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Abstract Background The childbirth experience of primipara profoundly impacts her future physical and mental health, reproductive intention, and choice of childbirth mode. This study aimed to explore the current situation of primipara’s childbirth experience, to analyze the factors influencing negative childbirth experience, and to explore the relationship between childbirth experience and reproductive intention. Methods A cross-sectional survey of a convenience sample of 522 primipara 1–5 days postpartum was conducted at five hospitals in Guangdong Province (May to July 2024). Data were collected using the General Information Questionnaire, the Social Support Rating Scale, the Childbirth Readiness Scale, the Caring Behaviors Inventory Scale, the Wijma Delivery Experience Questionnaire, and the Questionnaire on Reproduction Intention of Primipara. Results The mean score of fear of childbirth was 68.86 ± 17.68. A total of 137 respondents met the clinical criteria for fear of childbirth (≥ 85 points), indicating that 26.2% of primipara had a negative experience of childbirth. Binary logistic regression model showed that elderly primipara [odds ratio (OR) (95% confidence interval (CI)): 11.167 (2.737–45.559)], pregnancy comorbidities or maternal childbirth complications [OR (95%CI): 6.596 (3.046–14.287)], childbirth intervention [OR (95%CI): 6.168 (2.869–13.258)], and severe pain [OR (95%CI): 4.660 (2.197–9.882)] were risk factors for negative childbirth experience. Childbirth accompaniment [OR (95%CI): 0.081 (0.018–0.368)], high level of social support [OR (95%CI): 0.768 (0.704–0.839)], and high level of childbirth readiness [OR (95%CI): 0.878 (0.812–0.950)] protected against a negative birth experience. There was a negative correlation between the fear of childbirth score and reproduction intention scores. Conclusions Childbirth accompaniment and high levels of social support and childbirth readiness can reduce primipara’s perception of negative childbirth experience. Negative childbirth experience can reduce reproduction intention.

Abstract Background Duchenne Muscular Dystrophy (DMD) is an X-linked disorder caused by mutations in the DMD gene, with large deletions being the most common type of mutation. Inversions involving the DMD gene are a less frequent cause of the disorder, largely because they often evade detection by standard diagnostic methods such as multiplex ligation probe amplification (MLPA) and whole exome sequencing (WES). Case presentation : Our research identified two intrachromosomal inversions involving the dystrophin gene in two unrelated families through Long-read sequencing (LRS). These variants were subsequently confirmed via Sanger sequencing. The first case involved a pericentric inversion extending from DMD intron 47 to Xq27.3. The second case featured a paracentric inversion between DMD intron 42 and Xp21.1, inherited from the mother. In both cases, simple repeat sequences (SRS) were present at the breakpoints of these inversions. Conclusions Our findings demonstrate that LRS is an effective tool for detecting atypical mutations. The identification of SRS at the breakpoints in DMD patients enhances our understanding of the mechanisms underlying structural variations, thereby facilitating the exploration of potential treatments.

Abstract Background Carboxylesterase 1(CES1) is expressed mainly in the liver and adipose tissue and is highly hypothesized to play an essential role in metabolism. Our study aimed to investigate the association between CES1 and metabolic syndrome (MetS) and metabolic dysfunction associated steatotic liver disease (MASLD) in children with obesity in China. Methods This study included 72 children with obesity aged 6-13years (including 25(35%) diagnosed as MetS and 36(50%) diagnosed as MASLD). All subjects were measured in anthropometry, serum level of biochemical parameters related to obesity, circumstance levels of insulin-like growth factor1, adipokines (adiponectin, leptin and growth differentiation factor 15) and CES1. Results Higher serum CES1 level were found in the MetS group (P = 0.004) and the MASLD group (P

Abstract Objective This study investigated the characteristics of newly diagnosed type 1 diabetes mellitus (T1DM) related to autoimmunity and the frequency of diabetic ketoacidosis (DKA) in children and adolescents from 2017–2022 in China. Research design and methods Single-center regional data from the Department of Pediatric Endocrinology, Tongji Hospital, were used to compare 88 children and adolescents newly diagnosed with T1DM from 2020 to 2022 (i.e. during the COVID-19 pandemic in China) and 76 children and adolescents diagnosed with T1DM from 2017 to 2019. Auto-antibodies, including glutamic acid decarboxylase-65 and insulin auto-antibodies, were detected by enzyme-linked immunoassays. DKA was defined as a pH 0.05). The C-peptide level and HbA1c (%) were positively correlated with onset age (R1 = 0.389, p

Abstract Residual powder is a defect in powder bed fusion-based additive manufacturing (3D printing), and it is difficult to completely remove it from as-printed materials. In addition, it is not necessary to apply 3D printed implants with residual powder in the clinic. The immunological response triggered by the residual powder is an important area of study in medical research. To further understand the possible immunological reactions and hidden dangers caused by residual powders in vivo, this study compared the immunological reactions and osteolysis caused by typical powders for four implant materials: 316 L stainless steel, CoCrMo, CP-Ti, and Ti-6Al-4V (particle size range of 15–45 μm), in a mouse skull model. Furthermore, the possible immunological responses and bone regeneration induced by the four 3D printed implants with residual powder in a rat femur model were compared. In the mouse skull model, it was found that the 316L-S, CoCrMo-S, and especially the 316L-M powders, upregulated the expression of pro-inflammatory factors, increased the ratio of RANKL/OPG, and activated more functional osteoclasts, resulting in more severe bone resorption compared with those in other groups. In the rat femur model, which is more suitable for clinical practice, there is no bone resorption in implants with residual powders, but they show good bone regeneration and integration ability because of their original roughness. The results indicate that the expressions of inflammatory cytokines in all experimental groups were the same as those in the control group, showing good biological safety. The results answered some critical questions related to additively manufactured medical materials in vivo and indicated that as-printed implants may have great potential in future clinical applications. Graphical Abstract

BackgroundThe performance of existing image-based training models in evaluating bowel preparation on colonoscopy videos was relatively low, and only a few models used external data to prove their generalization. Therefore, this study attempted to develop a more precise and stable AI system for assessing bowel preparation of colonoscopy video.MethodsWe proposed a system named ViENDO to assess the bowel preparation quality, including two CNNs. First, Information-Net was used to identify and filter out colonoscopy video frames unsuitable for Boston bowel preparation scale (BBPS) scoring. Second, BBPS-Net was trained and tested with 5,566 suitable short video clips through three-dimensional (3D) convolutional neural network (CNN) technology to detect BBPS-based insufficient bowel preparation. Then, ViENDO was applied to complete withdrawal colonoscopy videos from multiple centers to predict BBPS segment scores in clinical settings. We also conducted a human-machine contest to compare its performance with endoscopists.ResultsIn video clips, BBPS-Net for determining inadequate bowel preparation generated an area under the curve of up to 0.98 and accuracy of 95.2%. When applied to full-length withdrawal colonoscopy videos, ViENDO assessed bowel cleanliness with an accuracy of 93.8% in the internal test set and 91.7% in the external dataset. The human-machine contest demonstrated that the accuracy of ViENDO was slightly superior compared to most endoscopists, though no statistical significance was found.ConclusionThe 3D-CNN-based AI model showed good performance in evaluating full-length bowel preparation on colonoscopy video. It has the potential as a substitute for endoscopists to provide BBPS-based assessments during daily clinical practice.

Titanium meshes are widely utilized in alveolar bone augmentation, and this study aims to enhance the properties of titanium meshes through heat treatment (HT) and the synergistic finishing technology of electric field and flow field (EFSF). Our findings illustrate that the titanium mesh exhibits improved mechanical properties following HT treatment. The innovative EFSF technique, in combination with HT, has a substantial impact on improving the surface properties of titanium meshes. HT initiates grain fusion and reduces surface pores, resulting in enhanced tensile and elongation properties. EFSF further enhances these improvements by significantly reducing surface roughness and eliminating adhered titanium powder, a byproduct of selective laser melting printing. Increased hydrophilicity and surface-free energy are achieved after EFSF treatment. Notably, the EFSF-treated titanium mesh exhibits reduced bacterial adhesion and is non-toxic to osteoblast proliferation. These advancements increase its suitability for clinical alveolar bone augmentation.

PurposeThe present study aimed to explore the feasibility and safety of Transarterial embolization (TAE) in the treatment of obstetrics and gynecological hemorrhagic diseases transradial approach (TRA) compared to transfemoral approach (TFA).MethodsThis cohort study was conducted on patients with obstetrics and gynecology bleeding diseases from June 2021 to November 2022. Clinical characteristics of the patients were comparable between the two groups. The success rate of puncture and embolization, radiation dose, operation time, fluoroscopy time (FT), as well as complications of each patient were recorded and then retrospectively analyzed the data. The European Five-dimensional Health Scale (ED-5Q) and visual analog scale (VAS) were used to assess the quality of life (QOL) on the day of discharge and 30 days after surgery between the two groups.ResultsA total of 71 patients undergoing TAE were allocated to the TRA (n = 31) or TFA (n = 40) group in this study. Puncture and embolization were completed in all patients. Compared to the TFA group, the radiation dose of the TRA group (343.89 ± 108.81 mGy vs. 469.29 ± 198.66 mGy; p = 0.029) is significantly reduced. Minor complications occurred in only one patient (3.2%) in the TRA group. The surgery-related quality of life EQ-5D index score on the day of discharge in the TRA group (0.72 ± 0.12 vs. 0.65 ± 0.11; p = 0.017) was significantly higher than that in the TFA group, and the VAS score (2.55 ± 0.62 vs. 2.95 ± 0.85; p = 0.025) of catheter site discomfort was significantly lower in the TRA group were than in the TFA group, but no significant difference was observed in the QOL assessment at 30 days post-surgery.ConclusionTransradial approach TAE has comparable efficacy and safety to TFA TAE in treating obstetrics and gynecological bleeding diseases. This access can improve patient QOL without affecting surgical safety.

Abstract Background Rubinstein–Taybi syndrome (RSTS) is a rare autosomal‐dominant genetic disease caused by variants of CREBBP (RSTS1) or EP300 (RSTS2) gene. RSTS2 is much less common, with less than 200 reported cases worldwide to date. More reports are still needed to increase the understanding of its clinical manifestations and genetic characteristics. Methods The clinical data of two children with RSTS2 were analyzed retrospectively, and their clinical manifestations, auxiliary examinations, and mutational spectrum were summarized. Liquid chromatography–tandem mass spectrometer (LC–MS/MS) technology was used to detect the levels of steroid hormones if possible. Results After analyzing the clinical and genetic characteristics of two boys with RSTS2 (0.7 and 10.4 years old, respectively) admitted in our hospital, we identified two novel heterozygous variants in the EP300 exon 22 (c.3750C > A, p. Cys1250*, pathogenic; c.1889A > G, p. Tyr630Cys, likely pathogenic), which could account for their phenotype. In addition to common clinical manifestations such as special facial features, microcephaly, growth retardation, intellectual disability, speech delay, congenital heart defect, recurrent respiratory infections, and immunodeficiency, we found one of them had a rare feature of adrenal insufficiency, and LC–MS/MS detection showed an overall decrease in steroid hormones. Conclusion In our study, we identified two novel variants in the EP300 exon 22, and for the first time, we reported a case of RSTS2 associated with adrenal insufficiency, which will enrich the clinical and mutational spectrum of this syndrome.

Abstract Background Intensive physical stress in sepsis can induce the disorder of endocrine function and impact the clinical course and prognosis. Low T3 syndrome has been verified to be the predictive indicator of poor prognosis in several researches. Reports on the influence factors of thyroid hormonal levels in children with severe sepsis are rare. We aim to investigate the thyroid hormonal variations in the course of sepsis and analyze that how to be affected by clinical data and inflammatory biomarkers. Methods In the case-control study, 184 children with sepsis and 323 controls were included in Tongji Hospital, Wuhan, China, in 2019. Data on clinical and inflammatory parameters were collected from all participants. Circulating FT3(Free Triiodothyronine) levels were measured by Electrochemiluminescence immunoassay. Finally, we investigated the correlation between FT3 and related variables with linear regression analysis. Results Serum FT3 was lower in the sepsis group than in control group(2.59 + 1.17 vs 2.83 + 1.01 pg/mL, p 0.3) of FT3 levels with ferritin, PCT, duration of symptoms, SOFA score, and mortality were revealed. Moreover, we observed that FT3 had the positive correlation with albumin, as well as white blood cell count. Conclusions Concentrations of serum FT3 are dramatically declined in sepsis children than in control children. Our results demonstrate that recognizing the potential abnormality of thyroid hormones in sepsis patients and examine timely through abnormal common clinical data and inflammatory biomarkers is a fine option.

Abstract Background To evaluate the effectiveness of individualized-dose polyethylene glycol recombinant human growth hormone (PEG-rhGH) for short stature. Methods This real-world study enrolled children with short stature in 19 hospitals throughout China. They were treated with PEG-rhGH for 6 months. The starting dosage ranged from 0.10 to 0.20 mg/kg/week. The primary outcome was the change in height standard deviation score (ΔHt SDS). Results Five hundred and ten patients were included and grouped based on dosage as A (0.10–0.14 mg/kg/week), B (0.15–0.16 mg/kg/week), C (0.17–0.19 mg/kg/week), and D (0.20 mg/kg/week). The mean 6-month ΔHt SDS for the total cohort was 0.49 ± 0.27, and the means differed among the four dose groups (P = 0.002). The ΔHt SDS was lower in group A than in groups B (LSM difference [95%CI], -0.09 [-0.17, -0.01]), C (LSM difference [95%CI], -0.10 [-0.18, -0.02]), and D (LSM difference [95%CI], -0.13 [-0.21, -0.05]) after adjusting baseline covariates. There were no significant differences among groups B, C, and D. When the baseline IGF-1 was 0 SDS, the △Ht SDS was not different among the four groups (P = 0.931 and P = 0.400). In children with baseline IGF-1 SDS of -2 ~ 0 SDS, a higher dosage was associated with a better treatment effect (P = 0.003), and the △Ht SDS was lower in older children than in younger ones (P

ABSTRACT X‐linked hypophosphatemia (XLH) is a rare, inherited, multisystem disorder characterized by hypophosphatemia that occurs secondary to renal phosphate wasting. Mutations in PHEX gene (located at Xp22.1) in XLH alter bone mineral metabolism, resulting in diverse skeletal, dental, and other extraskeletal abnormalities that become evident in early childhood and persist into adolescence and adult life. XLH impacts physical function, mobility, and quality of life, and is associated with substantial socioeconomic burden and health care resource utilization. As the burden of illness varies with age, an appropriate transition of care from childhood and adolescence to adulthood is necessary to meet growth‐related changes and minimize long‐term sequelae of the condition. Previous XLH guidelines that encompassed transition of care have focused on Western experience. Regional differences in resource availability warrant tailoring of recommendations to the Asia‐Pacific (APAC) context. Hence, a core expert panel of 15 pediatric and adult endocrinologists from nine countries/regions across APAC convened to formulate evidence‐based recommendations for optimizing XLH care. A comprehensive literature search on PubMed using MeSH and free‐text terms relevant to predetermined clinical questions on diagnosis, multidisciplinary management, and transition of care of XLH revealed 2171 abstracts. The abstracts were reviewed independently by two authors to shortlist a final of 164 articles. A total of 92 full‐text articles were finally selected for data extraction and drafting the consensus statements. Sixteen guiding statements were developed based on review of evidence and real‐world clinical experience. The GRADE criteria were used to appraise the quality of evidence supporting the statements. Subsequently, a Delphi technique was utilized to rate the agreement on statements; 38 XLH experts (15 core, 20 additional, 3 international) from 15 countries/regions (12 APAC, 3 EU) participated in the Delphi voting to further refine the statements. Statements 1–3 cover the screening and diagnosis of pediatric and adult XLH; we have defined the clinical, imaging, biochemical, and genetic criteria and raised red flags for the presumptive and confirmatory diagnosis of XLH. Statements 4–12 tackle elements of multidisciplinary management in XLH such as therapeutic goals and options, composition of the multidisciplinary team, follow‐up assessments, required monitoring schedules, and the role of telemedicine. Treatment with active vitamin D, oral phosphate, and burosumab is discussed in terms of applicability to APAC settings. We also expound on multidisciplinary care for different age groups (children, adolescents, adults) and pregnant or lactating women. Statements 13–15 address facets of the transition from pediatric to adult care: targets and timelines, roles and responsibilities of stakeholders, and process flow. We explain the use of validated questionnaires, desirable characteristics of a transition care clinic, and important components of a transfer letter. Lastly, strategies to improve XLH education to the medical community are also elaborated in statement 16. Overall, optimized care for XLH patients requires prompt diagnosis, timely multidisciplinary care, and a seamless transfer of care through the coordinated effort of pediatric and adult health care providers, nurse practitioners, parents or caregivers, and patients. To achieve this end, we provide specific guidance for clinical practice in APAC settings. © 2023 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

Although thymidylate synthase (TYMS) inhibitors have served as components of chemotherapy regimens, the currently available inhibitors induce TYMS overexpression or alter folate transport/metabolism feedback pathways that tumor cells exploit for drug resistance, limiting overall benefit. Here we report a small molecule TYMS inhibitor that i) exhibited enhanced antitumor activity as compared with current fluoropyrimidines and antifolates without inducing TYMS overexpression, ii) is structurally distinct from classical antifolates, iii) extended survival in both pancreatic xenograft tumor models and an hTS/Ink4a/Arf null genetically engineered mouse tumor model, and iv) is well tolerated with equal efficacy using either intraperitoneal or oral administration. Mechanistically, we verify the compound is a multifunctional nonclassical antifolate, and using a series of analogs, we identify structural features allowing direct TYMS inhibition while maintaining the ability to inhibit dihydrofolate reductase. Collectively, this work identifies nonclassical antifolate inhibitors that optimize inhibition of thymidylate biosynthesis with a favorable safety profile, highlighting the potential for enhanced cancer therapy.

ObjectiveThe aim of this study was to assess whether size for gestational age and dehydroepiandrosterone sulfate (DHEAS) are associated with cardiometabolic risk in central precocious puberty (CPP) girls.MethodsThe retrospective study included 443 patients with newly diagnosed CPP. Subjects were categorized by birth weight for gestational age (appropriate [AGA], small [SGA], and large [LGA] for gestational age) and serum DHEAS concentration (high [≥75th percentile] and normal [

IntroductionThe impairment of blood-brain barrier (BBB) is one of the key contributors to maternal inflammation induced brain damage in offspring. Our previous studies showed Fibrinogen-like protein 2 (FGL2) deficiency alleviated maternal inflammation induced perinatal brain damage. However, its role in BBB remains undefined.MethodsLipopolysaccharide (LPS) was intraperitoneally injected to dams at Embryonic day 17 to establish maternal inflammation model. FGL2 knockout mice and primary brain microvascular endothelial cells (BMECs) were used for the in-vivo and in-vitro experiments. BBB integrity was assessed by sodium fluorescein extravasation and tight junction (TJ) protein expression. Oxidative stress and the activation of PI3K/NF-κB pathway were evaluated to explore the mechanisms underlying.ResultsUpon maternal inflammation, BBB integrity was remarkedly reduced in neonatal mice. Meanwhile, FGL2 expression was consistently increased in BBB-impaired brain as well as in LPS-treated BMECs. Moreover, FGL2 deficiency attenuated the hyperpermeability of BBB, prevented the decline of TJ proteins, and reduced the cytokine expressions in LPS-exposed pups. Mechanistically, the indicators of oxidative stress, as well as the activation of PI3K/NF-κB pathway, were upregulated after LPS exposure in vivo and in vitro. FGL2 deletion decreased the generation of ROS and NO, reduced the endothelial iNOS and NOX2 expressions, and suppressed the PI3K/NF-κB pathway activation. Besides, inhibition of PI3K by LY294002 decreased the oxidative stress in LPS-treated wild-type BMECs. While, overexpression of PI3K by lentivirus reemerged the induction of NOX2 and iNOS as well as NF-κB activation in FGL2-deleted BMECs.ConclusionOur findings indicate that FGL2 deficiency alleviates the maternal inflammation-induced BBB disruption by inhibiting PI3K/NF-κB mediated oxidative stress in BMECs. Targeting FGL2 may provide a new therapy for prenatal brain damage of offspring.

Pure metals tend to have a superior malleability compared to alloys. However, the applicability of pure metals is limited by their low strengths and hardness properties. In this study, strong and ductile pure Ti was synthesized via an approach involving powder modification and additive manufacturing (AM) under a reactive atmosphere. Specifically, pure Ti was processed by laser powder bed fusion in an environment containing a mixture of argon and nitrogen gases. In-situ high-energy synchrotron X-ray diffraction analysis reveals that in-situ nitrogen strengthening of the pure Ti occurs during the reactive AM of Ti. Furthermore, the presence of a nitrogen solid solution leads to the formation of high-strength pure Ti (yield strength of ∼979 MPa and ultimate tensile strength of ∼1058 MPa, respectively). This material exhibits excellent uniform elongation (11%) due to strong work hardening caused by the interaction of interstitial elements and submicrostructure. The proposed reactive AM approach paves the way for in-situ strengthening of pure metals and alloys.

Maternal obesity has a significant impact on the metabolism of offspring both in childhood and adulthood. The metabolic regulation of offspring is influenced by the intrauterine metabolic programming induced by maternal obesity. Nevertheless, the precise mechanisms remain unclear. The hypothalamus is the primary target of metabolic programming and the principal regulatory center of energy metabolism. Accumulating evidence has indicated the crucial role of hypothalamic regulation in the metabolism of offspring exposed to maternal obesity. This article reviews the development of hypothalamus, the role of the hypothalamic regulations in energy homeostasis, possible mechanisms underlying the developmental programming of energy metabolism in offspring, and the potential therapeutic approaches for preventing metabolic diseases later in life. Lastly, we discuss the challenges and future directions of hypothalamic regulation in the metabolism of children born to obese mothers.

Abstract Background Rapid Advice Guidelines (RAG) provide decision makers with guidance to respond to public health emergencies by developing evidence-based recommendations in a short period of time with a scientific and standardized approach. However, the experience from the development process of a RAG has so far not been systematically summarized. Therefore, our working group will take the experience of the development of the RAG for children with COVID-19 as an example to systematically explore the methodology, advantages, and challenges in the development of the RAG. We shall propose suggestions and reflections for future research, in order to provide a more detailed reference for future development of RAGs. Result The development of the RAG by a group of 67 researchers from 11 countries took 50 days from the official commencement of the work (January 28, 2020) to submission (March 17, 2020). A total of 21 meetings were held with a total duration of 48 h (average 2.3 h per meeting) and an average of 16.5 participants attending. Only two of the ten recommendations were fully supported by direct evidence for COVID-19, three recommendations were supported by indirect evidence only, and the proportion of COVID-19 studies among the body of evidence in the remaining five recommendations ranged between 10 and 83%. Six of the ten recommendations used COVID-19 preprints as evidence support, and up to 50% of the studies with direct evidence on COVID-19 were preprints. Conclusions In order to respond to public health emergencies, the development of RAG also requires a clear and transparent formulation process, usually using a large amount of indirect and non-peer-reviewed evidence to support the formation of recommendations. Strict following of the WHO RAG handbook does not only enhance the transparency and clarity of the guideline, but also can speed up the guideline development process, thereby saving time and labor costs.

Abstract Background SOX3 is essential for pituitary development normally at the earliest stages of development. In humans, variants of SOX3 can cause X-linked hypopituitarism with various clinical manifestations, with or without mental retardation. Case presentation We present an 8-year-old Chinese patient with congenital hypopituitarism who had a 6.180 Mb duplication on Xq26.3q27.1 including SOX3, F9, and eight other contiguous genes. The main complains of the boy was short stature. His height was 90.1 cm (− 5.87SDS), weight 11.5 kg (− 5.25SDS). He developed growth hormone (GH) deficiency, cryptorchidism and low thyroid function. Pituitary magnetic resonance imaging revealed the pituitary dysplasia. After diagnosis, levothyroxine was given for one month first, and the thyroid function basically returned to normal, but the growth situation did not improve at all. Then recombinant human GH was given, his height, growth rate and height SDS were improved significantly in the 2 years follow-up. The level of height SDS improved from − 5.87 SDS before treatment to − 3.27 SDS after the first year of treatment and − 1.78 SDS after the second years of treatment. Gonadal function and long-term prognosis of the patient still need further observation and follow-up. Conclusions This is the first case of Chinese male patient with multiple hypophysis dysfunction caused by SOX3 duplication, which will expand the range of phenotypes observed in patients with duplication of SOX3.

Abstract The coronavirus disease 2019 (COVID-19) is a highly transmissible disease caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that poses a major threat to global public health. Although COVID-19 primarily affects the respiratory system, causing severe pneumonia and acute respiratory distress syndrome in severe cases, it can also result in multiple extrapulmonary complications. The pathogenesis of extrapulmonary damage in patients with COVID-19 is probably multifactorial, involving both the direct effects of SARS-CoV-2 and the indirect mechanisms associated with the host inflammatory response. Recognition of features and pathogenesis of extrapulmonary complications has clinical implications for identifying disease progression and designing therapeutic strategies. This review provides an overview of the extrapulmonary complications of COVID-19 from immunological and pathophysiologic perspectives and focuses on the pathogenesis and potential therapeutic targets for the management of COVID-19.

Studying parasitic nematodes, which generate a massive hazard to animal health, is more difficult than studying free-living nematodes as appropriate animal models are essential, and the relationship between parasites and hosts is extremely complex. Strongyloides stercoralis is an intestinal nematode parasite that mainly infects dogs, humans and other primates. Currently, S. stercoralis worms needed for research mainly rely on their natural host, the dog. This study explored a method of using Meriones meridianus as a model for S. stercoralis. The immunosuppressed M. meridianus were infected with S. stercoralis subcutaneously, and post-parasitic, first-stage larvae (PP L1) were detected in the faeces, with more larvae in female gerbils. In addition, parasitic females (PFs), third-stage larvae (L3s) and rhabditiform larvae were found primarily in the small intestines and lungs of infected gerbils. The PFs and auto-infective third-stage larvae (aL3s) obtained from M. meridianus are morphologically identical to those obtained from beagles and Meriones unguiculatus. Moreover, the infection of S. stercoralis caused changes to biochemical indicators in the serum and in the physiology of M. meridianus. The results demonstrated that M. meridianus can be infected by S. stercoralis, and this model provides a great tool for exploring the biological processes of this parasite and its interaction with the host.

Intrauterine growth restriction combined with postnatal accelerated growth (CG-IUGR) could lead to long-term detrimental metabolic outcomes characte rized by insulin resistance. As an indispensable co-receptor of Wnt signaling, L RP6 plays a critical role in the susceptibility of metabolic disorders. However, whether LRP6 is involved in the metabolic programing is still unknown. We hypothesized that CG- IUGR programed impaired insulin sensitivity through the impaired LRP6-mediated Wnt signaling in skeletal muscle. A CG-IUGR rat model was employed. The transcriptional a nd translational alterations of the components of the Wnt and the insulin signaling in the skeletal muscle of the male CG-IUGR rats were determined. The role of LRP6 on t he insulin signaling was evaluated by shRNA knockdown or Wnt3a stimulation of LRP6. Comp ared with controls, the male CG-IUGR rats showed an insulin-resistant phenotype, wi th impaired insulin signaling and decreased expression of LRP6/β-catenin in skeletal muscle. LRP6 knockdown led to reduced expression of the IR-β/IRS-1 in C2C12 cell line, while Wnt3a-mediated LRP6 expression increased the expression of IRS-1 and IGF-1R but not IR-β in the primary muscle cells of male CG-IUGR rats. The impaired LRP6/β-catenin/IGF-1R/IRS-1 signaling is probably one of the critical mechanisms underlying the programed impaired insulin sensitivity in male CG-IUGR.

Abstract Background Our study aims to summarize the clinical characteristics of rare types of congenital adrenal hyperplasia (CAH) other than 21-hydroxylase deficiency (21-OHD), and to explore the clinical applications of genetic analysis and liquid chromatography tandem-mass spectrometry (LC-MS/MS) in rare CAH. Methods We retrospectively analysed the clinical data of 5 rare cases of CAH admitted to our hospital and summarized their clinical manifestations, auxiliary examinations, diagnosis and mutational spectrum. Results After gene sequencing, complex heterozygous variants were detected in all patients (2 cases were lipoid congenital adrenal hyperplasia (LCAH), 11β-hydroxylase deficiency (11β-OHD), 3β-hydroxysteroid dehydrogenase deficiency (3β-HSD deficiency) and P450 oxidoreductase deficiency (PORD) each accounted for 1 case), which were consistent with their clinical manifestations. Among them, 4 novel variants were detected, including c.650 + 2 T > A of the StAR gene, c.1145 T > C (p. L382P) of the CYP11B1 gene, c.1622C > T (p. A541V) and c.1804C > T (p. Q602 *) of the POR gene. The LC-MS/MS results for steroid hormones in patients were also consistent with their genetic variants: 2 patients with LCAH showed a decrease in all steroid hormones; 11β-OHD patient showed a significant increase in 11-deoxycortisol and 11-deoxycorticosterone; patient with 3β-HSD deficiency showed a significant increase in DHEA; and PORD patient was mainly characterized by elevated 17OHP, progesterone and impaired synthesis of androgen levels. Conclusions The clinical manifestations and classification of CAH are complicated, and there are cases of missed diagnosis or misdiagnosis. It’s necessary to combine the analysis of clinical manifestations and auxiliary examinations for diagnosis; if necessary, LC-MS/MS analysis of steroid hormones or gene sequencing is recommended for confirming diagnosis and typing.

Abstract Background This study aimed to investigate the transmission of cytomegalovirus (CMV) via breast milk in low birth weight (LBW) and premature infants and its effects. Methods PubMed, Medline, Cochrane Library, and Embase were searched for studies (without language and time restriction) published before March 27, 2020, that examined the effect of CMV transmitted by breast milk on LBW and premature infants. The rates of breast milk-acquired CMV infection, CMV-related symptoms, and CMV-related sepsis-like syndrome (CMV-SLS) in LBW and premature infants were pooled from each study. Results Eighteen studies with 1920 LBW and premature infants were included. The pooled CMV infection rate from breast milk for infants fed untreated breast milk was significantly higher than those fed frozen breast milk [19.3, 95% confidence interval (CI) = 11.8–29.9% vs. 13.5, 95% CI = 8.0–22.0%, P

PurposeTo investigate the effectiveness and safety of gonadotropin-releasing hormone analogue (GnRHa) in combination with recombinant human growth hormone (rhGH) in girls with central precocious puberty (CPP).MethodsClinical data of 80 girls diagnosed with idiopathic central precocious puberty (ICPP) between January 2017 and June 2021 were retrospectively analyzed. Treatment strategy involved GnRHa alone (group A: n=34) and GnRHa+rhGH (group B: n=46). Children’s heights (Ht), weights (Wt) and sex hormone levels were measured every 3 months after treatment and bone age (BA) every six months. Heights, growth velocity (GV), predicted adult height (PAH), weights, body mass index (BMI), sex hormone levels and bone age were compared between the two groups.ResultsChildren in group B showed greater height gain at the 12th, 24th and 30th months after treatment (p0.05). Levels of LH and FSH were lower in both groups after treatment with no statistical differences between groups (p>0.05). The gap between bone age and chronological age gradually decreased in both groups and no abnormal progression of bone age or other adverse side effects occurred.ConclusionsThe combination of GnRHa with rhGH produced better height gains than GnRHa alone for patients with CPP. The gonadal axis was suppressed and progression of bone age delayed with good safety and efficacy.

Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by variable impairment of social communication and repetitive behaviors, highly restricted interests, and/or sensory behaviors beginning early in life. Many individuals with ASD have dysfunction of microglia, which may be closely related to neuroinflammation, making microglia play an important role in the pathogenesis of ASD. Mounting evidence indicates that microglia, the resident immune cells of the brain, are required for proper brain function, especially in the maintenance of neuronal circuitry and control of behavior. Dysfunction of microglia will ultimately affect the neural function in a variety of ways, including the formation of synapses and alteration of excitatory–inhibitory balance. In this review, we provide an overview of how microglia actively interact with neurons in physiological conditions and modulate the fate and functions of synapses. We put a spotlight on the multi-dimensional neurodevelopmental roles of microglia, especially in the essential influence of synapses, and discuss how microglia are currently thought to influence ASD progression.

Abstract Background A case of isolated growth hormone deficiency type IA (IGHD IA) caused by novel compound heterozygous mutation in the GH1 gene was reported in this study, which aimed to provide insights that will benefit future diagnosis and treatment. Case presentation We analyzed and summarized the clinical data and genetic test results from a patient with IGHD admitted in March 2019 to the Department of Pediatrics Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology. We described the results from a 1-year-9-months old female, whose chief complaint was “growth retardation for more than one year”. Her birth length was 49.0 cm, and her birth weight was 3.05 kg. Suboptimal intake (breastfeeding) jaundice lasted for approximately two months following birth. When evaluated at the age of 1-year-9-months old, the patient’s height was 61.0 cm (− 7.24 SD), and her weight was 6.4 kg (− 1.50 SD). The patient’s physical characteristics included yellowish hair, large and unclosed anterior fontanelles, raised forehead, and a low and flat nose. The major abnormalities observed from the auxiliary examinations included low GH (T, inherited from her mother) in intron 1 of the GH1 gene and a deletion that encompassed the same gene (chr17: 61973811–61996255, inherited from her father). After hormone replacement therapy with L-thyroxine and recombinant human GH (rhGH), the patient’s thyroid function returned to normal, and her serum IGF-1 level significantly improved, which resulted in an accelerated increase in height. Conclusion This study described a case of IGHD caused by novel compound heterozygous mutations in the GH1 gene. This study suggested that closer attention should be directed to genetic testing and diagnosis based on clinical characteristics to avoid misdiagnosis.

ObjectivesTo investigate the pharmacokinetics (PK) and pharmacodynamics (PD) of Y-shape branched PEGylated recombinant human growth hormone (YPEG-rhGH) and evaluate its short-term efficacy and safety in children with growth hormone deficiency (GHD).MethodsA total of 43 children with GHD from 12 sites in China were enrolled in this randomized, multicenter, active-controlled, double-blind (YPEG-rhGH doses) trial. Patients were randomized 1:1:1:1 to 100, 120, and 140 μg/kg/week of YPEG-rhGH groups and daily rhGH 35 μg/kg/day groups. The treatment lasted 12 weeks. The primary outcome was the area under the curve of the change of insulin-like growth factor-1 (IGF-1). The secondary outcome was the height velocity (HV) increment at week 12.ResultsA dose-dependent response of maximum plasma concentration (Cmax) and area under the concentration-time curves from 0 to 168 hours (AUC0-168h) were observed for YPEG-rhGH. The ratio of Cmax and the ratio of AUC0-168h from the first to the last dosing were 1.09~1.11 and 1.22~1.26 respectively. A YPEG-rhGH dose-dependent increase in area under effect curve (AUEC) of IGF-1 fold change was observed. Model-derived mean IGF-1 SDS was in the normal range for all three YPEG-rhGH doses. At week 12, HV was 7.07, 10.39, 12.27 cm/year, and 11.58 cm/year for YPEG-rhGH 100, 120, and 140 μg/kg/week and daily rhGH respectively. Adherence and safety were consistent with the profile of daily rhGH. No related serious adverse events were reported.ConclusionThe PK/PD suggests that YPEG-rhGH is suitable for the once-weekly treatment of pediatric GHD. YPEG-rhGH 120 ~ 140 μg/kg/week provides the closest HV increment with similar safety and tolerability compared to daily rhGH 35 μg/kg/day in children with GHD.Clinical Trial RegistrationClinicalTrials.gov, identifier [NCT04513171].

Haemonchus contortus poses a severe hazard to the healthy development of the sheep industry and threatens the welfare of sheep. Ivermectin is the primary anthelmintic used for the prevention and treatment of H. contortus parasitism. However, the widespread and uncontrolled application of ivermectin has resulted in the development and spread of resistant strains of H. contortus. P-glycoprotein (P-gp) plays important roles in the pharmacology and toxicology of ivermectin, and changes in P-gp expression levels can be used to analyze the resistance of H. contortus to ivermectin. This study aimed to analyze the effects of ivermectin on P-gp expression in H. contortus L3 larvae isolated from China and to evaluate whether changes in P-gp expression levels can be used to analyze resistant H. contortus strains. In the absence of drug treatment, the ivermectin-resistant strains isolated in China showed increased expression of P-gp11 (p < 0.01) compared with sensitive strains from elsewhere, whereas the expressions of P-gp2 and P-gp9.1 were downregulated (p < 0.01). When the same strain was compared before and after drug treatment, obvious differences in expression were observed between the different strains. Ivermectin-induced P-gp expression was found to be very complex among the L3 larvae of different strains. In addition, it was confirmed that using P-gp to determine ivermectin resistance in H. contortus strains from different geographic environments can yield different results.

Jintrolong® is a long-acting PEGylated recombinant human growth hormone (PEG-rhGH) developed for weekly injection in patients with pediatric growth hormone deficiency (PGHD). Although PEG modification of therapeutic proteins is generally considered safe, concerns persist about the potential for adverse vacuolation in tissues with long-term exposure to PEG-included therapies, particularly in children. We assessed the safety of Jintrolong® in cynomolgus monkeys with an examination of vacuolation in the brain choroid plexus (CP) and reported long-term clinical safety data obtained from children with PGHD. The toxicity of Jintrolong® was assessed following the 52-week administration with doses at 0.3, 1, or 3 mg/kg/week. The levels of vacuolation of CP in animals were dose-dependent and at least partially reversible after a 104- or 157-week recovery period. Vacuolation in the CP epithelium did not lead to obvious subcellular structural or cell functional abnormalities. Compared with the clinical dose of 0.2 mg/kg/week Jintrolong® in PGHD patients, exposure in monkeys under NOAEL 3 mg/kg/week exhibited safety margins greater than 120.5, the predicted minimum dose to induce vacuolation in monkeys is equivalent to 1.29 mg/kg/week in humans, which is 6.45-fold higher than the clinical dose. The safety data acquired in clinical trials for Jintrolong® were also analyzed, which included phase III (360 patients), phase IV (3,000 patients) of 26-week treatment, and a follow-up study with treatment lasting for 3 years. There was no statistically significant difference in the incidence of adverse reactions between the Jintrolong® group and the daily rhGH control group (no PEG), and no new adverse effects (AE) were observed in the Jintrolong® group at the clinical therapeutic dose of 0.2 mg/kg/week.

BackgroundGlycogen storage disease type Ia is a rare metabolic disorder that leads to excessive glycogen and fat accumulation in organs, characterized by hepatomegaly, hypoglycemia, lactic acidemia, hyperlipidemia, hyperuricemia, puberty delay, and growth retardation. Here, we report on a patient with glycogen storage disease type Ia treated with growth hormone.Case PresentationA 10-year-old boy had growth retardation for 6 years, and was admitted to clarify the cause of his short stature. We found that his bone age was 5.5 years, significantly lower than his physical age, while his serum IGF-1 and IGFBP-3 were 23.30 and 1620.0 ng/mL, respectively, both lower than normal. His medical history revealed that he had suffered from steatohepatitis, hyperlipidemia, and hypoglycemia since he was 11 months of age. Whole exome sequencing (WES) showed compound heterozygous mutations in exons 2 and 5 of the glucose-6-phosphatase (G6PC) gene on chromosome 17: c.G248A (p.R83H) and c.G648T (p.L216L). The patient was finally diagnosed with GSD Ia. After growth hormone (GH) treatment and corn starch therapy for 14 months, his height significantly increased (by 13 cm). The serum IGF-1 level increased to the normal range but his lipid levels and liver function did not significantly increase.ConclusionWe describe a young patient with a compound heterozygous G6PC variant in a Chinese family; his height increased significantly after growth hormone and corn starch interventions. This case emphasizes that WES is essential for early diagnosis, and that growth hormone treatment may increase the height of patients with GSD Ia safely.

Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder, characterized by marked genetic heterogeneity. In this study, two independent microarray datasets of cerebellum of ASD were integrative analyzed by NetworkAnalyst to screen candidate crucial genes. NetworkAnalyst identified two up-regulated genes, Jun proto-oncogene (JUN) and platelet derived growth factor receptor alpha (PDGFRA), as the most crucial genes in cerebellum of ASD patients. Based on KEGG pathway database, genes associated with JUN in the cerebellum highlight the pathways of Th17 cell differentiation and Th1 and Th2 cell differentiation. Genes associated with PDGFRA in the cerebellum were found enriched in pathways in EGFR tyrosine kinase inhibitor resistance and Rap1 signaling pathway. Analyzing all differentially expressed genes (DEGs) from the two datasets, Gene Set Enrichment Analysis (GSEA) brought out IL17 signaling pathway, which is related to the expression of JUN and PDGFRA. The ImmuCellAI found the elevated expression of JUN and PDGFRA correlating with increased Th17 and monocytes suggests JUN and PDGFRA may regulate Th17 cell activation and monocytes infiltrating. Mice model of maternal immune activation demonstrated that JUN and PDGFRA are up-regulated and related to the ASD-like behaviors that provide insights into the molecular mechanisms underlying the altered IL17 signaling pathway in ASD and may enable novel therapeutic strategies.

Background: Pearson’s syndrome (PS) is a rare multi-system disorder caused by mitochondrial DNA deletion. Most PS cases in the literature are individual reports, and there is a lack of systematic analysis of clinical features and gene mutations in large samples.Objective: To report a case of PS and summarize the clinical features and genetic characteristics of PS by reviewing the literature.Methods: We reported a case of PS in a boy with severe anemia and multi-system disorder. Genetic etiology was identified by mitochondrial DNA sequencing and whole-exon sequencing. Clinical features and gene mutations were summarized by literature review.Results: The patient had major clinical manifestations with recurrent anemia and multiple organ failure after infection. Mitochondrial DNA sequencing revealed a de novo heteroplasmic deletion of 3.063 kb (nt 6,224–9,287) with 75% heteroplasmy in peripheral blood. A total of 139 PS cases were retrieved after a literature search. The most common initial symptom was refractory anemia requiring repeated blood transfusion (86.2%), digestive system symptoms (26.9%), and failure to thrive (15.4%). During the course of disease, the observed symptoms were bone marrow failure (100%), metabolic disorders (61.87%) and gastrointestinal symptoms (61.87%), failure to thrive (48.9%), renal disorders (42.45%), and pancreatic exocrine insufficiency (39.6%). The mean heteroplasmy of mitochondrial DNA mutation in peripheral blood in deaths (76.29 ± 11.86%, n = 29) was higher than that in survivals (59.92 ± 23.87%, n = 26, p < 0.01). Among the patients with the 4.977 kb deletion, the heteroplasmy in peripheral blood in deaths (79.64 ± 9.71%, n = 11) was higher than that in survivals (56.67 ± 27.65%, n = 9, p < 0.05).Conclusion: PS can affect multiple systems, and mitochondrial DNA sequencing should be performed early. The heteroplasmy in peripheral blood is related to prognosis.

Abstract Background To investigate the clinical and genetic characteristics of patients with glycogen storage disease type Ib (GSD Ib). Case presentation This report retrospectively analyzed the clinical data of 3 patients with GSD Ib admitted into our hospital, and summarized their onset characteristics, clinical manifestations, related examinations and treatment as well as mutational spectrum. After gene sequencing, the diagnosis of GSD Ib was confirmed in all 3 patients. Five variants of SLC37A4 gene were detected, of which c. 572C > T was the common variant and c. 680G > A was a novel variant. The 3 cases of GSD Ib were mainly affected by liver enlargement, growth retardation, etc., and all had a history of repeated infections. At the onset, patients mainly manifested as mildly elevated alanine-aminotransferase (ALT), accompanied by decreased absolute neutrophil count (ANC), hypertriglyceridemia, and metabolic disorders (hypoglycemia, hyperlactic acidemia, metabolic acidosis, etc.). After long-term treatment by oral uncooked cornstarch, the abnormal liver enzymes gradually returned to normal, and metabolic abnormalities were basically controlled most of the time. With increasing age, ANC of 2 patients decreased progressively, whereas the times of infections was reduced. Conclusions We reported 3 cases with GSD Ib and a novel SLC37A4 variant. The possibility of GSD type Ib should be kept on alert when a patient suffers recurrent infections, accompanied by hepatomegaly, elevated liver enzymes, hypoglycemia, dyslipidemia, and metabolic disorders.

A major problem faced by the agricultural industry is the resistance of Haemonchus contortus to anthelmintic drugs. For a better understanding of the response of H. contortus to IVM and for the screening of drug-resistance-related genes, we used RNA sequencing and isobaric tags for relative and absolute quantification (iTRAQ) technology to detect the transcriptomic and proteomic changes in H. contortus after ivermectin treatment. An integrated analysis of the two omics showed that the differentially expressed genes and proteins were significantly enriched in the pathways of amino acid degradation, the metabolism of xenobiotics by cytochrome P450, the biosynthesis of amino acids, and the tricarboxylic acid cycle. We found that the upregulated UDP-glycosyltransferases (UGT), glutathione S-transferase (GST), cytochrome P450 (CYP), and p-glycoprotein (Pgp) genes play important roles in drug resistance in H. contortus. Our work will help in the understanding of the transcriptome and proteome changes in H. contortus after IVM and will facilitate the discovery of genes related to drug resistance. This information can be further applied to increase the understanding of the response of IVM in relation to H. contortus.

The physical properties, group composition, stable carbon isotope, and biomarker compound distribution characteristics of crude oil in the Archean buried hill were studied and compared with the geochemical characteristics of Paleogene crude oil, in order to discuss the geochemical characteristics and sources of crude oil from the Archean buried hill JZ25-1S in the Liaoxi Low Uplift. The crude oil from the second member of the Paleogene Shahejie Formation and the Archean buried hill in this area are mainly light and medium crude oil. The oil has medium saturated hydrocarbon, high aromatic hydrocarbon, high non-hydrocarbon and asphaltene contents. The carbon isotopes of the crude oil are distributed between -26.2‰ and -24.4‰, and the isotopic fractionation among group components is small. The chromatographic curve clearly shows the "bulge" formed by biodegradation, the single peak and post-kurtosis state is dominant, the Pr/Ph value is generally around 1.3, and the Pr/nC17, Ph/nC18 values are both high. The sterane characteristics of crude oil show a high gammacerane abundance, the C27 rearranged sterane and 4-methyl sterane contents are medium, the dinostane content is low, and the regular sterane C27, C28, C29 fingerprints are partial"V" or "L" shaped. However, the characteristics of Archean crude oil from wells JZ25-1S-4D and JZ25-1-10D are quite different from the above-mentioned crude oil. Comprehensive analysis suggests that the main body of crude oil from the Paleogene and Archean buried hills in the JZ25-1S area is a mixture from the Es3 member of the Liaoxi Sag and the Es1 member of the Liaozhong Sag. Its parent material comes from a weakly reducing environment with moderate salinity and is mainly derived from algae and other phytoplankton. The crude oil has a high degree of maturity and is severely biodegraded. The Archean buried hill crude oil from wells JZ25-1S-4D and JZ25-1-10D is derived from the Es3 member source rock in the Liaoxi Sag, which was deposited in a weakly reducing freshwater environment with high maturity and weak biodegradation.

We report the detection and decline over time of severe acute respiratory syndrome coronavirus 2 antibodies in infants born to women with coronavirus disease. Among 11 infants tested at birth, all had detectable IgG and 5 had detectable IgM. IgG titers with positive IgM declined more slowly than those without.

Whether severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) affects the fetus in utero is important to the well-being of the mother and neonate. We report the case of a full-term neonate born to a mother who developed symptoms of coronavirus disease 2019 (COVID-19) at 32 weeks of gestation. The placental pathology showed slight local inflammation. Serial quantitative antibody measurements in the neonate showed elevated levels of IgM on the day of birth and a gradual decline to negative levels within 28 days of life; the levels of IgG declined gradually, but IgG was still positive on day 50 of life. The sequential dynamic changes in antibody levels in the neonate were consistent with those in his mother. One-step reverse transcriptase droplet digital PCR testing for SARS-CoV-2 nucleic acid in throat and anal swabs showed positive results (750 and 892 copies/ml) on day 7 of life and negative results on day 14 of life. The neonate had no symptoms of COVID-19. This report enables us to re-evaluate the significance of IgM detection in intrauterine SARS-CoV-2 infection and presents a favorable prognosis for the neonate with long-term exposure to maternal COVID-19, despite a high possibility of intrauterine infection.

Abstract Background Spondyloepiphyseal dysplasia tarda (SEDT) is a rare X-linked recessive inherited osteochondrodysplasia caused by mutations in the TRAPPC2 gene. It is clinically characterized by disproportionate short stature and early onset of degenerative osteoarthritis. Clinical diagnosis can be challenging due to the late-onset of the disease and lack of systemic metabolic abnomalites. Genetic diagnosis is critical in both early diagnosis and management of the disease. Here we reported a five-generation Chinese SEDT family and described the novel molecular findings. Methods Detailed family history and clinical data were collected. Genomic DNA was extracted from venous blood samples of family members. The exons of genes known to be associated with skeletal disorders were captured and deep sequenced. Variants were annotated by ANNOVAR and associated with multiple databases. Putative variants were confirmed by Sanger sequencing. The identified variant was classified according to the American College of Medical Genetics (ACMG) criteria. Results The proband was a 27-year-old Chinese male who presented with short-trunk short stature and joint pain. His radiographs showed platyspondyly with posterior humping, narrow hip-joint surfaces, and pelvic osteosclerosis. A pedigree analysis of 5 generations with 6 affected males revealed an X-linked recessive mode of inheritance. Affected males were diagnosed as SEDT according to the clinical and radiological features. Next-generation sequencing identified a novel variant of c.216_217del in the exon 4 of TRAPPC2 gene in the proband and other affected males. This variant resulted in the shift of reading frame and early termination of protein translation (p.S73Gfs*15). The mother and maternal female relatives of the proband were heterozygous carriers of the same variant, while no variations were detected in this gene of his father and other unaffected males. Based on the ACMG criteria, the novel c.216_217del variant of the TRAPPC2 gene was the pathogenic variant of this SEDT family. Conclusion In this study we identified the novel pathogenic variant of of c.216_217del in the gene of TRAPPC2 in this five-generation Chinese SEDT family. Our findings expand the clinical and molecular spectrum of SEDT and helps the genetic diagnosis of SEDT patients.

Context Obacunone, a limonoid abundantly found in Citrus fruits, exhibits a variety of bioactivities. Objective To investigate the effects of obacunone on a colorectal cancer (CRC) mouse model, and clarify its potential molecular mechanisms. Materials and methods The male Balb/c mice were induced with azoxymethane and dextran sulfate sodium for 12 weeks. Obacunone (50 mg/kg) was administered via oral gavage three times every week until the end of the experiment. Disease indexes including body weight, spleen weight, bloody diarrhea, colon length, histopathological score, and tumor size were measured. The anti-proliferation activities of obacunone were analyzed by MTT or flow cytometry. The expression of protein and mRNA related to cell proliferation or inflammatory cytokines was determined by Western blot, q-PCR and IHC. Results Obacunone significantly alleviated bloody diarrhea, colon shortening (7.35 ± 0.2128 vs. 8.275 ± 0.2169 cm), splenomegaly, histological score (9 ± 0.5774 vs. 6 ± 0.5774) and reduced tumor size (4.25 ± 0.6196 vs. 2 ± 0.5669). Meanwhile, the expression of protein and mRNA related to cell proliferation or inflammatory cytokines was remarkably decreased in tumor tissue. Obacunone inhibited the proliferation activities of colorectal cancer cells. Moreover, obacunone induced colorectal cancer cells G1 and G2 phases arrest, and suppressed the expression of cell cycle genes. Conclusions Obacunone could alleviate CRC via inhibiting inflammatory response and tumor cells proliferation. The results may contribute to the effective utilization of obacunone or its derivatives in the treatment of human CRC.

Objective. A 3-month depot of leuprorelin acetate (LA) was introduced in China in July 2020. However, the clinical experience is limited. The purpose of this study was to compare the efficacy of a LA 11.25 mg 3-month depot with that of a 3.75 mg 1-month depot in suppressing pubertal development for the treatment of central precocious puberty (CPP). Subjects and Methods. A prospective study, including 78 girls with CPP treated with LA, was conducted. 31 patients were treated with a LA 3-month depot, and 47 were treated with a LA 1-month depot. Participants were interviewed at baseline and 6 months. Anthropometric, metabolic, and reproductive data were assessed at each interview. Bone age, serum endocrine hormones, maximum diameter of uterus and volume of ovary of each patient were evaluated. A pharmacoeconomic evaluation was also conducted. Results. Treatment with a 3-month depot was similar to treatment with a 1-month depot in terms of baseline characteristics. After 6 months of treatment, a suppressed level of luteinizing hormone (LH) (LH

There are abundant hydrocarbon resources in the western subsag of Bozhong sag in the Bohai Bay Basin, where oil–gas discoveries have been made in those shallow Neogene and Paleogene reservoirs and deep Mesozoic buried hill reservoirs, but no better understandings have yet been achieved in terms of the process of hydrocarbon accumulation and the relationship between deep buried hill reservoirs and the allocation of shallow reservoirs. Based on the organic geochemical analysis of source rocks and basin modeling of hydrocarbon generation evolution, distribution characteristics of fluid inclusion and homogeneous temperature measurement, combined with the characteristics of oil-source biomarkers, the process of hydrocarbon accumulation in this study area was resumed based upon the regional tectonic background. The following findings were obtained. (1) There are 3 sets of source rocks in the third and first members of Paleogene Shahejie Fm, and the second lower member of Paleogene Dongying Fm; the reservoirs in the peripheral uplift zones include Mesozoic volcanic rocks, Archean metamorphic rocks, and Paleogene–Neogene delta–fluvial porous sandstones. Hydrocarbon generated in this sag migrated along the fault and the unconformity surface to the slope before accumulated in the peripheral tectonic zones, resulting in 3 sets of source–reservoir–caprock assemblages formed with the characteristics of reservoir formation in compound oil and gas accumulation zones. (2) The stratum in the third member of Shahejie Fm is the main source rock. (3) The above three assemblages went through four periods of generating process during the geological time of 11–1 Ma. Vertically hydrocarbon sources first filled in the deep Mesozoic and Archean reservoirs, then migrated and accumulated in the shallow Neogene and Paleogene reservoirs, where multiple shore-term rapid filling of high-temperature fluids led to this typical oil and gas pooling mode. Keywords: Bohai Bay Basin, Western subsag of Bozhong sag, Mesozoic, Buried-hill, Composite hydrocarbon reservoir, Oil source correlation, Shallow oil and gas reservoir, Allocation relationship

Background: Congenital nephrogenic diabetes insipidus (CNDI) is a rare inherited disease that is caused by mutations in arginine vasopressin receptor 2 (AVPR2) or aquaporin 2 (AQP2). Functional analysis of the mutated receptor is necessary to verify the impact of the mutation on receptor function and suggest some possible therapeutic strategies for specific functional defects.Methods: Family history and clinical information were collected. Whole-exome sequencing and sanger sequencing were performed to determine the potential genetic cause of diabetes insipidus. The identified variant was classified according to the American College of Medical Genetics (ACMG) criteria. Bioinformatic analysis was performed to predict the function of the identified variation. Moreover, wild-type and mutated AVPR2 vectors were constructed and transfection to HEK-293T cells. Immunofluorescence experiments were performed to investigate the expression and localization of the mutated protein and cAMP parameter assays were used to measure its activity in response to AVP.Results: The heights of the adult members affected with polyuria and polydipsia were normal, but all affected children had growth retardation. Next-generation sequencing identified a novel mutation in AVPR2 gene (c.530T > A) in this family. Bioinformatic analysis indicated that the mutation in AVPR2 changed the hydropathic characteristic of the protein and was probably deleterious. Although immunofluorescence showed that the mutated AVPR2 was normally expressed in the cell surface, the intracellular cAMP concentration stimulated by AVP was significantly lower in cells transfected with mutated AVPR2 than cells transfected with wild-type AVPR2. Based on the ACMG criteria, the novel c.530T > A variant of the AVPR2 gene was likely pathogenic and the affected family members were diagnosed as CNDI. After the confirmation of the diagnosis, the proband was treated with compound amiloride hydrochloride and rhGH, the symptoms of polyuria, polydipsia and growth retardation were all improved.Conclusion: These findings suggested that the novel mutation in AVPR2 (c.530T > A) was a true disease-causing variant with mild effects, which could be classified as a type III mutant receptor. Moreover, investigations of the function of growth hormone axis could be important for the pediatric CNDI patients with extreme short stature, and rhGH treatment might improve the final adult heights in these patients.

Abstract Background ACAN (OMIM 155760) is located on chromosome 15q26 and encodes the production of aggrecan. Aggrecan is a large chondroitin sulfate proteoglycan with a molecular weight of 254 kDa and contains 2530 amino acids. It is a critical structural component of the extracellular matrix of cartilage, including growth plate, articular, and intervertebral disk cartilage. It plays a key role in bone development. Methods Here, we describe two pedigrees with loss‐of‐function variants in ACAN. Whole exome sequencing was performed for the probands from each family. We illustrate the clinical variability associated with ACAN variants. Results The proband of pedigree A manifested short stature, relative macrocephaly, mild flat nasal bridge, low‐set ears, short neck, and short thumbs. The proband of pedigree B had short height, abnormal vertebral development, and central precocious puberty. By trio‐based whole exome sequencing and in silico analyses, we identified two de novo heterozygous variants of ACAN: NM_013227.4: c.116dupT, p.Arg40Glufs*51 and NM_013227.4: c.2367delC, p.Ser790Glnfs*20 (accession number: AC103982.10). Conclusion The clinical manifestations of ACAN gene variants are diverse. ACAN gene variants are important genetic factors for short stature and should be considered as the differential diagnosis of children with idiopathic short stature (ISS).

Nematodirus causes major economic losses in the development of the livestock industry, as they are common gastrointestinal parasites of cattle, sheep, and other ruminants. The present study investigated Nematodirus infections in sheep in the Hulunbuir and Xilingol Grasslands, two well-known natural pastures in Inner Mongolia, China. The results indicated that the average infection rate was more than 50%. Furthermore, a naturally occurring strain of Nematodirus was obtained using numerous isolation methods in the survey region. Conventional morphology and molecular biology were used to identify the strain. The larval migration inhibition test was used to determine the ivermectin level in the isolated strain. The results indicated that the larvae belonged to the species Nematodirus oiratianus. The strain was found to be ivermectin-resistant. Thus, these results recorded the detailed development processes of Nematodirus eggs, providing novel insights regarding the prevention and control of nematodes by using conventional anthelmintic regimens and by offering valuable species resources for studying anthelmintic resistance in nematodes.

The enhancement of the heat transfer assisted by ultrasound is considered to be an interesting and highly efficient cooling technology, but the investigation and application of ultrasound in minichannel heat sinks to strengthen the flow boiling heat transfer are very limited. Herein, a novel installation of ultrasound transducers in the flow direction of a minichannel heat sink is designed to experimentally study the characteristics of heat transfer in flow boiling and the influence of operation parameters (e.g., heat flux, mass flux rate) and ultrasound parameters (e.g., frequency, power) on the flow boiling heat transfer in a minichannel heat sink with and without ultrasound field. Bubble motion and flow pattern in the minichannel are analyzed by high-speed flow visualization, revealing that the ultrasound field induces more bubbles at the same observation position and a forward shift of the onset of nucleation boiling along the flow direction, as ultrasonic cavitation produces a large number of bubbles. Moreover, bubbles hitting the channel wall on the left and right sides are found, and the motion speed of the bubbles is increased by 31.9% under the ultrasound field. Our results demonstrate that the heat transfer coefficient obtained under the ultrasound field is 53.9% higher than in the absence of the ultrasound field under the same conditions, and the enhancement ratio is decreased in the high heat flux region due to the change of the flow regime with increasing heat flux. This study provides a theoretical basis for the application of an ultrasound field in minichannel heat sinks for the enhancement of flow boiling heat transfer.

Objective: This study aims to explore whether pneumoperitoneum is the only surgical indication for neonates with necrotizing enterocolitis (NEC) and to analyze when early surgical intervention should be considered.Methods: A retrospective case series study was conducted including six neonates with stage 2a−2b NEC who received surgeries without absolute indication but with failed conservative treatment. In the meantime, seven infants who received surgery due to pneumoperitoneum and 32 infants treated with conservative treatment were also included for comparison.Results: Our results indicated that the six infants who received surgical treatment without pneumoperitoneum had a better prognosis compared to the seven infants who underwent surgical treatment after the onset of pneumoperitoneum. None of the infants who received early surgical treatment developed short bowel syndrome or neurodevelopmental impairment, while four out of six infants exhibited growth retardation. On the other hand, a total of five out of the seven infants who received surgical treatment after pneumoperitoneum forfeited further treatment, two developed short bowel syndrome, and one experienced neurodevelopmental impairment. Lower gestational age and birth weight, fetal growth restriction (FGR), perinatal asphyxia, postnatal steroid and vascular active drug use, blood transfusion, and hemodynamic significant patent ductus arteriosus were identified as risk factors associated with surgical repair for infants with NEC. In a laboratory test, infants who needed surgeries had a lower platelet count and a higher C-reactive protein value.Conclusion: Aggressive surgical treatment should be considered in infants with severe necrotizing enterocolitis before the onset of pneumoperitoneum. Lower gestational age and birth weight, FGR, perinatal asphyxia, postnatal steroid and vascular active drug use, blood transfusion, and hsPDA may be associated with surgical repair for infants with NEC.

PurposeTo investigate the features and treatment status of children with type 1 diabetes mellitus (T1DM) in China.MethodsWe recruited patients