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Children are the future of the world, but their health and future are facing great uncertainty because of the coronavirus disease 2019 (COVID-19) pandemic. In order to improve the management of children with COVID-19, an international, multidisciplinary panel of experts developed a rapid advice guideline at the beginning of the outbreak of COVID-19 in 2020. After publishing the first version of the rapid advice guideline, the panel has updated the guideline by including additional stakeholders in the panel and a comprehensive search of the latest evidence. All recommendations were supported by systematic reviews and graded using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system. Expert judgment was used to develop good practice statements supplementary to the graded evidence-based recommendations. The updated guideline comprises nine recommendations and one good practice statement. It focuses on the key recommendations pertinent to the following issues: identification of prognostic factors for death or pediatric intensive care unit admission; the use of remdesivir, systemic glucocorticoids and antipyretics, intravenous immunoglobulin (IVIG) for multisystem inflammatory syndrome in children, and high-flow oxygen by nasal cannula or non-invasive ventilation for acute hypoxemic respiratory failure; breastfeeding; vaccination; and the management of pediatric mental health.This updated evidence-based guideline intends to provide clinicians, pediatricians, patients and other stakeholders with evidence-based recommendations for the prevention and management of COVID-19 in children and adolescents. Larger studies with longer follow-up to determine the effectiveness and safety of systemic glucocorticoids, IVIG, noninvasive ventilation, and the vaccines for COVID-19 in children and adolescents are encouraged.• Several clinical practice guidelines for children with COVID-19 have been developed, but only few of them have been recently updated. • We developed an evidence-based guideline at the beginning of the COVID-19 outbreak and have now updated it based on the results of a comprehensive search of the latest evidence.• The updated guideline provides key recommendations pertinent to the following issues: identification of prognostic factors for death or pediatric intensive care unit admission; the use of remdesivir, systemic glucocorticoids and antipyretics, intravenous immunoglobulin for multisystem inflammatory syndrome in children, and high-flow oxygen by nasal cannula or non-invasive ventilation for acute hypoxemic respiratory failure; breastfeeding; vaccination; and the management of pediatric mental health.

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.

Background: Perthes disease is an idiopathic femoral head necrosis disease in children. Although it is believed that the prognosis after surgery within 5 years of age is good, there are very few reports in the literature regarding concurrent growth hormone deficiency and the outcome of growth hormone treatment. We retrospectively analyzed and summarized the clinical data of patients with Perthes disease and GHD in a child treated with rhGH for four years. Case report: We reported the case of an 11.9-year-old boy diagnosed with “Perthes disease” at 2.7 years. He underwent surgery at the age of 4.8 years and recovered well. At 6.7 years old, he was admitted for “slow growth in height for more than four years.” Physical examination demonstrated severe short stature with a height of 108.8 cm ( Conclusion: The benefits of rhGH in children with Perthes disease and GHD may outweigh its risks. However, its safety requires long-term follow-up evaluation.

We previously showed that elevated TYMS exhibits oncogenic properties and promotes tumorigenesis after a long latency, suggesting cooperation with sequential somatic mutations. Here we report the cooperation of ectopic expression of human TYMS with loss of Ink4a/Arf, one of the most commonly mutated somatic events in human cancer. Using an hTS/Ink4a/Arf−/− genetically engineered mouse model we showed that deregulated TYMS expression in Ink4a/Arf null background accelerates tumorigenesis and metastasis. In addition, tumors from TYMS-expressing mice were associated with a phenotype of genomic instability including enhanced double strand DNA damage, aneuploidy and loss of G1/S checkpoint. Downregulation of TYMS in vitro decreased cell proliferation and sensitized tumor cells to antimetabolite chemotherapy. In addition, depletion of TYMS in vivo by TYMS shRNA reduced tumor incidence, delayed tumor progression and prolonged survival in hTS/Ink4a/Arf−/− mice. Our data shows that activation of TYMS in Ink4a/Arf null background enhances uncontrolled cell proliferation and tumor growth, supporting the development of new agents and strategies targeting TYMS to delay tumorigenesis and prolong survival.

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 RESULTS The median age of the 164 children and adolescents newly diagnosed with T1DM from 2017 to 2022 was 7.0 years (interquartile range [IQR]: 3.8–10.0 years; 51.83% male). The mean annual incidence of T1DM was 4.25/100,000. The estimated frequency of auto-antibody positivity was 51.22% (n = 84), and there was no difference between the 2020–2022 group and 2017–2019 group (55.68% [n = 49] vs. 46.5% [n = 35]; p = 0.219). The incidence of DKA among the entire cohort was 57.93% (n = 95). The frequency of DKA was not significantly higher in the 2020–2022 group compared with the 2017–2019 group (60.23% [n = 53] vs. 55.26% [n = 42]; p = 0.521). We found no significant difference in the frequency of DKA between patients who were negative vs. positive for auto-antibodies in the 2020–2022 group (64.10% [n = 25] vs. 57.14% [n = 28], p > 0.05). The C-peptide level and HbA1c (%) were positively correlated with onset age (R1 = 0.389, p CONCLUSIONS This study showed the annual incidence of T1DM was 4.25/100,000, gradually increased over the study period, and there was no significant increase in T1DM with auto-antibody positivity in children and adolescents newly diagnosed from 2020–2022 in China compared with the previous 3 years. Furthermore, the frequencies of DKA were not significantly different between patients who were negative vs. positive for auto-antibodies.

Background: Tricho-rhino-phalangeal syndrome (TRPS) is a rare genetic disorder characterized by craniofacial and skeletal abnormalities, which is caused by variations in the TRPS1 gene. Methods: Clinical information and follow-up data were collected. Whole-exome sequencing (WES) was performed for variations and validated by Sanger sequencing. Bioinformatic analysis was performed to predict the pathogenicity of the identified variation. Moreover, wild-type and mutated TRPS1 vectors were constructed and transfected into human embryonic kidney (HEK) 293T cells. Immunofluorescence experiments were performed to assess the localization and expression of the mutated protein. Western blot analysis and RT-qPCR were used to detect the expression of downstream genes. Results: The affected family members had typical craniofacial phenotype including sparse lateral eyebrows, pear-shaped nasal tip, and large prominent ears, plus skeletal abnormalities including short stature and brachydactyly. WES and Sanger sequencing identified the TRPS1 c.880_882delAAG variation in affected family members. In vitro functional studies showed that the TRPS1 variation did not affect the cellular localization and the expression of TRPS1, but the transcriptional repression effect of the TRPS1 on the RUNX2 and STAT3 was disturbed. The proband and his brother have been treated with growth hormone (GH) for two years until now, and we observed the improvement of the linear growth in both. Conclusions: The variation of c.880_882delAAG in TRPS1 was responsible for the pathogenesis of the Chinese family with TRPS I. The treatment of GH could be beneficial for the height outcome in TRPS I patients, and earlier initiation and longer duration of the therapy in prepubertal or early pubertal stage could be associated with better height outcomes.

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.

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.

We aimed to elucidate the impact of metabolic syndrome (MS) and nonalcoholic fatty liver disease (NAFLD) on treatment-naïve patients with chronic hepatitis B (CHB) and normal alanine aminotransferase (ALT).We analyzed the clinical characteristics of a cross-sectional cohort of treatment-naïve patients with CHB and ALT in the upper limit of normal (ULN) from October 2018 to July 2021. ALT ≤ 0.5 ULN was stratified as low-normal ALT (LNALT) and 0.5 ULN ALT ≤ ULN as high-normal ALT (HNALT). Transient elastography (TE) was used to evaluate liver steatosis and fibrosis.Among 733 patients with CHB enrolled, 23.1% of them had MS, 37.2% of them had NAFLD, and 5.9% of them had significant fibrosis. The proportions of patients with MS, steatosis, and significant fibrosis in the HNALT group were higher than those in the LNALT group (31.4% vs. 14.1%, p 0.001; 48.7% vs. 25.2%, p 0.001; and 8.0% vs. 3.6%, p = 0.013, respectively). Multiple linear regression showed that steatosis (beta = 0.098, p = 0.001) and MS (beta = 0.092, p = 0.002) were independently related to ALT levels in the normal range. Multivariate logistic regression showed that age (OR 1.049, 95% CI 1.012-1.087, p = 0.010), aspartate aminotransferase (AST) (OR 1.059, 95% CI 1.005-1.115, p = 0.030), and severe steatosis (OR 2.559, 95% CI 1.212-5.403, p = 0.014) were independently associated with significant fibrosis. When analyzed in the subgroup of CHB with NAFLD, age (OR 1.060, 95% CI 1.006-1.117, p = 0.029) and severe steatosis (OR 2.962, 95% CI 1.126-7.792, p = 0.028) were still statistically significant.The accumulation of MS components exacerbated hepatic steatosis. Severe NAFLD was independently associated with significant fibrosis. This emphasizes the importance of screening for MS and NAFLD in patients with CHB and normal ALT, where a more active intervention may apply.

Context The evidence of long-term polyethylene glycol recombinant human GH (PEG-rhGH) in pediatric GH deficiency (GHD) is limited. Objective This study aimed to examine the effectiveness and safety of long-term PEG-rhGH in children with GHD in the real world, as well as to examine the effects of dose on patient outcomes. Design A prospective, observational, posttrial study (NCT03290235). Setting, participants and intervention Children with GHD were enrolled from 81 centers in China in 4 individual clinical trials and received weekly 0.2 mg/kg/wk (high-dose) or 0.1 to Main outcomes measures Height SD score (Ht SDS) at 12, 24, and 36 months. Results A total of 1170 children were enrolled in this posttrial study, with 642 patients in the high-dose subgroup and 528 in the low-dose subgroup. The Ht SDS improved significantly after treatment in the total population (P < 0.0001), with a mean change of 0.53 ± 0.30, 0.89 ± 0.48, 1.35 ± 0.63, 1.63 ± 0.75 at 6 months, 12 months, 24 months, and 36 months, respectively. In addition, the changes in Ht SDS from baseline were significantly improved in the high-dose subgroup compared with the low-dose subgroup at 6, 12, 24, and 36 months after treatment (all P < 0.05). A total of 12 (1.03%) patients developed serious adverse events. There was no serious adverse event related to the treatment, and no AEs leading to treatment discontinuation or death occurred. Conclusions PEG-rhGH showed long-term effectiveness and safety in treating children with GHD. Both dose subgroups showed promising outcomes, whereas PEG-rhGH 0.2 mg/kg/wk might show additional benefit.

Although the concomitance of nonalcoholic fatty liver disease (NAFLD) and viral hepatitis is soaring, there is not much knowledge about the impact of NAFLD on viral hepatitis. Here, we aimed to investigate how NAFLD influences the pathogenesis of viral hepatitis. Wild-type C3H/HeN mice with NAFLD induced by high-fat diet were infected with murine hepatitis virus 3 (MHV-3) and sacrificed at Days 4, 8, 12, and 16 post infection. Although there was no difference in the survival rate between mice with and without NAFLD, individuals with steatosis suffered more severe and prolonged liver injury demonstrated by transaminases and histology examination. The intrahepatic viral load was higher in NAFLD group during early infection, although it declined ultimately. On the contrary, the serum antiviral antibody titer remained in a lower level in mice with NAFLD throughout the investigation. In NAFLD group, the production of proinflammatory cytokines (tumor necrosis factor α, interleukin 1β, interleukin 6, and interleukin 17A) and the frequencies of antiviral immune cells (NKG2D

Background Bacterial infection is one of the most frequent complications in acute-on-chronic liver failure (ACLF), which leads to high mortality. However, a specific prognostic model for ACLF patients with bacterial infection has not been well established. Aim To establish and validate a nomogram for predicting 30-day mortality of hepatitis B virus-related ACLF (HBV-ACLF) patients with bacterial infection. Methods A total of 513 ACLF patients for HBV reactivation were enrolled in the prospective cohort, and 224 patients with bacterial infection were for derivation. Independent predictors were identified using multivariate logistic model and then assembled into a nomogram to predict 30-day mortality. The performance of the nomogram was assessed based on its calibration, discrimination and clinical utility in a retrospective cohort of 192 HBV-ACLF patients with bacterial infection. Results Age, total bilirubin, lactate dehydrogenase, international normalized ratio and soluble interleukin-2 receptor were shown to be independent risk factors for 30-day mortality of HBV-ACLF patients with bacterial infection and the nomogram was constructed. The nomogram showed a good calibration and discrimination in the derivation cohort, with an area under the receiver operating characteristic curve (AUC) of 0.883. Application of the nomogram in the validation cohort also showed a good calibration and discrimination, with the AUC of 0.852. Decision curve analysis confirmed the clinical utility of the nomogram. Conclusion The nomogram was established and validated for predicting 30-day mortality of HBV-ACLF patients with bacterial infection, which may facilitate optimal therapeutic strategies to improve the prognosis of these patients.

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.

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 |r| > 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.

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.

Oestradiol (E2) is a critical factor for multiple systems' development during the embryonic period. Here, we aimed to investigate the effects of oestradiol on intrahepatic bile duct development, which may allow a better understanding of congenital bile duct dysplasia. DLK+ hepatoblasts were extracted from the C57BL/6CrSlc foetal mice and randomly divided into control group, oestradiol groups (1, 10, 100 nM) and oestradiol (10 nM) + DAPT (inhibitor of Notch signalling; 40 µM) group for in vitro experiments. For in vivo analysis, pregnant mice were divided into control group, oestradiol (intraperitoneal injection of 0.6 mg/kg/day) ± DAPT (subcutaneous injection of 10 mg/kg/day) groups and tamoxifen (gavage administration of 0.4 mg/kg/day) group. The results showed that oestradiol promoted hepatoblast differentiation into cholangiocytes and intrahepatic bile duct development during the embryonic period. Tamoxifen, an antioestrogenic drug, inhibited the above processes. Moreover, oestradiol promoted the expression of Notch signalling pathway‐associated proteins and genes both in vitro and in vivo. Notably, DAPT addition inhibited the oestradiol‐mediated effects. In conclusion, oestradiol can promote hepatoblast differentiation into cholangiocytes and intrahepatic bile duct development of C57BL/6CrSlc mice during embryonic period via the Notch signalling pathway.

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.

Colorectal cancer (CRC) is one of the most common human malignancies in the digestive tract with high mortality. Alantolactone (ATL), as a plant-derived sesquiterpene lactone, has shown a variety of pharmacological activities, such as antibacterial, anti-inflammatory, anti-virus and so on. However, the exact molecular mechanism of ATL in colorectal cancer remains largely unknown. Here, we performed a study to explore the effect and mechanism of ATL on colorectal cancer. The CCK-8 assay, colony formation assay, Wound-healing and Transwell assays were performed to evaluate the cytotoxic effect, antiproliferative effect, anti-migratory and anti-invasive properties of ATL respectively. The xenograft tumor model was established in Balb/c mice to evaluate the anti-tumor effect. The expression levels of proteins involved the MAPK-JNK/c-Jun signaling pathway were measured by Western blot and RT-qPCR both in cells and tumor tissues. The results showed that ATL could inhibit the cells activities of various colon cancer cell lines. Moreover, ATL could induce HCT-116 cells nuclear pyknosis, mitochondrial membrane potential loss, G0/G1 phase arrest, as well as enhance the proportion of apoptosis cells and inhibit colony formation. The migration distance and invasion rate of cells were significantly reduced after treated with ATL. Additionally, in the xenograft model, ATL (50mg/kg) significantly decreased the tumor tumor volume and weight (p ˂ 0.001). For the anti-colon cancer mechanism, the ATL showed the anti-proliferative and pro-apoptosis effect by activating MAPK-JNK/c-Jun signaling pathway. In conclusion, ATL exhibits anti-proliferation and apoptosis-promoting potential in colon cancer via the activation of MAPK-JNK/c-Jun signaling pathway.

Introduction As a homologue of the angiotensin-converting enzyme (ACE), angiotensin-converting enzyme 2 (ACE2) has been identified as the main receptor for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) invasion. We aimed to investigate the role of serum ACE in predicting the coronavirus disease 2019 (COVID-19) disease progression and the underlying mechanisms. Methods We retrospectively enrolled 120 patients with confirmed COVID-19 who underwent serum ACE detection on admission. The clinical characteristics and laboratory findings during hospitalization were evaluated dynamically to identify the potential risk factors for disease progression. Results ACE level was demonstrated as one of the independent risk factors. Patients with ACE level ≤ 33.5 U/L showed a higher cumulative virus RNA detection rate, elevated pro-inflammatory mediators levels, declined lymphocyte count, and decreased SARS-CoV-2-specific antibodies than those with ACE level > 33.5 U/L. Conclusion Lower serum ACE levels in relation to delayed virus elimination, hyperinflammatory condition, and impaired host antiviral immune responses contribute to disease progression of COVID-19.

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 Conclusions PEG-rhGH could effectively increase height in prepubertal short children. When the baseline IGF-1 was Trial registration ClinicalTrials.gov: NCT03249480, retrospectively registered.

Background and Aims Bacterial swarming, a collective movement on a surface, has rarely been associated with human pathophysiology. This study aims to define a role for bacterial swarmers in amelioration of intestinal stress. Methods We developed a polymicrobial plate agar assay to detect swarming and screened mice and humans with intestinal stress and inflammation. From chemically induced colitis in mice, as well as humans with inflammatory bowel disease, we developed techniques to isolate the dominant swarmers. We developed swarm-deficient but growth and swim-competent mutant bacteria as isogenic controls. We performed bacterial reinoculation studies in mice with colitis, fecal 16S, and meta-transcriptomic analyses, as well as in vitro microbial interaction studies. Results We show that bacterial swarmers are highly predictive of intestinal stress in mice and humans. We isolated a novel Enterobacter swarming strain, SM3, from mouse feces. SM3 and other known commensal swarmers, in contrast to their mutant strains, abrogated intestinal inflammation in mice. Treatment of colitic mice with SM3, but not its mutants, enriched beneficial fecal anaerobes belonging to the family of Bacteroidales S24-7. We observed SM3 swarming associated pathways in the in vivo fecal meta-transcriptomes. In vitro growth of S24-7 was enriched in presence of SM3 or its mutants; however, because SM3, but not mutants, induced S24-7 in vivo, we concluded that swarming plays an essential role in disseminating SM3 in vivo. Conclusions Overall, our work identified a new but counterintuitive paradigm in which intestinal stress allows for the emergence of swarming bacteria; however, these bacteria act to heal intestinal inflammation.

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 P = 0.172 ) to 0.37 ± 0.39 and 0.44 ± 0.76 ( P = 0.758 ) in the 3-month and 1-month groups, respectively. Follicle stimulating hormone and estradiol levels, bone age/chronological age (BA/CA), height velocity, maximum diameter of uterus and volume of ovary did not show any distinction between the two groups after 6 months of treatment, but both were significantly ameliorated compared with the baseline. The loss of working time of parents and study time of patients and the numbers of visits, injections and laboratory examinations obviously decreased in the 3-month depots. Conclusion. An LA 3-month depot was equally effective and safe as a 1-month depot for hormonal suppression and bone maturation inhibition, providing clinical experience in China. The 11.25 mg depot of LA is a safe, efficient, and economical treatment method for the advanced activation of the hypothalamic-pituitary-gonadal (HPG) axis.

Background 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. Methods 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: 316L 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. Results 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 absorption 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. Conclusions 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.

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.

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.

Objective To evaluate the safety and efficacy of weekly PEGylated-recombinant human growth hormone (PEG-rhGH) in children with idiopathic short stature (ISS) in China. Design and methods This was a multicenter, phase II study in which all subjects were randomized 1:1:1 to weekly s.c. injections of PEG-rhGH 0.1 (low-dose (LD) group) or 0.2 mg/kg/week (high-dose (HD) group) or control for 52 weeks. The primary end point was change (Δ) in height s.d. score (HT-SDS) from baseline to week 52. Secondary end points were height velocity (HV), bone maturity, insulin-like growth factor-1 (IGF-1) SDS, and IGF-1/insulin-like growth factor-binding protein-3 (IGFBP-3) molar ratio. Results A total of 360 children with ISS were recruited in the study (n = 120 in each group). At week 52, ΔHT-SDS was 0.56 ± 0.26, 0.98 ± 0.35, and 0.20 ± 0.26 in the LD, HD, and control groups, respectively (within-group P < 0.0001; intergroup P < 0.0001). Statistically significant values of ΔHV, IGF-1, IGF-1/IGFBP-3 ratio, and IGF-1 SDS at week 52 from baseline were observed in both treatment groups (P < 0.0001). There were clear dose-dependent responses for all auxological variables. PEG-rhGH was well tolerated throughout the treatment period with treatment-emergent adverse events (TEAEs) reported in 86.5%, 84.6%, and 91.3% of children in the HD, LD, and control groups, respectively. The incidence of TEAEs was similar in all treatment groups despite the difference in doses. A total of 27 (8.7%) children experienced drug-related TEAEs. Conclusion Fifty-two-week treatment with PEG-rhGH 0.1 or 0.2 mg/kg/week achieved significant improvement in HT-SDS and other growth-related variables, including HV, IGF-1 SDS, and IGF-1/IGFBP-3 ratio, in a dose-dependent manner. Both doses were well tolerated with similar safety profiles.

The Krüppel-like factor 11 (KLF11) gene causes maturity-onset diabetes of the young 7 (MODY7). There are few reports on the clinical and functional characteristics of KLF11 mutations in patients with MODY7, making diagnosis and treatment complicated.We report a novel KLF11 variant associated with MODY7 in a Chinese family. The proband had hyperglycemia at 9 years of age, and his mother had developed diabetes at age 28 years. Both required insulin injections from the initial phase of the disease. They were negative for islet cell autoantibodies and had normal fasting C-peptide levels. We observed changes in the levels of fasting blood glucose, C-peptide, and islet cell autoantibodies in the proband over 4.5 years.Whole-exon sequencing was used to screen the proband and his family members for KLF11 variants. The heterozygous KLF11 variant (c.1045CT, p. Pro349Ser) was identified in the proband, his mother, his maternal grandmother, and an elderly aunt, although the latter two individuals were unaffected. In silico analyses indicated that this variant involved a change in the amino acid side chain in the transcriptional regulatory domain 3. Luciferase reporter assays revealed that the variant had impaired insulin promoter regulation activity. Moreover, in vitro analyses showed that this variant impaired insulin secretion from pancreatic beta cells.This study documents a novel heterozygous KLF11 variant (p. Pro349Ser) as a potential monogenic mutation associated with MODY7 in a family. This variant impairs insulin secretion from pancreatic beta cells, possibly by repressing insulin promoter regulation activity.

The immunomodulatory role of natural killer (NK) cells has been recognized recently, but its effects on CD4+CD25+ regulatory T cells (Tregs) during chronic hepatitis B (CHB) infection and treatment remain unclear. A total of 116 nucleos(t)ide analogue (NA)-treated CHB patients were included. An inverse correlation between the peripheral frequencies of NK cells and Tregs was found in NA suppressed patients following pegylated interferon-ɑ (PegIFN-ɑ)–based treatment. Furthermore, NK cells suppressed the proliferation and differentiation of Tregs through secreting IFN-γ as was evidenced in the circulation of NA-treated CHB patients as well as in liver of HBV-carrier mouse model. Additionally, the inhibition could be enhanced by PegIFN-ɑ treatment, which was correlated to more vigorous HBV-specific T-cell responses and marked reduction in HBsAg. Our study reveals a novel immunomodulatory mechanism of NK cells and provides a theoretical basis for PegIFN-ɑ as an immunotherapy agent in treating patients with CHB.

Previous studies have shown that a high baseline triglyceride-glucose (TyG) index is a potential risk factor for type 2 diabetes mellitus (T2DM). However, for a low TyG index, findings have been inconsistent. Moreover, the association between the baseline TyG index and incident T2DM in individuals with normal glycemic levels remains unclear. Therefore, this longitudinal study further examined and characterized the association between the baseline TyG index and incident T2DM in Japanese adults with normal glycemic levels. .The participants (7857 men and 6440 women) were selected from the NAGALA (NAfld in the Gifu Area Longitudinal Analysis) study that was conducted from 2004 to 2015. Cox proportional hazards models were used to evaluate the associations between baseline TyG index and T2DM incidence, and a two-piecewise linear regression model was used to examine the threshold effect of the baseline TyG index on incident T2DM using a smoothing function.During a median follow-up period of 5.26 (women) and 5.88 (men) years, 47 women and 182 men developed T2DM. The risk of T2DM was strongly associated with the baseline TyG index in the fully adjusted model in men but not in women, and no dose-dependent positive relationship between incident T2DM and the TyG index was observed across the TyG tertiles. Interestingly, the two-piecewise linear regression analysis revealed a U-shaped association between the baseline TyG index and incident T2DM. Baseline TyG index lower than the threshold values (TyG index 7.27 in women and7.97 in men) were negatively associated with incident T2DM (hazard ratio [HR] = 0.09, 95% confidence interval [CI] = 0.01-0.93, P = 0.0435 for women and HR = 0.21, 95% CI = 0.08-0.57, P = 0.0021 for men). In contrast, baseline TyG index higher than the threshold values (TyG index 7.27 in women and7.97 in men) were positively associated with incident T2DM (HR = 2.76, 95% CI = 1.20-6.34, P = 0.0166 for women and HR = 2.42, 95% CI = 1.66-3.53, P 0.0001 for men).A U-shaped association was observed between the baseline TyG index and incident T2DM in a Japanese population.

Background Recombinant human growth hormone (rhGH) was approved for the therapy of pediatric patients with growth hormone deficiency (GHD) by the Food and Drug Administration (FDA) of the United States in 1985. This study aims to evaluate the effects of rhGH therapy on thyroid function in pediatric patients with GHD. Methods A total of 55 pediatric patients, who had been diagnosed with GHD and received rhGH therapy for 6-24 months, and who could regularly come to our hospital for outpatient visits from May 1, 2014 to April 30, 2017, were selected for the study. All of the patients were treated for at least six months, among which 44 patients were treated for 12 months, and 32 patients were treated for 18 months, and 16 patients were treated for 24 months. Results (I) During the course of the rhGH therapy, none of the patients had a free thyroxine (FT4) level lower than the normal lower limit. (II) The FT4 level decreased during the course of the therapy, when compared to the level at baseline, and the difference was statistically significant after 24 months of therapy. In the puberty group, the FT4 level had significantly decreased by the 12th month of therapy, when compared to the baseline, but there was no significant change in the FT4 and thyroid-stimulating hormone (TSH) levels at the remaining observation time points of treatment. Conclusions Growth hormone (GH) replacement therapy may affect the metabolism of the thyroid hormone in pediatric patients with GHD. During the course of treatment, the changes in thyroid function in pediatric patients with GHD should be regularly monitored in order to identify any abnormal thyroid function in its early stages.

BACKGROUND: To compare the physical development status, level of blood glucose and lipid metabolism in small for gestational age (SGA) and appropriate for gestational age (AGA) groups with central precocious puberty (CPP). METHODS: This was a retrospective study. Three hundred and twenty-two girls with CPP were divided into the AGA group (304 cases) and the SGA group (18 cases). Physical index such as height, weight, and body mass index (BMI), as well as sex hormones, adrenal androgens, blood lipid levels, fasting blood glucose, insulin levels, and homeostasis model assessment of insulin resistance (HOMA-IR) were compared between the two groups. RESULTS: Height, weight, and BMI in the SGA group were lower than those in the AGA group (P0.05). The fasting blood glucose, insulin level, HOMA-IR, high-density lipoprotein (HDL) and the average level of triglycerides were similar between these two groups (P>0.05). There was a statistically significant difference in total cholesterol and low-density lipoprotein (LDL) between the two groups (P

Background: Coronavirus disease 2019 (COVID-19) is a serious and even lethal respiratory illness. The mortality of critically ill patients with COVID-19, especially short term mortality, is considerable. It is crucial and urgent to develop risk models that can predict the mortality risks of patients with COVID-19 at an early stage, which is helpful to guide clinicians in making appropriate decisions and optimizing the allocation of hospital resoureces. Methods: In this retrospective observational study, we enrolled 949 adult patients with laboratory-confirmed COVID-19 admitted to Tongji Hospital in Wuhan between January 28 and February 12, 2020. Demographic, clinical and laboratory data were collected and analyzed. A multivariable Cox proportional hazard regression analysis was performed to calculate hazard ratios and 95% confidence interval for assessing the risk factors for 30-day mortality. Results: The 30-day mortality was 11.8% (112 of 949 patients). Forty-nine point nine percent (474) patients had one or more comorbidities, with hypertension being the most common (359 [37.8%] patients), followed by diabetes (169 [17.8%] patients) and coronary heart disease (89 [9.4%] patients). Age above 50 years, respiratory rate above 30 beats per minute, white blood cell count of more than10 × 109/L, neutrophil count of more than 7 × 109/L, lymphocyte count of less than 0.8 × 109/L, platelet count of less than 100 × 109/L, lactate dehydrogenase of more than 400 U/L and high-sensitivity C-reactive protein of more than 50 mg/L were independent risk factors associated with 30-day mortality in patients with COVID-19. A predictive CAPRL score was proposed integrating independent risk factors. The 30-day mortality were 0% (0 of 156), 1.8% (8 of 434), 12.9% (26 of 201), 43.0% (55 of 128), and 76.7% (23 of 30) for patients with 0, 1, 2, 3, ≥4 points, respectively. Conclusions: We designed an easy-to-use clinically predictive tool for assessing 30-day mortality risk of COVID-19. It can accurately stratify hospitalized patients with COVID-19 into relevant risk categories and could provide guidance to make further clinical decisions.

Context Aggrecan, encoded by the ACAN gene, is the main proteoglycan component in the extracellular cartilage matrix. Heterozygous mutations in ACAN have been reported to cause idiopathic short stature. However, the prevalence of ACAN pathogenic variants in Chinese short stature patients and clinical phenotypes remain to be evaluated. Objective We sought to determine the prevalence of ACAN pathogenic variants among Chinese short stature children and characterize the phenotypic spectrum and their responses to growth hormone therapies. Patients and Methods Over 1000 unrelated short stature patients ascertained across China were genetically evaluated by next-generation sequencing–based test. Result We identified 10 novel likely pathogenic variants and 2 recurrent pathogenic variants in this cohort. None of ACAN mutation carriers exhibited significant dysmorphic features or skeletal abnormities. The prevalence of ACAN defect is estimated to be 1.2% in the whole cohort; it increased to 14.3% among those with advanced bone age and to 35.7% among those with both advanced bone age and family history of short stature. Nonetheless, 5 of 11 ACAN mutation carries had no advanced bone age. Two individuals received growth hormone therapy with variable levels of height SD score improvement. Conclusion Our data suggest that ACAN mutation is 1 of the common causes of Chinese pediatric short stature. Although it has a higher detection rate among short stature patients with advanced bone age and family history, part of affected probands presented with delayed bone age in Chinese short stature population. The growth hormone treatment was moderately effective for both individuals.

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.