two groups according to thresholds in the nonimplanted ear: (1) single-sided deaf (SSD); pure-tone thresholds25 dB HL at all audiometric frequencies, and (2) Asymmetric hearing loss (AHL; one or more thresholds25 dB HL). SRTs were measured for target sentences produced by a male talker in the presence of two masker talkers (different male or female talkers). The target sentence was always presented via loudspeaker directly in front of the listener (0°), and the maskers were either colocated with the target (0°) or spatially separated from the target at ±90°. Three segregation cue conditions were tested to measure masking release (MR) relative to the baseline condition: (1) Talker sex, (2) Spatial, and (3) Talker sex + Spatial. For CI users, SRTs were measured with the CI on or off.Binaural MR was significantly better for the NH group than for the AHL or SSD groups ( P0.001 in all cases). For the NH group, mean MR was largest with the Talker sex + spatial cues (18.8 dB) and smallest for the Talker sex cues (10.7 dB). In contrast, mean MR for the SSD group was largest with the Talker sex + spatial cues (14.7 dB), and smallest with the Spatial cues (4.8 dB). For the AHL group, mean MR was largest with the Talker sex + spatial cues (7.8 dB) and smallest with the Talker sex (4.8 dB) and the Spatial cues (4.8 dB). MR was significantly better with the CI on than off for both the AHL ( P = 0.014) and SSD groups ( P0.001). Across all unilaterally deaf CI users, monaural (acoustic ear alone) and binaural MR were significantly correlated with unaided pure-tone average thresholds in the nonimplanted ear for the Talker sex and Talker sex + spatial conditions ( P0.001 in both cases) but not for the Spatial condition.Although the CI benefitted unilaterally deaf listeners' segregation of competing speech, MR was much poorer than that observed in NH listeners. Different from previous findings with steady noise maskers, the CI benefit for segregation of competing speech from a different talker sex was greater in the SSD group than in the AHL group.

Background Diabetic foot (DF) is one of the most common and serious complications of diabetes mellitus (DM), which brings great psychological and economic pressure to patients. This study aimed to evaluate the efficacy of stem cells in the treatment of diabetic foot. Methods All relevant studies in Cochrane, Embase, PubMed, Web of Science, China National Knowledge Infrastructure, and WanFang databases were systematically searched for meta-analysis. The outcomes consisted of ulcer or wound healing rate, amputation rate, new vessels, ankle–brachial index (ABI), transcutaneous oxygen pressure (TcPO2), pain-free walking distance, and rest pain score. Dichotomous outcomes were described as risk ratios (RR) with 95% confidence intervals (CIs), while continuous data were presented as standardized mean differences (SMDs) with 95% CIs. Statistical analysis was performed with RevMan 5.3 software. Results A total of 14 studies with 683 participants were included in the meta-analysis. Meta-analysis showed that stem cell therapy was more effective than conventional therapy in terms of ulcer or wound healing rate [OR = 8.20 (5.33, 12.62)], improvement in lower extremity ischemia(new vessels) [OR = 16.48 (2.88, 94.18)], ABI [MD = 0.13 (0.04, 0.08)], TcO2[MD = 4.23 (1.82, 6.65)], pain-free walking distance [MD = 220.79 (82.10, 359.48)], and rest pain score [MD = − 1.94 (− 2.50, − 1.39)], while the amputation rate was significantly decreased [OR = 0.19 (0.10, 0.36)]. Conclusions The meta-analysis of the current studies has shown that stem cells are significantly more effective than traditional methods in the treatment of diabetic foot and can improve the quality of life of patients after treatment. Future studies should conduct large-scale, randomized, double-blind, placebo-controlled, multicenter trials with high-quality long-term follow-up to demonstrate the most effective cell types and therapeutic parameters for the treatment of diabetic foot.

To systematically analyse and discuss whether suppressive heterogeneous brain tumours (BTs) belong to a common brain network and provide a theoretical basis for identifying BT patients with a high risk of depression and select therapeutic targets for clinical treatment. The PubMed database was systematically searched to obtain relevant case reports, and lesion locations were manually traced to standardised brain templates according to ITK-SNAP descriptive literature. Resting-state functional magnetic resonance imaging data sets were collected from 1,000 healthy adults aged 18–35 years. Each lesion location or functional connectivity area of the lesion network. Connectivity analysis was performed in an MN152 space, and Fisher z-transformation was applied to normalise the distribution of each value in the functional connectivity correlation map, and T maps of each tumour location network were calculated with the T score of individual voxels. This T score indicates the statistical significance of voxelwise connectivity at each tumour location. The lesion networks were thresholded at T = 7, creating binarised maps of brain regions connecting tumour locations, overlaying network maps to identify tumour-sensitive hubs and also assessing specific hubs with other conditional controls. A total of 18 patients describing depression following focal BTs were included. Of these cases, it was reported that depression-related tumours were unevenly distributed in the brain: 89% (16/18) were positively correlated with the left striatum, and the peak of the left striatum lesion network continuously overlapped. The depression-related tumour location was consistent with the tumour suppressor network (89%). These results suggest that sensitive hubs are aligned with specific networks, and specific hubs are aligned with sensitive networks. Brain tumour-related depression differs from acute lesion-related depression and may be related to the mapping of tumours to depression-related brain networks. It can provide an observational basis for the neuroanatomical basis of BT-related depression and a theoretical basis for identifying patients with BTs at high risk of depression and their subsequent clinical diagnosis and treatment.

To investigate the impact of the COVID-19 outbreak on the behaviours, mental health and seizure control of adult patients with epilepsy (PWE) and to identify the correlation of seizure increase and the COVID-19 outbreak to guide the medical care of individuals with epilepsy during a public health crisis.This study was conducted at 28 centres from February 2020 to April 2020. Participants filled out a 62-item online survey including sociodemographic, COVID-19-related, epilepsy-related and psychological variables and were divided into two groups based on whether their seizure frequency increased during the COVID-19 pandemic. Chi-square tests and t-tests were used to test differences in significant characteristics. Multiple logistic regression analyses were used to identify risk factors for seizure worsening.A total of 1,237 adult PWE were enrolled for analysis. Of this sample, 31 (8.33%) patients experienced an increase in seizures during the pandemic. Multivariate logistic regression suggested that feeling nervous about the pandemic (P0.05), poor quality of life (P = 0.001), drug reduction/withdrawal (P = 0.032), moderate anxiety during the COVID-19 outbreak (P = 0.046) and non-seizure free before the COVID-19 outbreak (P0.05) were independently related to seizure increase during the pandemic.During the COVID-19 pandemic, PWE with poor quality of life and mental status, as well as AED reduction/withdrawal, were more likely to experience seizure increase. This observation highlights the importance of early identification of the population at high risk of seizure worsening and implementation of preventive strategies during the pandemic.

Impaired wound healing represents an unsolved medical need with a high impact on patients´ quality of life and global health care. Even though its causes are diverse, ischemic-hypoxic conditions and exacerbated inflammation are shared pathological features responsible for obstructing tissue restoration. In line with this, it has been suggested that promoting a normoxic pro-regenerative environment and accelerating inflammation resolution, by reinstating the lymphatic fluid transport, could allow the wound healing process to be resumed. Our group was first to demonstrate the functional use of scaffolds seeded with photosynthetic microorganisms to supply tissues with oxygen. Moreover, we previously proposed a photosynthetic gene therapy strategy to create scaffolds that deliver other therapeutic molecules, such as recombinant human growth factors into the wound area. In the present work, we introduce the use of transgenic Synechococcus sp. PCC 7002 cyanobacteria (SynHA), which can produce oxygen and lymphangiogenic hyaluronic acid, in photosynthetic biomaterials. We show that the co-culture of lymphatic endothelial cells with SynHA promotes their survival and proliferation under hypoxic conditions. Also, hyaluronic acid secreted by the cyanobacteria enhanced their lymphangiogenic potential as shown by changes to their gene expression profile, the presence of lymphangiogenic protein markers and their capacity to build lymph vessel tubes. Finally, by seeding SynHA into collagen-based dermal regeneration materials, we developed a viable photosynthetic scaffold that promotes lymphangiogenesis in vitro under hypoxic conditions. The results obtained in this study lay the groundwork for future tissue engineering applications using transgenic cyanobacteria that could become a therapeutic alternative for chronic wound treatment. Statement of significance In this study, we introduce the use of transgenic Synechococcus sp. PCC 7002 (SynHA) cyanobacteria, which were genetically engineered to produce hyaluronic acid, to create lymphangiogenic photosynthetic scaffolds for dermal regeneration. Our results confirmed that SynHA cyanobacteria maintain their photosynthetic capacity under standard human cell culture conditions and efficiently proliferate when seeded inside fibrin-collagen scaffolds. Moreover, we show that SynHA supported the viability of co-cultured lymphatic endothelial cells (LECs) under hypoxic conditions by providing them with photosynthetic-derived oxygen, while cyanobacteria-derived hyaluronic acid stimulated the lymphangiogenic capacity of LECs. Since tissue hypoxia and impaired lymphatic drainage are two key factors that directly affect wound healing, our results suggest that lymphangiogenic photosynthetic biomaterials could become a treatment option for chronic wound management.

Objective To examine the longitudinal associations of fetal growth with adverse child growth outcomes and to assess whether maternal metabolic factors modify the associations. Design Prospective cohort study. Setting Born in Guangzhou Cohort Study, China. Population A total of 4818 mother–child pairs. Methods Fetal growth was assessed according to estimated fetal weight (EFW) from 22 weeks of gestation until birth and the measurement of the birthweight. Fetal growth Z‐scores were computed from random effects in the multilevel linear spline models to represent fetal size in early pregnancy (22 weeks of gestation) and growth in mid‐pregnancy (22–27 weeks of gestation), early third trimester (28–36 weeks of gestation) and late third trimester (≥37 weeks of gestation). Main outcome measures Z‐scores for childhood stunting, low weight, overweight or obesity, length/height for age (LAZ/HAZ), weight for age (WAZ) and body mass index for age (BMIZ) at the age of 3 years. Adjusted associations were examined using multiple Poisson or linear regression models. Results Increased Z‐scores of fetal size in early pregnancy and growth in mid‐pregnancy and early third trimester were associated with a higher risk of childhood overweight or obesity (risk ratios 1.25–1.45). Fetal growth in each period was negatively associated with stunting and low weight, with the strongest associations observed for fetal size in early pregnancy and growth in mid‐pregnancy. The results for continuous outcomes (LAZ/HAZ, WAZ and BMIZ) were similar. The associations of fetal growth with overweight or obesity in childhood were stronger among mothers who were underweight and who were overweight or obese than among mothers of normal weight. Conclusions Accelerated fetal growth before 37 weeks of gestation is associated with children who are overweight or obese, whereas the critical period for stunting and low weight occurs before 28 weeks of gestation. Tweetable abstract Fetal growth during different periods is differentially associated with childhood stunting, underweight and overweight or obesity.

Abstract Chlamydia trachomatis (C. trachomatis) is the leading cause of preventable blindness worldwide and the most prevalent cause of bacterial sexually transmitted diseases. At present, there is no available vaccine, and recurrences after antibiotics treatment are substantial problems. Major outer membrane protein (MOMP) accounts for 60% of the outer mass of C. trachomatis, functioning as trimeric porin, and it is highly antigenic. Therefore, MOMP is the most promising candidate for vaccine developing and target therapy of Chlamydia. Affibody, a new class of affinity ligands derived from the Z-domain in the binding region of Staphylococcus aureus protein A, has been the focus of researchers as a viable alternative to antibodies. In this study, the MOMP-targeted affibody molecule (ZMOMP:461) was screened by phage-displayed peptide library. Further, the affinity and specificity were characterized by surface plasmon resonance (SPR) and Western blot. Immunofluorescence assay (IFA) indicated that the MOMP-binding affibody could recognize native MOMP in HeLa229 cells infected C. trachomatis. Immunoprecipitation assay confirmed further that ZMOMP:461 molecule specifically recognizes the epitope on relaxed trimer MOMP. Our findings provide strong evidence that affibody molecule (ZMOMP:461) serves as substitute for MOMP antibody for biological applications and has a great potential for delivering drugs for target therapy. Key points • We screened a novel affibody molecule ZMOMP:461 targeting Chlamydia trachomatis MOMP. • ZMOMP:461 recognizes the recombinant and native MOMP with high affinity and specificity. • ZMOMP:461 could be internalized into live target cells.

Background: Cervical cancer induced by infection with human papillomavirus (HPV) remains a leading cause of mortality for women worldwide although preventive vaccines and early diagnosis have reduced morbidity and mortality. Advanced cervical cancer can only be treated with either chemotherapy or radiotherapy but the outcomes are poor. The median survival for advanced cervical cancer patients is only 16.8 months. Methods: We undertook a structural search of peer-reviewed published studies based on 1). Characteristics of programmed cell death ligand-1/programmed cell death-1(PD-L1/PD-1) expression in cervical cancer and upstream regulatory signals of PD-L1/PD-1 expression, 2). The role of the PD-L1/PD-1 axis in cervical carcinogenesis induced by HPV infection and 3). Whether the PD-L1/PD-1 axis has emerged as a potential target for cervical cancer therapies. Results: One hundred and twenty-six published papers were included in the review, demonstrating that expression of PD-L1/PD-1 is associated with HPV-caused cancer, especially with HPV 16 and 18 which account for approximately 70% of cervical cancer cases. HPV E5/E6/E7 oncogenes activate multiple signalling pathways including PI3K/AKT, MAPK, hypoxia-inducible factor 1α, STAT3/NF-kB and microRNA, which regulate PD-L1/PD-1 axis to promote HPV-induced cervical carcinogenesis. The PD-L1/PD-1 axis plays a crucial role in the immune escape of cervical cancer through inhibition of host immune response. Creating an "immune-privileged" site for initial viral infection and subsequent adaptive immune resistance, which provides a rationale for the therapeutic blockade of this axis in HPV-positive cancers. Currently, Phase I/II clinical trials evaluating the effects of PDL1/ PD-1 targeted therapies are in progress for cervical carcinoma, which provide an important opportunity for the application of anti-PD-L1/anti-PD-1 antibodies in cervical cancer treatment. Conclusion: Recent research developments have led to an entirely new class of drugs using antibodies against the PD-L1/PD-1 thus promoting the body’s immune system to fight cancer. The expression and roles of the PD-L1/ PD-1 axis in the progression of cervical cancer provide great potential for using PD-L1/PD-1 antibodies as a targeted cancer therapy.

Nevus-like basal cell carcinoma syndrome (NBCCS) is a rare autosomal dominant disease characterized by the occurrence of multiple maxillofacial keratocysts, basal cell carcinoma, child medulloblastoma, and various skeletal and soft tissue dysplasia. In 2020, a patient with NBCCS dominated by facial basal cell carcinoma was admitted to Xiangya Hospital of Central South University. The patient was an elderly woman. Ten years ago, the systemic mass appeared, especially on the face, but it was not treated. Later, these masses gradually increased in volume and number, and showed invasive properties. The nasal mass was broken and suppurated, seriously affecting the patient's life quality. The patient came to the hospital to improve the symptoms.痣样基底细胞癌综合征(nevoid basal cell carcinoma syndrome，NBCCS)是一种罕见的常染色体显性疾病，其临床表现为多发性颌骨角化囊肿和基底细胞癌、儿童髓母细胞瘤及各种骨骼和软组织发育异常。2020年中南大学湘雅医院整形美容外科收治1例以面部基底细胞癌为主的NBCCS患者。该患者为老年女性，10年前出现全身特别是面部多发肿物，未予治疗。后肿物逐渐增大、增多，并表现出侵袭性。因鼻部肿物破溃化脓，严重影响患者的生活而就诊。鼻部肿物分泌物培养出金黄色葡萄球菌、雷氏普鲁威登菌。鼻腔鼻窦增强MRI示右侧面颊部皮下软组织及左侧鼻腔前外侧黏膜受侵，考虑为皮肤多发恶性病变。入院后行局部麻醉后手术切除部分肿物。肿物病理检查结果示基底细胞癌。后于全身麻醉下行全身多处肿物切除术，术后病理检查结果示多发性基底细胞癌，侵及真皮深层近皮下脂肪层，结合临床及免疫组织化学检查结果诊断为NBCCS；未见明确脉管内癌栓及侵犯神经现象。随访1年未发现复发及新发肿物。NBCCS发病率低，患者生活质量差，临床症状差异大，治疗方案需个体化且治疗时间长。.

PURPOSE Neoadjuvant chemotherapy (NAC) has been widely used in patients with breast cancer to minish tumor burden and increase resection rate of cancer. T-cell repertoire has been believed to be able to monitor antitumor immune responses. This study aimed to explore the dynamic change of T-cell repertoire and its clinical value in evaluating the tumor response in patients with breast cancer receiving NAC. MATERIALS AND METHODS Ninety-four patients who underwent NAC before surgery were recruited, and peripheral blood samples were collected at multiple time points during NAC. High-throughput T-cell receptor (TCR)-β sequencing was used to characterize the T-cell repertoire of every sample and analyzed the changes in circulating T-cell repertoire during NAC. RESULTS We found that the diversity of TCR repertoires was associated with age and clinical stage of the patients with breast cancer. The distribution of Vβ and Jβ genes in TCR repertoires was skewed in patients with human epidermal growth factor receptor 2–positive (HER2+) breast cancer. Vβ20.1 and Vβ30 expression levels before NAC correlate with tumor response after all cycles of NAC in HER2– and HER2+ patients, respectively. Some CDR3 motifs that correlated with clinical response in either HER2+ or HER2– patients were identified. Besides, TCR repertoire evolved during NAC and the diversity of TCR repertoire decreased more after two cycles of NAC in patients with good tumor response after all cycles of NAC (P = .0061). CONCLUSION Our results demonstrated that TCR repertoire correlated with the characteristics of the tumor, such as the expression status of HER2. Moreover, some characteristics of TCR repertoires that correlated with clinical response were identified and they might provide useful information to tailor therapeutic regimens at the early cycle of NAC., This study identified T-cell repertoires that correlated with clinical response in patients with breast cancer.

SARS-CoV-2 has spread worldwide causing more than 400 million people with virus infections since early 2020. Currently, the existing vaccines targeting the spike glycoprotein (S protein) of SARS-CoV-2 are facing great challenge from the infection of SARS-CoV-2 virus and its multiple S protein variants. Thus, we need to develop a new generation of vaccines to prevent infection of the SARS-CoV-2 variants. Compared with the S protein, the nucleocapsid protein (N protein) of SARS-CoV-2 is more conservative and less mutations, which also plays a vital role in viral infection. Therefore, the N protein may have the great potential for developing new vaccines.The N protein of SARS-CoV-2 was recombinantly expressed and purified in Escherichia coli. Western Blot and ELISA assays were used to demonstrate the immunoreactivity of the recombinant N protein with the serum of 22 COVID-19 patients. We investigated further the response of the specific serum antibodies and cytokine production in BALB/c mice immunized with recombinant N protein by Western Blot and ELISA.The N protein had good immunoreactivity and the production of IgG antibody against N protein in COVID-19 patients was tightly correlated with disease severity. Furthermore, the N protein was used to immunize BALB/c mice to have elicited strong immune responses. Not only high levels of IgG antibody, but also cytokine-IFN-γ were produced in the N protein-immunized mice. Importantly, the N protein immunization induced a high level of IgM antibody produced in the mice.SARS-CoV-2 N protein shows a great big bundle of potentiality for developing a new generation of vaccines in fighting infection of SARS-CoV-2 and its variants.

The study aimed to explore the risk factors of effects of patients with vascular mild cognitive impairment (VaMCI) through functional magnetic resonance imaging (fMRI). In this study, 62 patients were selected from the department of neurology, admitted to Changzhi People's Hospital from October 1, 2018 to February 1, 2020. Patients with VaMCI were defined as the VaMCI group according to Clinical Dementia Rating (CDR), and subjects with normal cognitive function were defined as the normal control (NC) group. All patients underwent fMRI to identify the amplitude low-frequency fluctuation (ALFF) and regional homogeneity (ReHo) values, and to analyze their association with VaMCI. The results showed that the VaMCI group had lower scores for Mini-mental State Examination (MMSE), Montreal Cognitive Assessment (MoCA), and their subitems (visual space and execution, recall, attention and computation, and language ability) than NC group, with statistical differences (P < 0.05). In VaMCI group, the brain regions with increased ALFF values were the left temporal lobe, left parietal lobe, right temporal lobe, right parietal lobe, and posterior cingulate gyrus. Of them, the left parietal lobe and right temporal lobe were negatively correlated with the recall score on MMSE scale (r = −0.216, r = −0.132, P < 0.01). In VaMCI group, the brain regions with decreased ReHo values were the left temporal lobe, occipital lobe, and left middle temporal gyrus. Of them, the left temporal lobe and occipital lobe were positively correlated with MoCA score (r = 0.473, r = 0.848, P < 0.01). In conclusion, VaMCI patients have cognitive impairment and abnormally increased spontaneous brain activity, especially in the left parietal lobe and the right temporal lobe. At rest, VaMCI patients show decreased whole-brain ReHo in the left medial temporal lobe and occipital lobe. Hypertension is a high-risk factor for cognitive impairment in VaMCI patients. The study can provide a theoretical basis for early diagnosis of VaMCI.

Women's blood pressure (BP) changes throughout pregnancy. The effect of BP trajectories on preterm delivery is not clear. The authors aim to evaluate the association between maternal BP trajectories during pregnancy and preterm delivery. The authors studied pregnant women included in the Born in Guangzhou Cohort Study in China between February 2012 and June 2016. Maternal BP was measured at antenatal visits between 13 and 40 gestational weeks, and gestational age of delivery data was collected. The authors used linear mixed models to capture the BP trajectories of women with term, and spontaneous and iatrogenic preterm delivery. BP trajectories of women with various gestational lengths (34, 35, 36, 37, 38, 39, 40 weeks) were compared. Of the 17 426 women included in the analysis, 618 (3.55%) had spontaneous preterm delivery; 158 (.91%) had iatrogenic preterm delivery; and 16 650 (95.55%) women delivered at term. The BP trajectories were all J-shaped curves for different delivery types. Women with iatrogenic preterm delivery had the highest mean BP from 13 weeks till delivery, followed by those with spontaneous preterm delivery and term delivery (p .001). Trajectory analysis stratified by maternal parity showed similar results for nulliparous and multiparous women. Excluding women with pre-eclampsia and gestational hypertension (GH) significantly attenuated the aforementioned association. Also, women with shorter gestational length tend to have higher BP trajectories during pregnancy. In conclusion, Women with spontaneous preterm delivery have a higher BP from 13 weeks till delivery than women with term delivery, while women with iatrogenic preterm delivery have the highest BP.

DNA-encoded library (DEL) technology has been used as an ultra-high-throughput screening approach for hit identification of drug targets. This process is an affinity-based selection and requires incubation of DEL molecules with the target. Currently, in most reported cases, the input (i.e., the copy number) of individual DEL molecules varies from 105 to 107. With the ever-increasing DEL size and screening cost, lowering the input of DEL molecules while maintaining an appropriate signal-to-noise ratio in a selection is of paramount importance. In this article, we varied the input of DEL ranging from 103 to 105 in selections with two different protein targets to explore the lower limit of DEL molecule input. The results could facilitate the optimization of the DEL selection process and reduce costs related to library consumption.

Background/aimsFew studies have objectively examined the quality of eye care in China. We assessed refractive care using the incognito standardised patient (SP) approach, a gold standard for evaluating clinical practice.MethodsA total of 52 SPs were trained to provide standardised responses during eye examinations, and underwent automated and non-cycloplegic, subjective refraction by a senior ophthalmologist from Zhongshan Ophthalmologic Center, a national-level clinical and research centre. SPs subsequently received subjective refraction and eye exams at a randomly selected sample of 40 public hospitals and 93 private optical shops in Shaanxi, Northwestern China. Difference between expert and local refraction in the better-seeing eye was calculated by the vector diopteric method, and completeness of exams assessed against national standards. SP and provider demographic information and provider clinical experience were recorded.ResultsSPs (n=52, mean (range) age, 25.7 (22–31) years, 28.8% male) underwent 133 eye exams (mean total duration 15.0±11.7 min) by 133 local refractionists (24–60 years, 30.3% male). Only 93 (69.9%), 121 (91.0%) and 104 (78.2%) of local refractionists assessed vision, automated and subjective refraction, respectively. The median inaccuracy was −0.25 diopters (D), while 25.6% of results differed by an absolute value of ≥1.0 D and 6.0% by ≥2.0 D. Predictors of inaccurate refraction included spectacle power ConclusionInaccurate refractions are common in Northwestern China, particularly in public facilities. Important assessments, including subjective refraction, are frequently omitted.

Purpose The purpose of this study was to compare the perioperative parameters of quadrant, sextant, and grid lens fragmentation patterns in femtosecond laser-assisted cataract surgery (FLACS). Design Prospective randomized clinical trial. Methods S etting : Eye Center of the Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China. S tudy population : A total of 894 eyes in 661 patients with cataracts were enrolled. I ntervention or observation procedures : the nuclear density was graded according to the Emery-Little classification. Patients received lens fragmentation using a quadrant, sextant, or grid pattern after random allocation. Evaluations included intraoperative parameters, complications, and postoperative outcomes. M ain outcome measurements : effective phacoemulsification time (EPT), intraoperative complications, visual acuity and intraocular pressure at one day postoperatively, as well as endothelial cell density, endothelial cell loss, and central corneal thickness at 1 week postoperatively. Results In grade 1 nuclei, the mean EPT in the grid group was the shortest compared to those in the quadrant (P = 0.011) and sextant (P = 0.001) groups. In grade 2 nuclei, all 3 patterns showed no significant differences in the mean EPT (P > 0.05). In grade 3 nuclei, the sextant group revealed shorter mean EPT than the grid (P = 0.017) and quadrant (P > 0.05) groups. In grades 4 and 5 nuclei, the quadrant pattern had the shortest mean EPT among all 3 patterns (P Conclusions The grid and quadrant patterns allow for shorter EPT in soft (grade 1) and hard (grades 4 and 5) nuclei, respectively. All 3 patterns can be selected for treating grade 2 nuclei. The sextant pattern may be the best option when treating grade 3 nuclei. The grid pattern should be avoided in hard nuclei combined with glaucoma or glaucoma suspect.

Apolipoprotein A-I (apoA-I) is cross-linked and dysfunctional in human atheroma. Although multiple mechanisms of apoA-I cross-linking have been demonstrated in vitro, the in vivo mechanisms of cross-linking are not well-established. We have recently demonstrated the highly selective and efficient modification of high-density lipoprotein (HDL) apoproteins by endogenous oxidized phospholipids (oxPLs), including γ-ketoalkenal phospholipids. In the current study, we report that γ-ketoalkenal phospholipids effectively cross-link apoproteins in HDL. We further demonstrate that cross-linking impairs the cholesterol efflux mediated by apoA-I or HDL3 in vitro and in vivo. Using LC-MS/MS analysis, we analyzed the pattern of apoprotein cross-linking in isolated human HDL either by synthetic γ-ketoalkenal phospholipids or by oxPLs generated during HDL oxidation in plasma by the physiologically relevant MPO-H(2)O(2)-NO(2)(−) system. We found that five histidine residues in helices 5–8 of apoA-I are preferably cross-linked by oxPLs, forming stable pyrrole adducts with lysine residues in the helices 3–4 of another apoA-I or in the central domain of apoA-II. We also identified cross-links of apoA-I and apoA-II with two minor HDL apoproteins, apoA-IV and apoE. We detected a similar pattern of apoprotein cross-linking in oxidized murine HDL. We further detected oxPL cross-link adducts of HDL apoproteins in plasma and aorta of hyperlipidemic LDLR(−/−) mice, including cross-link adducts of apoA-I His-165–apoA-I Lys-93, apoA-I His-154–apoA-I Lys-105, apoA-I His-154–apoA-IV Lys-149, and apoA-II Lys-30–apoE His-227. These findings suggest an important mechanism that contributes to the loss of HDL's atheroprotective function in vivo.

The green fluorescent protein (GFP)-based reporter system has been widely harnessed as a quick quantitative activity assessment method for characterizing CRISPR-Cas via flow cytometry. However, due to the small size (738 nt) of the GFP coding sequence, the targeting sites for certain CRISPR-Cas are greatly restricted. To address this, here we developed a GFP tagged polycistronic reporter system to determine the activity of CRISPR-Cas in human cells. Specifically, the system contains the herpes simplex virus thymidine kinase (

To report on a case of mosaicism 13q inversion duplication, analyze its mechanism, and discuss the correlation between its genotype and phenotype.Amniotic fluid and umbilical cord blood were collected at 23 and 32 weeks of gestation, respectively. Combined with G-banding chromosome karyotyping analysis, single nucleotide polymorphism array (SNP-array) and fluorescence in situ hybridization (FISH) were used to confirm the result.The karyotype of the fetus was determined as 47,XY,+inv dup(13)(q14.3q34)/46,XY. After careful counseling, the couple decided to continue with the pregnancy, and had given birth to a boy at 40 weeks' gestation. Except for a red plaque (hemangioma) on the nose bridge, no obvious abnormality (intelligence to be evaluated) was discovered.To provide reference for clinical genetic counseling and risk assessment, the location and proportion of new centromere formation should be fully considered in the case of mosaicism 13q inversion duplication.

In ischemic stroke (IS), accumulation of the misfolded proteins in the endoplasmic reticulum (ER) and mitochondria-induced oxidative stress (OS) has been identified as the indispensable inducers of secondary brain injury. With the increasing recognition of an association between ER stress and OS with ischemic stroke and with the improved understanding of the underlying molecular mechanism, novel targets for drug therapy and new strategies for therapeutic interventions are surfacing. This review discusses the molecular mechanism underlying ER stress and OS response as both causes and consequences of ischemic stroke. We also summarize the latest advances in understanding the importance of ER stress and OS in the pathogenesis of ischemic stroke and discuss potential strategies and clinical trials explicitly aiming to restore mitochondria and ER dynamics after IS.

This study was to explore the application of MRI based on artificial intelligence technology combined with neuropsychological assessment to the cognitive impairment of patients with neurological cerebrovascular diseases. A total of 176 patients were divided into a control group, a vascular cognitive impairment non-dementia (VCIND) group, a vascular dementia (VD) group, and an Alzheimer's disease (AD) group. All patients underwent MRI and neuropsychological evaluation and examination, and an improved fuzzy C-means (FCM) clustering algorithm was proposed for MRI processing. It was found that the segmentation accuracy (SA) and similarity (KI) data of the improved FCM algorithm used in this study were higher than those of the standard FCM algorithm, bias-corrected FCM (BCFCM) algorithm, and rough FCM (RFCM) algorithm (p < 0.05). In the activities of daily living (ADL), the values in the VCIND group (23.55 ± 6.12) and the VD group (28.56 ± 3.1) were higher than that in the control group (19.17 ± 3.67), so the hippocampal volume was negatively correlated with the ADL (r = −0.872, p < 0.01). In the VCIND group (52.4%), VD group (31%), and AD group (26.1%), the proportion of patients with the lacunar infarction distributed on both sides of the brain and the number of multiple cerebral infarction lesions (76.2, 71.4, and 71.7%, respectively) were significantly higher than those in the control group (23.9 and 50%). In short, the improved FCM algorithm showed a higher segmentation effect and SA for MRI of neurological cerebrovascular disease. In addition, the distribution, number, white matter lesions, and hippocampal volume of lacunar cerebral infarction were related to the cognitive impairment of patients with cerebrovascular diseases.

Background Maternal pre-pregnancy body mass index (BMI) and gestational weight gain (GWG) have been linked to offspring allergic disorders. However, associations observed in previous studies were inconsistent and might be confounded by unmeasured familial factors. We aimed to examine the associations of maternal weight with offspring allergic disorders by using paternal BMI as a negative control exposure. Methods We included the data of 10522 children from the Born in Guangzhou Cohort Study, 2012-2017. Data on maternal weight were obtained from questionnaires and obstetric records, and paternal weight was collected from questionnaires. Atopic dermatitis (AD) and wheezing at the age of one year were defined according to parent-reported physician diagnosis. Risk ratios (RRs) were estimated by log-binominal regression with mutual adjustment for maternal and paternal weight status. Results By the age of one year, 16.2% and 7.9% of children were diagnosed with AD and wheezing, respectively. While maternal pre-pregnancy BMI as a continuous variable was not associated with offspring AD, infants of pre-pregnancy overweight/obese women had a higher risk of AD than those born to normal-weight women; no such associations were observed for paternal BMI. Both maternal pre-pregnancy BMI and paternal BMI were positively associated with the risk of offspring wheezing. Maternal GWG was not associated with AD or wheezing. Conclusions Our findings suggest that maternal pre-pregnancy overweight/obesity might increase the risk of infant AD via intrauterine mechanisms, whereas the association with wheezing might be confounded by uncontrolled familial factors. These findings may be valuable in early-life prevention for offspring allergic diseases.

Generally, cochlear implants (CIs) are effective in helping patients improve their hearing performance; however, some patients have poor hearing performance owing to facial nerve stimulation (FNS), which is often associated with cochlear anomalies. We report a case with a normal cochlea and severe and persistent FNS owing to cochlear–facial dehiscence (CFD) that affected the CI outcomes. Preoperatively, a careful review of the computed tomography images before CI surgery is necessary not only for patients with otosclerosis and inner ear malformations but also for patients with normal cochlear structures because facial nerve anomalies could be present.

Background China suffers from a low exclusive breastfeeding rate. Though it has been proofed that paternal support benefits breastfeeding a lot, the correlation between father’s co-residence and exclusive breastfeeding in China remain undiscovered. This study is to provide population-based evidence for the association of paternal co-residence on exclusive breastfeeding in rural western China. We also attempt to detect how the process works by examining the correlation between the father’s co-residence and breastfeeding family support as well as maternal decision-making power. Methods A cross-sectional study was conducted in 13 nationally-designated poverty-stricken counties in the Qinba Mountains area in 2019. Data on breastfeeding practices, the status of fathers co-residence, breastfeeding family support, and maternal decision-making power were collected via structured questionnaires from 452 caregivers-infant pairs. Multivariate regressions were conducted to explore the correlation between paternal co-residence and exclusive breastfeeding. Results The exclusive breastfeeding (0–6 months) rate was 16% in rural western China. Fathers’ co-residence was associated with a lower exclusive breastfeeding rate (OR = 0.413, 95% CI = 0.227–0.750, P = 0.004) and the rate did not improve when the father was the secondary caregiver. Even ruling out support from grandmothers, the association was still negative. Paternal co-residence did not improve maternal perceived breastfeeding family support, neither practically nor emotionally (β =0.109, P = 0.105; β =0.011,P = 0.791, respectively) and it reduced maternal decision-making power (β = − 0.196, P = 0.007). Conclusions Fathers’ co-residence is negatively associated with the exclusive breastfeeding rates in rural western China. More skill-based practical and emotional strategies should be considered on father’s education to help them better involvement and show more respect to mothers’ decisions.

Objective This study aimed to identify risk factors for 30-day mortality in patients who received DeBakey type I aortic dissection (AD) repair surgery. Methods A total of 830 consecutive patients who received acute DeBakey type I AD surgery between 2014 and 2019 were included in the study. The associations between 30-day mortality and perioperative parameters were examined in order to identify risk factors. Results Our data suggested that the overall 30-day mortality rate of all enrolled patients was 11.7%. Unsurprisingly, non-survivors were older and more frequently accompanied with histories of cardiovascular diseases. For intraoperative parameters, the prevalence of coronary artery bypass grafting and cardiopulmonary bypass times were increased in non-survivors. In addition, acute kidney injury (AKI), dialysis, stroke, and deep sternal wound infection were more commonly seen among non-survivors. The multivariate logistic regression analysis suggested that cardiovascular disease history, preoperative D-dimer level, drainage volume 24 h after surgery, and postoperative AKI were independent risk factors for 30-day mortality after DeBakey type I aortic dissection repair surgery. Conclusions Our study demonstrated that cardiovascular disease history, preoperative D-dimer level, drainage volume 24 h after surgery as well as postoperative AKI were risk factors for 30-day mortality after DeBakey type I aortic dissection repair surgery.

Background Hepatic dysfunction (HD) increases the morbidity and mortality rates after cardiac surgery. However, few studies have investigated the association between HD and acute DeBakey type I aortic dissection (ADIAD) surgery. This retrospective study aimed to identify risk factors for developing HD in patients who received acute type I aortic dissection repair and its consequences. Methods A total of 830 consecutive patients who received ADIAD surgery from January 2014 to December 2019 at our center were screened for this study. The End-Stage Liver Disease (MELD) score more than 14 was applied to identify postoperative HD. Logistic regression model was applied to identify risk factors for postoperative HD, Kaplan–Meier survival analysis and Cox proportional hazards regression assay were conducted to analyze the association between HD and postoperative long-term survival. Results Among 634 patients who eventually enrolled in this study, 401 (63.2%) experienced postoperative HD with a 30-Day mortality of 15.5%. Preoperative plasma fibrinogen level (PFL) [odds ratio (OR): 0.581, 95% confidence interval (CI): 0.362–0.933, P = 0.025], serum creatinine (sCr) on admission (OR: 1.050, 95% CI 1.022–1.079, P P = 0.039), and postoperative mechanical ventilation (MV) duration (OR: 1.019, 95% CI 1.003–1.035, P = 0.020) were identified as independent risk factors for developing postoperative HD by multivariate analyses. In addition, the Kaplan–Meier analysis indicated that the long-term survival rate was significantly different between patients with or without postoperative HD. However, the hazard ratios of long-term survival for these two groups were not significantly different. Conclusions HD was a common complication after ADIAD surgery and associated with an increasing 30-Day mortality rate. Decreased PFL, elevated sCr, prolonged CPB duration, and longer postoperative MV time were independent risk factors for postoperative HD.

There is a paucity of data describing the safety and efficacy of acute type A aortic dissection (ATAAD) repair surgeries in dialysis patients. Our study aimed to investigated the influence of dialysis on early and late outcomes in end-stage renal disease (ESRD) patients who received repair surgery for ATAAD. A total of 882 ATAAD patients who received emergency aortic dissection repair at our center from January 2015 to December 2019 were retrospectively screened in this study and divided into the dialysis group (n = 16) and the non-dialysis group (n = 866), depending on whether they required dialysis for preoperative ESRD. No significant difference of age, preoperative hemodynamics, organ ischemia conditions, operative variables as well as the 30-Day mortality and in-hospital complications was discovered between two groups. However, the survival rates and the proportion of late aortic event (sudden death and reoperation) free population at 1 and 3 years after surgery were significantly decreased in dialysis patients compared to non-dialysis patients. Our study indicated that the short-term surgical outcomes of ATAAD in dialysis patients were comparable to non-dialysis patient. However, the dialysis patients were associated with a worse long-term prognosis.

Background Acute kidney injury (AKI) is a serious complication that often occurred after acute type A aortic dissection (ATAAD) surgery. Previous studies proved that the Kidney Disease Improving Global Outcomes (KDIGO) defined stage 3 AKI was associated with lower long-term survival rate. However, the risk factors for developing stage 3 AKI had not been identified. The aim of the study was to explore the risk factors for developing KDIGO stage 3 after ATAAD operation. Methods This study included 993 patients who received ATAAD operation from 2014 to 2019 at the Nanjing Drum Tower Hospital. Postoperative AKI was diagnosed according to the KDIGO criteria. Multivariate logistic regression analyses were applied to identify risk factors for stage 3 AKI. Kaplan–Meier survival analyses and Cox proportional hazards regression model were conducted to explore the association between different AKI stages and postoperative survival rate. Results The mean age of all enrolled patients was 53.0 ± 13.1 years. A total of 236 (23.8%) patients suffered postoperative stage 3 AKI including 165 patients who required renal replacement therapy. Advanced age (odds ratio [OR] 1.031; 95% confidence interval [CI] 1.005–1.057; P = 0.018), prolonged cardiopulmonary bypass (CPB) duration (OR 1.010; 95% CI 1.002–1.018; P = 0.013), and higher drainage volume 24 h after surgery (OR 1.000; 95% CI 1.000–1.001; P = 0.033) were identified as independent risk factors for developing stage 3 AKI. In addition, our result showed that the mortality rate was correlated significantly with the severity of AKI defined by KDIGO criteria and the Cox regression analysis showed that only stage 3 AKI, but not stage 1 and 2, was an independent risk factor for mortality (Hazard ratio 10.365, 95% CI 4.208 to 25.528; P Conclusions Our study suggested that stage 3 postoperative AKI was significantly associated with decreased postoperative survival rate after ATAAD surgery. Advanced age, increased CPB duration and drainage volume 24 h after surgery were identified as risk factors for developing stage 3 AKI.

Background Atherosclerotic plaque vulnerability is a key feature of atheroprogression and precipitating acute cardiovascular events. Although the pivotal role of epigenetic regulation in atherosclerotic plaque destabilization is being recognized, the DNA methylation profile and its potential role in driving the progression and destabilization of atherosclerotic cardiovascular disease remains largely unknown. We conducted a genome-wide analysis to identify differentially methylated genes in vulnerable and non-vulnerable atherosclerotic lesions to understand more about pathogenesis. Results We compared genome-wide DNA methylation profiling between carotid artery plaques of patients with clinically symptomatic (recent stroke or transient ischemic attack) and asymptomatic disease (no recent stroke) using Infinium Methylation BeadChip arrays, which revealed 90,368 differentially methylated sites (FDR 0.03) corresponding to 14,657 annotated genes. Among these genomic sites, 30% were located at the promoter regions and 14% in the CpG islands, according to genomic loci and genomic proximity to the CpG islands, respectively. Moreover, 67% displayed hypomethylation in symptomatic plaques, and the differentially hypomethylated genes were found to be involved in various aspects of inflammation. Subsequently, we focus on CpG islands and revealed 14,596 differentially methylated sites (|delta beta|> 0.1) located at the promoter regions of 7048 genes. Integrated analysis of methylation and gene expression profiles identified that 107 genes were hypomethylated in symptomatic plaques and showed elevated expression levels in both advanced plaques and ruptured plaques. The imprinted gene PLA2G7, which encodes lipoprotein-associated phospholipase A2 (Lp-PLA2), was one of the top hypomethylated genes with an increased expression upon inflammation. Further, the hypomethylated CpG site at the promoter region of PLA2G7 was identified as cg11874627, demethylation of which led to increased binding of Sp3 and expression of Lp-PLA2 through bisulfate sequencing, chromatin immunoprecipitation assay and enzyme-linked immunosorbent assay. These effects were further enhanced by deacetylase. Conclusion Extensive DNA methylation modifications serve as a new and critical layer of biological regulation that contributes to atheroprogression and destabilization via inflammatory processes. Revelation of this hitherto unknown epigenetic regulatory mechanism could rejuvenate the prospects of Lp-PLA2 as a therapeutic target to stabilize the atherosclerotic plaque and reduce clinical sequelae.

Background Despite the well-studied effects of gestational weight gain (GWG) on offspring health, little is known about the association of trimester-specific GWG with offspring birth weight among underweight pregnant women. This study aimed to explore the association of trimester-specific GWG rate with small for gestational age (SGA) in underweight women. Methods The GWG rate of underweight pregnant women (pre-pregnancy body mass index [BMI] lower than 18.5 kg/m2) of the Born in Guangzhou Cohort Study was calculated as the weight gain during a specific trimester divided by the corresponding duration of week. Total GWG was calculated as the weight difference between pre-pregnancy and delivery, and was categorized into inadequate, adequate, and excessive weight gain based on the 2009 Institute of Medicine (IOM) weight gain recommendation. The INTERGROWTH-21st standards were used to define SGA. Logistic regression models were used to examine the associations of total GWG and trimester-specific GWG rates with SGA. Associations between trimester-specific GWG rates and SGA were also analyzed separately based on different total GWG categories (i.e. inadequate and adequate/excessive GWG). Results Of the 3839 participants, SGA births occurred in 397 (10.3%), and mean GWG was 14.9 kg (SD 3.9). A lower risk of SGA was observed among women with higher GWG rate (per 0.5 kg/week increase) during the first (adjusted OR [aOR] 0.74, 95%CI 0.57, 0.96) and second (adjusted OR [aOR] 0.40, 95%CI 0.30, 0.55) but not third trimester. Similar association between higher GWG rate during the second trimester and a decreased risk of SGA were observed among women with inadequate ( Conclusions Second-trimester GWG might be the key driver for the association between inadequate GWG and increased risk of SGA births in underweight women.

Despite the recent breakthrough in cataract drug development, further improvements have been limited by the lack of human in vitro cataract disease models. This study, therefore, aims to generate a qualified cataract disease model. Mature lentoid bodies (LBs) on Day 25 (D25), which were differentiated from human induced pluripotent stem cells (iPSCs) using the "fried egg" method, were continually culturing (control) or extra treated with either ultraviolet (UV) radiation or hydrogen peroxide (H2 O2 ). The LBs' shape alteration and opacity were examined using light microscopy and mean gray value evaluation. Their structure and crystallin expression were examined using immunofluorescence and transmission electron microscopy (TEM). Real-time polymerase chain reaction and western blot were used to investigate the potential role of autophagy in cloudy LBs. Mature LBs became cloudy with time which was accelerated by H2 O2 . Immunofluorescence examinations and TEM showed that the H2 O2 -treated and control LBs had similar shapes, lens capsule, and monolayer lens epithelial cell (LEC) structures. However, we were unable to do further assessment of the UV-treated LBs as the structures of LBs were easily damaged when treated with UV radiation. Cells containing aggregated protein (αA-crystallin and αB-crystallin) puncta were more abundant in the H2 O2 -treated LBs as compared with control LBs. Moreover, LC3B expression decreased with age in anterior lens capsules obtained from age-related cataracts (ARCs) patients as compared with LC3B levels in primary LECs, which is consistent with that LC3B expression in LBs was lower on D45 than on D25. Our study found that human iPSCs-derived LBs became cloudy with time which was accompanied by protein aggregation, and this phenomenon was accelerated by H2 O2 , suggesting that LBs with extending culture may serve as a human model for in vitro ARCs.

Affibodies targeting intracellular proteins have a great potential to function as ideal therapeutic agents. However, little is known about how the affibodies enter target cells to interact with intracellular target proteins. We have previously developed the HPV16E7 affibody (ZHPV16E7384) for HPV16 positive cervical cancer treatment. Here, we explored the underlying mechanisms of ZHPV16E7384 and found that ZHPV16E7384 significantly inhibited the proliferation of target cells and induced a G1/S phase cell cycle arrest. Furthermore, ZHPV16E7384 treatment resulted in the upregulation of retinoblastoma protein (Rb) and downregulation of phosphorylated Rb (pRb), E2F1, cyclin D1, and CDK4 in the target cells. Moreover, treatment with dynamin or the caveolin-1 inhibitor not only significantly suppressed the internalization of ZHPV16E7384 into target cells but also reversed the regulation of cell cycle factors by ZHPV16E7384. Overall, these results indicate that ZHPV16E7384 was likely internalized specifically into target cells through dynamin- and caveolin-1 mediated endocytosis. ZHPV16E7384 induced the cell cycle arrest in the G1/S phase at least partially by interrupting HPV16E7 binding to and degrading Rb, subsequently leading to the downregulation of E2F1, cyclin D1, CDK4, and pRb, which ultimately inhibited target cell proliferation. These findings provide a rationale of using ZHPV16E7384 to conduct a clinical trial for target therapy in cervical cancer.

Membranous nephropathy (MN), an autoimmune glomerular disease, is one of the most common causes of nephrotic syndrome in adults. In current clinical practice, the diagnosis is dependent on renal tissue biopsy. A new method for diagnosis and prognosis surveillance is urgently needed for patients. In the present study, we recruited 66 MN patients before any treatment and 11 healthy control (HC) and analyzed multiple aspects of the immunoglobulin heavy chain (IGH) repertoire of these samples using high-throughput sequencing. We found that the abnormalities of CDR-H3 length, hydrophobicity, somatic hypermutation (SHM), and germ line index were progressively more prominent in patients with MN, and the frequency of IGHV3-66 in post-therapy patients was significantly lower than that in pre-therapy patients. Moreover, we found that the IGHV3-38 gene was significantly related to PLA2R, which is the most commonly used biomarker. The most important discovery was that several IGHV, IGHD transcripts, CDR-H3 length, and SHM rate in pre-therapy patients had the potential to predict the therapeutic effect. Our study further demonstrated that the IGH repertoire could be a potential biomarker for prognosis prediction of MN. The landscape of circulating B-lymphocyte repertoires sheds new light on the detection and surveillance of MN.

The presigmoid retrolabyrinthine approach (PRA) for small vestibular schwannoma (VS) has unique advantages. Combination with partial labyrinthectomy further makes up its defect of high demand for anatomy.Aimed to describe our use of the PRA with partial labyrinthectomy in VS surgery.We retrospectively analyzed 10 patients diagnosed with VS who underwent PRA between September 2017 and November 2020. Their perioperative data were analyzed.Six tumors were on the left and three were on the right. One case was due to neurofibromatosis type 2 with bilateral involvement and underwent internal auditory canal decompression by PRA without tumor removal; all other patients underwent total tumor resection. Four patients underwent cochlear implantation simultaneously because of hearing loss that was detected during surgery. Three patients underwent partial labyrinthectomy. Five patients achieved hearing preservation, and one experienced hearing improvement. One of the three patients who underwent partial labyrinthectomy maintained hearing. All patients' pre- and postoperative facial nerve functions were House-Brackmann grade I. After a median follow-up time of 13 months, no tumors recurred.PRA for small VS is a safe and effective surgery that can achieve facial nerve and hearing preservation. Combination with partial labyrinthectomy can also preserve hearing.

Wideband Absorbance Immittance (WAI) has been available for more than a decade, however its clinical use still faces the challenges of limited understanding and poor interpretation of WAI results. This study aimed to develop Machine Learning (ML) tools to identify the WAI absorbance characteristics across different frequency-pressure regions in the normal middle ear and ears with otitis media with effusion (OME) to enable diagnosis of middle ear conditions automatically. Data analysis included pre-processing of the WAI data, statistical analysis and classification model development, and key regions extraction from the 2D frequency-pressure WAI images. The experimental results show that ML tools appear to hold great potential for the automated diagnosis of middle ear diseases from WAI data. The identified key regions in the WAI provide guidance to practitioners to better understand and interpret WAI data and offer the prospect of quick and accurate diagnostic decisions.

No cochlear otosclerosis in infants with congenital bilateral SNHL has been reported.We report an infant male with bilateral cochlear otosclerosis, suggesting that cochlear otosclerosis may be a congenital disease and to further analyze the etiology of and genetic expression in congenital bilateral cochlear otosclerosis. We also describe the clinical characteristics and experience of patients with bilateral cochlear otosclerosis treated with cochlear implants (CIs).Seven patients, including an infant, who were diagnosed with cochlear otosclerosis underwent CI surgery. Their medical records, audiological and radiological results, surgical procedures, and CI outcomes were collected and reviewed.The median age at hearing loss was 38 years, ranging from 0 to 47 years. The child had bilateral hearing loss at birth and received a CI at 1 year of age. He also had growth retardation and was diagnosed with 3q+/3p- syndrome. All patients (8 ears) had better postoperative auditory performance than that preoperatively.Although cochlear otosclerosis often starts at middle age and progresses slowly, it may be a congenital disease that is related to chromosome abnormality. This disease presents with SNHL or MHL, and treatment with a CI is beneficial.

The International Classification of Functioning, Disability and Health (ICF) Rehabilitation Set was proposed by the WHO ICF Research branch as a minimum standard for assessing and reporting functioning in a wide range of clinical settings. This study investigates the psychometric properties of ICF Rehabilitation Set using Rasch analysis. It was a multicenter, cross-sectional study involving 515 inpatients in the subacute or chronic phase of recovery from various health conditions selected by quota sampling (stratified by neurological, cardiopulmonary, musculoskeletal and other conditions). Registered physicians or nurses used the developed operational items of the ICF Rehabilitation Set to rate patients' functioning. A Rasch model was performed in assessing the psychometric properties of the ICF Rehabilitation Set. Good reliability was observed in the activity and participation components, but the body functions component needs additional items to distinguish among people with moderate or severe problems. After recalibration, the body functions, activities and participation components showed fit to the Rasch model. However, deletions mandated by the Rasch model decreased the functioning information reflected by the ICF Rehabilitation Set.

Background Prevalence of neonatal microcephaly in populations without Zika-epidemics is sparse. The study aimed to report baseline prevalence of congenital microcephaly and its relationship with prenatal factors in an area at risk of Zika outbreak. Methods This study included singletons born after 24 gestational weeks in 2017–2018 at four hospitals in Guangzhou, China. Microcephaly was defined as a head circumference at birth >3SD below the mean for sex and gestational age. Prevalence of microcephaly was estimated by binomial exact method. Multivariable logistic regression was used to examine the associations of microcephaly with prenatal factors. The population attributable fraction (PAF) for associated risk factors was calculated. Results Of 46,610 live births included, 154 (3.3, 95% CI 2.8–3.9 per 1000 live births) microcephalies were identified. Maternal hepatitis B virus carriers (HBV, OR 1.80, 95% CI 1.05–3.10) and primipara (OR 2.68, 95% CI 1.89–3.81) had higher risk of having a microcephalic baby. Higher prevalence of microcephaly was observed in women who had premature labor (OR 1.98, 95% CI 1.17–3.34) and had a baby with fetal growth restriction (OR 16.38, 95% CI 11.81–22.71). Four identified factors (HBV, primiparity, preterm labor, and fetal growth restriction) contributed to 66.4% of the risk of microcephaly. Conclusions The prevalence of microcephaly in Guangzhou was higher than expected. This study identified four prenatal risk factors that, together, contributed to two-thirds of the increased risk of microcephaly. This is the first reported association between maternal HBV carrier status and microcephaly.

Background Schistosoma japonicum is a parasitic flatworm that is the aetiological agent of human schistosomiasis, an important cause of hepatic fibrosis. Schistosomiasis-induced hepatic fibrosis is a consequence of the highly fibrogenic nature of egg-induced granulomatous lesions, which are the main pathogenic features of schistosomiasis. Although global awareness of the association between schistosomiasis-induced hepatic fibrosis and S. japonicum infection is increasing, little is known about the molecular differences associated with rapid progression to schistosomiasis in cirrhotic patients. Methods We systematically used data-independent acquisition (DIA)-based liquid chromatography-mass spectrometry to identify differentially expressed proteins in serum samples from patients with advanced S. japonicum-induced hepatic fibrosis. Results Our analysis identified 1144 proteins, among which 66 were differentially expressed between the healthy control group and the group of patients with advanced S. japonicum-induced hepatic fibrosis stage F2 (SHF-F2) and 214 were differentially expressed between the SHF-F2 and SHF-F4 groups (up- or downregulation of at least 1.5-fold in serum samples). The results also indicated that two selected proteins (C1QA and CFD) are potential biomarkers for distinguishing between patients with SHF-F2 and those with SHF-F4 due to S. japonicum infection. Conclusions We provide here the first global proteomic profile of serum samples from patients with advanced S. japonicum-induced hepatic fibrosis. The proteins C1QA and CFD are potential diagnostic markers for patients with SHF-F2 and SHF-F4 due to S. japonicum infection, although further large-scale studies are needed. Our DIA-based quantitative proteomic analysis revealed molecular differences among individuals at different stages of advanced S. japonicum-induced hepatic fibrosis and may provide fundamental information for further detailed investigations. Graphical Abstract

The infection with HPV 16 and 18 high-risk types account for more than 80 % of cervical cancer incidence, but there is still no targeted agent against HPV for cervical cancer therapy. Our previous study constructed a bispecific affibody Z

Exposures to multiple air pollutants during pregnancy have been associated with the risk of gestational diabetes mellitus (GDM). However, their combined effects are unclear. We aimed to evaluate the combined associations of five air pollutants from pre-pregnancy to the 2nd trimester with GDM. This study included 20,113 participants from the Born in Guangzhou Cohort Study (BIGCS). The inverse distance-weighted models were used to estimated individual air pollutant exposure, namely ozone (O3), nitrogen dioxide (NO2), sulfur dioxide (SO2), particulate matter less than 10 microns in diameter (PM10), and less than 2.5 microns in diameter (PM2.5). We estimated stage-specific associations of air pollutants with GDM using generalized estimating equation, and departures from additive joint effects were assessed using the relative excess risk (RERI) and the joint relative risk (JRR). Of the 20,113 participants, 3440 women (17.1%) were diagnosed with GDM. In the adjusted model, increased concentrations of O3 and SO2 3–6 months before pregnancy were associated with GDM occurrence, as well as O3 and PM10 in the 1st trimester, the adjusted relative risk (95% confident intervals) [RRs (95%CI)] ranged from 1.05 (1.00, 1.09) to 1.21 (1.04, 1.40). The largest JRR for GDM was the combination of SO2, NO2, and PM10 in the 1st trimester (JRR = 1.32, 95% CI: 1.10, 1.59). The JRR for O3 and SO2 was less than their additive joint effects [RERI = -0.25 (−0.47, −0.04), P for interaction = 0.048]. Associations of air pollutants with GDM differed somewhat by pre-pregnancy BMI and season. This study added new evidence to the current understanding of the combined effects of multiple air pollutants on GDM. Public health strategies were needed to reduce the adverse effects of air pollution exposure on pregnant women.

Free trial is a widely used business strategy that takes advantage of information asymmetry. However, evidence on what we can learn and how rapidly we can learn from a free trial of health care is limited. This study evaluates the effect of a free trial of eyeglasses on children’s 8 items of perception related to eyeglasses use. An evaluation was conducted alongside a cluster-randomized controlled trial involved 832 myopic children from northwest rural China. A total of 428 myopic children from 42 schools were randomized to receive free eyeglasses, and 404 myopic children from 42 schools were randomized as control group. We find that the perceived costs and benefits of eyeglasses use and the perceived timing of wearing eyeglasses at the appropriate time can be learned from a free trial of eyeglasses. Compared with the control group in the long run, 5.6 percentage points more children in treatment group agreed that wearing eyeglasses was attractive, 16.5 percentage points more children agreed that wearing eyeglasses is helpful to academic performance, and 7.9 percentage points more children agreed that children with vision problems should wear eyeglasses. Due to the effects of a free product and the time to learning from experience, the magnitude of the impact of a free trial changed over time. We also find that the indirect experience, such as a vision protection course, cannot change children’ perceptions about the cost or benefits of eyeglasses use. The findings imply that children can learn significantly from the experience of a free trial of eyeglasses. A free trial is an effective strategy to solve the information asymmetry problem for health care. The first pair of eyeglasses of children can be one-off subsidized to trigger demand for eyeglasses use.

Nonalcoholic fatty liver disease (NAFLD) is a chronic disease affecting the health of many people worldwide. Previous studies have shown that dietary calcium supplementation may alleviate NAFLD, but the underlying mechanism is not clear. In this study investigating the effect of calcium on hepatic lipid metabolism, 8-week-old male C57BL/6J mice were divided into four groups (n = 6): (1) mice given a normal chow containing 0.5% calcium (CN0.5), (2) mice given a normal chow containing 1.2% calcium (CN1.2), (3) mice given a high-fat diet (HFD) containing 0.5% calcium (HFD0.5), and (4) mice fed a HFD containing 1.2% calcium (HFD1.2). To understand the underlying mechanism, cells were treated with oleic acid and palmitic acid to mimic the HFD conditions in vitro. The results showed that calcium alleviated the increase in triglyceride accumulation induced by oleic acid and/or palmitic acid in HepG2, AML12, and primary hepatocyte cells. Our data demonstrated that calcium supplementation alleviated HFD-induced hepatic steatosis through increased liver lipase activity, proving calcium is involved in the regulation of hepatic lipid metabolism. Moreover, calcium also increased the level of glycogen in the liver, and at the same time had the effect of reducing glycolysis and promoting glucose absorption. Calcium addition increased calcium levels in the mitochondria and cytoplasm. Taken together, we concluded that calcium supplementation could relieve HFD-induced hepatic steatosis by changing energy metabolism and lipase activity.

To explore the value of BACs-on-BeadsThe results of chromosomal karyotyping and BoBs of 1773 prenatal samples were compared. Microdeletions and microduplications detected by BoBs were subjected to chromosome microarray analysis (CMA) with informed consent from patients.BoBs has detected 46 cases of common aneuploidies involving chromosomes 13, 18, and 21, and 16 cases involving X and Y chromosomes. For 4 fetuses with normal results by BoBs, karyotyping analysis of amniotic fluid sample suggested low percentage mosaicisms (20%). BoBs has detected none of the 9 common microdeletions, but 14 male fetuses with Xp22 microdeletions and 5 with other microdeletions/microduplications. In 10 cases, the couples had chosen CMA verification, and the results were all consistent.As a rapid diagnostic technique, BoBs has a high accuracy for common aneuploidies, and is capable of discovering certain chromosome microdeletions and microduplications. The difficulty lies in the inability to detect low proportion mosaicisms and the consultation following detection for male fetuses carrying Xp22 microdeletions.

The treatment effect of ethanamizuril (EZL) to broiler chickens experimentally infected with 8 × 104 Eimeria tenella was evaluated. On the third day after infection, the broiler chickens were treated with EZL by gavage at doses of 2, 4, and 8 mg/kg body weight (bw) for once. For double administration, the challenged broiler chickens were administered EZL at doses of 1, 2, 4, and 8 mg/kg bw by gavage continually on the third day and fourth day and once a day. Throughout the experimental period, performance parameters including body weight gain, mortality, cecal lesion score, bloody diarrhoea and oocyst output were recorded. The anticoccidial efficacy was evaluated using the anticoccidial index (ACI). Meanwhile, the concentrations of EZL in chicken cecal contents were measured, and the data were analyzed with a non-compartmental model. The results indicated that EZL showed good anticoccidial activity at single dose of 4 mg/kgbw, with the corresponding ACI of 175.73. When the challenged chickens were treated with EZL under double administration, the EZL showed a medium level of anticoccidial activity at a dose of 2 mg/kg bw, with the corresponding ACI of 162.48. The maximum concentrations (Cmax) of EZL in content were 2.43 ± 1.16, 4.28 ± 1.56, and 8.57 ± 1.33 mg/kg after the chickens were administrated at doses of 2, 4, and 8 mg/kg bw, respectively. The respective areas under the curve were 36.93 ± 8.91, 96 ± 16.31, and 262.76 ± 51.52 mg/kg h. The respective half-lives (T1/2) were 10.82 ± 2.02, 10.53 ± 2.23, and 10.60 ± 1.50 h. The results show that when the concentrations of EZL in chicken cecal contents reached 4.28 ± 1.56 mg/kg, there is a significant therapeutic effect on chicken coccidiosis.

Telemedicine is a promising way to deliver patient education and health services, but access to information technology among potential patients is a prerequisite. This study surveyed the prevalence of smartphone use and the use of the Chinese social networking platform WeChat and Wi-Fi access in the homes of older adults in a western area of China. A convenience sample of 225 older adults with chronic diseases in two tertiary hospitals was interviewed regarding smartphone ownership, WeChat use, and access to Wi-Fi at home. Participant ability in performing the activities of daily living was also assessed. Logistic regressions were used to analyze the independently associated factors of smartphone ownership, WeChat use, and Wi-Fi access at home. The results show that the prevalence of smartphone use was 19.6%, only 8.9% of those surveyed used WeChat, but 39.6% had access to Wi-Fi at home. Education level was the only factor significantly associated with the three dependent variables. Ability in performing activities of daily living was positively correlated with access to Wi-Fi at home (odds ratio, 2.549; P = .011). It will be difficult to implement telemedicine through smartphones in such relatively poor areas of China. Better-educated older adults who are less dependent in performing activities of daily living are potential users of telemedicine.

Nasopharyngeal carcinoma (NPC) induced by latent infection with Epstein-Barr virus (EBV) remains the most common head and neck cancer in Southeast Asia, especially in the southern part of China. It is well known that persistent expression of two EBV latent membrane proteins (LMP1/LMP2A) plays a key role in nasopharyngeal carcinogenesis. Therefore, the therapeutic approach of targeting the LMP1/LMP2A protein and subsequently blocking the LMP1/LMP2A-mediated signalling pathway has been considered for treating patients with NPC. Recently, affibody molecules, a new class of small (~6.5 kDa) affinity proteins, have been confirmed to be powerful generalisable tools for developing imaging or therapeutic agents by targeting specific molecules. In this study, three EBV LMP2A N-terminal domain-binding affibody molecules (ZLMP2A-N85, ZLMP2A-N110 and ZLMP2A-N252) were identified by screening a phage-displayed peptide library, and their high affinity and specificity for the EBV LMP2A N-terminal domain were confirmed by surface plasmon resonance (SPR), indirect immunofluorescence, co-immunoprecipitation and near-infrared small animal fluorescence imaging in vitro and in vivo. Moreover, affibody molecules targeting the EBV LMP2A N-terminal domain significantly reduced the viability of the EBV-positive cell lines C666-1, CNE-2Z and B95-8. Further investigations showed that affibody ZLMP2A-N110 could inhibit the phosphorylation of AKT, GSK-3β and β-catenin signalling proteins, leading to suppression of β-catenin nuclear translocation and subsequent inhibition of c-Myc oncogene expression, which may be responsible for the reduced viability of NPC-derived cell lines. In conclusion, our findings provide a strong evidence that three novel EBV LMP2A N-terminal domain-binding affibody molecules have great potential for utilisation and development as agents for both molecular imaging and targeted therapy of EBV-related NPC.

Zinc deficiency is a risk factor for the development of obesity and diabetes. Studies have shown lower serum zinc levels in obese individuals and those with diabetes. We speculate that zinc supplementation can alleviate obesity and diabetes and, to some extent, their complications. To test our hypothesis, we investigated the effects of zinc supplementation on mice with high-fat diet (HFD)-induced hepatic steatosis in vivo and in vitro by adding zinc to the diet of mice and the medium of HepG2 cells. Both results showed that high levels of zinc could alleviate the glucose and lipid metabolic disorders induced by a HFD. High zinc can reduce glucose production, promote glucose absorption, reduce lipid deposition, improve HFD-induced liver injury, and regulate energy metabolism. This study provides novel insight into the treatment of non-alcoholic fatty liver disease and glucose metabolic disorder.