Objective To investigate the serum levels of soluble programmed death-1 (sPD-1) and soluble programmed death-ligand 1 (sPD-L1) in chronic hepatitis B (CHB) patients with clinical cure, the correlation between programmed death-1 (PD-1) and lymphocytes by flow cytometry, and the recovery of hepatitis B virus (HBV)-specific immunity. Methods A total of 26 CHB patients with clinical cure, 26 treatment-naïve CHB patients, and 26 healthy controls who were diagnosed at the outpatient service of Peking University First Hospital from January to May of 2022 were enrolled, and related clinical data and peripheral blood samples were collected. ELISA was used to measure the serum levels of sPD-1 and sPD-L1, and flow cytometry was used to measure the expression of PD-1 in peripheral blood lymphocytes. CHB patients with clinical cure were compared with the treatment-naïve CHB patients and the healthy controls. The Kruskal-Wallis H test was used for comparison of non-normally distributed continuous data between three groups, and the chi-square test was used for comparison of categorical data between groups. The Pearson correlation analysis or the Spearman correlation analysis was used to investigate the correlation between two continuous variables. Results For the 26 CHB patients with clinical cure, the mean time of antiviral therapy was 8.33 years, with entecavir as the antiviral drug. The CHB patients with clinical cure had significantly higher levels of sPD-1 and sPD-L1 than the healthy controls ( P < 0.05) and significantly lower percentages of PD-1 + cells/lymphocytes and PD-1 + CD8 + T cells/lymphocytes than the treatment-naïve CHB patients ( P < 0.05). In the treatment-naïve CHB patients, the serum levels of sPD-1 and sPD-L1 were moderately negatively correlated with HBsAg level ( r =-0.524 and -0.583, both P < 0.05). The serum levels of sPD-1 and sPD-L1 were moderately positively correlated with PD-1 + CD8 + T cells/lymphocytes ( r =0.535 and 0.419, both P < 0.05). In the CHB patients with clinical cure, the serum levels of sPD-1 and sPD-L1 were not correlated with age, sex, alanine aminotransferase, T cells/lymphocytes, CD8 + T cells/lymphocytes, PD-1 + T cells/lymphocytes or PD-1 + CD8 + T cells/lymphocytes (all P > 0.05). Conclusion The serum levels of sPD-1 and sPD-L1 in treatment-naïve CHB patients are mainly associated with exhausted CD8 + T cells in peripheral blood, while there is no significant correlation between serum sPD-1/sPD-L1 and exhausted CD8 + T cells in peripheral blood in CHB patients with clinical cure.

Anti-seizure medications (ASMs) are the main therapy for epilepsy.There are many kinds of ASMs with complex mechanism of action, so it is difficult for pharmacists to examine prescriptions.This paper put forward some suggestions on the indications, dosage forms/routes of administration, appropriateness of usage and dosage, combined medication and drug interaction, long-term prescription review, individual differences in pathophysiology of children, and drug selection when complicated with common epilepsy, for the reference of doctors and pharmacists.

Mandibular defects caused by injuries, tumors, and infections are common and can severely affect mandibular function and the patient's appearance. However, mandible reconstruction with a mandibular bionic structure remains challenging. Inspired by the process of intramembranous ossification in mandibular development, a hierarchical vascularized engineered bone consisting of angiogenesis and osteogenesis modules has been produced. Moreover, the hierarchical vascular network and bone structure generated by these hierarchical vascularized engineered bone modules match the particular anatomical structure of the mandible. The ultra-tough polyion complex has been used as the basic scaffold for hierarchical vascularized engineered bone for ensuring better reconstruction of mandible function. According to the results of in vivo experiments, the bone regenerated using hierarchical vascularized engineered bone is similar to the natural mandibular bone in terms of morphology and genomics. The sonic hedgehog signaling pathway is specifically activated in hierarchical vascularized engineered bone, indicating that the new bone in hierarchical vascularized engineered bone underwent a process of intramembranous ossification identical to that of mandible development. Thus, hierarchical vascularized engineered bone has a high potential for clinical application in mandibular defect reconstruction. Moreover, the concept based on developmental processes and bionic structures provides an effective strategy for tissue regeneration.
Bone Regeneration ; Bone Transplantation/methods* ; Hedgehog Proteins ; Humans ; Mandible/surgery* ; Osteogenesis

Objective:To investigate the clinical, skeletal muscle pathological, and genetic characteristics of fatal infantile hypertonic myofibrillar myopathy (FIHMM).Methods:The clinical manifestations, laboratory assessments data and gene sequencing results of 10 patients diagnosed with FIHMM in Shenzhen Children′s Hospital from February 2017 to April 2021 were retrospectively analyzed.Magnetic resonance imaging (MRI) of both musculoskeletal system and the brain, and electromyogram (EMG) were performed in 3 cases, while muscle biopsy was performed in 2 cases.Results:Among these 10 cases, 1 case was from Northeast China and 1 case from East China, while the rest 8 cases were from South China.Eight of the 10 patients were male, and the other 2 cases were female.They were all born normal and not related to each other.The age of onset varied from 2 to 12 months.The main clinical manifestations for all the patients were progressive rigidity of the rectus abdominis (8 cases), neck muscles (7 cases), rectus abdominis (2 cases) and intercostal muscles (1 case), resulting in respiratory failure.Mildly to moderately elevated serum creatine kinase level was detected (436-5 804 IU/L) (reference range: 24-229 IU/L). Complex repetitive discharges can be seen in the EMG, without any myotonic potential.Muscle fiber degeneration, necrosis, and vacuolar degeneration were noted in the histopathological examination of the vastus lateralis and rectus abdominis.An abnormal red granular deposit was observed in a portion of the field of the modified Gomory Trichrome staining.Immunohistochemistry showed substantial deposition of desmin.Under the electron microscopy, the sarcomere structure of the muscle fibers was seriously disordered, with the destruction of Z-bands and the presence of granular deposits.The whole-exome sequencing identified the same homozygous variation c. 3G>A, p.Met1? of CRYAB gene in all the patients, but heterozygous variation in their parents. Conclusions:Axial muscles involvement, such as rectus abdominis rigidity, is the main clinical characteristic of FIHMM.c.3G>A, p.Met1? mutation in the CRYAB gene is a hotspot mutation in Chinese children.

Onodera prognostic nutrition index (OPNI) is a simple and effective parameter. It is calculated by serum albumin level and peripheral blood lymphocyte count. Initially, OPNI is used to assess preoperative nutritional status and surgical risk. In recent years, researchers have found that OPNI is related to the prognosis of many tumors. Simple and accurate prognosis evaluation can help to select treatment methods for digestive system malignant tumors, determine the best pre-operative treatment time and operation time, and improve the survival rate of patients with diges-tive system malignant tumors. The authors review the related literatures at home and abroad, and summarize the research advances in the prognostic value of OPNI for malignant tumors of digestive systems.

Objective:To investigate the long term efficacy and side effects of a donor-derived CD19 chimeric antigen receptor (CAR) T-cell (HI19α-4-1BB-ζ CAR-T) therapy in the treatment of patients with relapsed B-cell acute lymphoblastic leukemia (B-ALL) after allogeneic hematopoietic stem cell transplantation (allo-HSCT) .Methods:A total of 9 subjects with relapsed B-ALL post allo-HSCT received donor-derived CD19 CAR-T therapy from July 2017 to May 2020. All subjects were infused with donor CD3-positive T cells after lymphodepletion chemotherapy, and a median dose of CAR-T cells was 1.79 (range, 0.86-3.53) ×10 6/kg. Results:①All subjects achieved complete remission and MRD-negative at 28-42 d post CAR-T cells infusion. ②Cytokine releasing syndrome (CRS) occurrd in all subjects and was grade 3 in 2, grade 2 in 4, grade 1 in 3 cases respectively. Four subjects developed immune effector cell-associated neurotoxicity syndrome (ICANS) , which was grade 2 in 1, grade 1 in 3. One subject developed grade IV acute graft-versus-host disease (GVHD) , and side effects were all controllable. ③Four subjects relapsed at a median period of 8.6 (4.6-19.3) months, 2 subjects died of disease progression after receiving chemotherapy and another one also died of disease progression 14 months after a second transplant, only 1 subject achieved complete remission after CD22 CAR-T cell therapy. Until last follow-up date, 6 subjects were leukemia-free and achieved complete donor chimerism. The estimated 1-year and 2-year leukemia-free survival (LFS) rate was 63.5% and 50.8%, with a median LFS of 18.1 months. ④After a median follow-up of 25.1 (range, 6.9-36.7) months, the estimated 2-year and 2.5-year OS rate were 87.5% and 52.5%, respectively.Conclusion:The donor-derived CD19 CAR-T cell therapy obtain a high remission rate in relapsed B-ALL patients post allo-HSCT with tolerable side effects, half subjects survived more than 2 years without disease recurrence, though long-term efficacy requires further observation. Chinese Clinical Trial Registry: ChiCTR1900025419

Thrombocytopenia is the main clinical manifestation or common complication of multiple diseases, but there is still a lack of systematic understanding of pathogenesis, underlying diseases and treatment strategies of thrombocytopenia. Based on evidence-based medicine, this consensus summarizes seven aspects related to thrombocytopenia, including definition, epidemiology, pathogenesis, clinical manifestations, laboratory examination, diagnosis and treatment. This consensus provides an important reference for the diagnosis and treatment of thrombocytopenia.

Objective:To explore the significance of multimodal monitoring in the monitoring and treatment of neurocritical care patients.Methods:104 neurocritical care patients admitted to the department of Critical Care Medicine of Fujian Provincial Hospital from March 2019 to January 2020 were enrolled. Patients were randomly assigned into two groups, with 52 in each group. In the routine monitoring treatment group, heart rate, blood pressure, respiratory rate and the changes in consciousness and pupils were monitored after operation. The patients were treated with routine medicine to reduce intracranial pressure (ICP), maintain proper cerebral perfusion pressure (CPP), balance fluid intake and output, and maintain the airway clear. Patients in the multimodal monitoring treatment group were treated with invasive ICP monitoring, ultrasound to assess brain structure, ultrasound to measure optic nerve sheath diameter (ONSD), transcranial color doppler (TCCD), internal jugular venous blood oxygen saturation monitoring, near-infrared spectroscopy (NIRS), non-invasive cerebral blood oxygen saturation monitoring and quantitative electroencephalogram monitoring. According to the monitoring results, the patients were given targeted treatment with the goal of controlling ICP and improving brain metabolism. The length of intensive care unit (ICU) stay, the incidences of neurological complications (secondary cerebral infarction, cerebral hemorrhage, high intracranial pressure, etc.), and the incidences of poor prognosis [6 months after the onset of Glasgow outcome score (GOS) 1 to 3] were compared between the two groups. Spearman rank correlation analysis of the correlation between invasive ICP and the ICP value which was calculated by TCCD. The receiver operating characteristic (ROC) curve of invasive ICP and pulsatility index of middle cerebral artery (PI MCA) were used to predict poor prognosis. Results:The length of ICU stay in the multimodal monitoring treatment group was significantly shorter than that of the routine monitoring treatment group (days: 6.27±3.81 vs. 9.61±5.09, P < 0.01), and the incidence of neurological complications was significantly lower than that in the routine monitoring treatment group (9.62% vs. 25.00%, P < 0.05). In the multimodal monitoring treatment group, 37 cases had a good prognosis and 15 cases had a poor prognosis, while the routine monitoring treatment group had a good prognosis in 27 cases and a poor prognosis in 25 cases. The incidence of poor prognosis in the multimodal monitoring treatment group was lower than that of the routine monitoring treatment group (28.85% vs. 48.08%, P < 0.05). In the multimodal monitoring treatment group, the invasive ICP and PI MCA of patients with good prognosis were significantly lower than those of patients with poor prognosis [invasive ICP (mmHg, 1 mmHg = 0.133 kPa): 16 (12, 17) vs. 22 (20, 24), PI MCA: 0.90±0.33 vs. 1.39±0.58, both P < 0.01]. There was no significant difference in resistance index of the middle cerebral artery (RI MCA) between the good prognosis group and the poor prognosis group (0.63±0.12 vs. 0.66±0.15, P > 0.05). There was a positive correlation between the invasive ICP and the ICP value which was calculated by TCCD ( r = 0.767, P < 0.001). ROC curve analysis showed that the area under ROC curve (AUC) of invasive ICP for poor prognosis prediction was 0.906, the best cut-off value was ≥ 18 mmHg, the sensitivity was 86.49%, and the specificity was 86.67%. The AUC of PI MCA for poor prognosis prediction was 0.759, the best cut-off value was ≥ 1.12, the sensitivity was 81.08%, and the specificity was 60.00%. The AUC of invasive ICP was greater than PI MCA ( Z = 2.279, P = 0.023). Conclusion:Comprehensive analysis of multimodal monitoring indicators for neurocritical care patients to guide clinical treatment can reduce the length of hospital stay, and reduce the risk of neurosurgery complications and disability; invasive ICP can predict poor prognosis of neurocritical care patients.

Objective:To explore the clinical characteristics of intellectual developmental disorder with cardiac arrhythmia syndrome (IDDCA) in a family caused by GNB5 gene variation and to review the literature.Methods:The clinical and genetic data of an infant with IDDCA, who visited Shenzhen Children′s Hospital in September 2018, were collected and analyzed. His parents′ and brother′s gene analysis was also done by the next-generation sequencing and confirmed by Sanger sequencing. Related literature up to March 2020 was searched in Online Mendelian Inheritance in Man (OMIM), PubMed, CNKI and Wanfang databases with “GNB5” “IDDCA” “LADCI” “intellectual developmental disorder with cardial arrhythmia” “language delay and attention deficit-hyperactivity disorder or cognitive impairment with or without cardiac arrhythmia” as the key words. The related papers were retrieved and analyzed to summarize the clinical and genetic characteristics of this disorder.Results:The proband was an 11-month-old boy who presented with mental and motor developmental retardation, accompanied with convulsion and muscle weakness. Sinus arrest was also detected. His electroencephalogram (EEG) and flash visual evoked potential (FVEP) were both abnormal. Genetic analysis identified the homozygous frameshift variation of GNB5 gene (c.136delG, p.Glu46Argfs*8) in this infant and heterozygous variation in his parents, confirmed the diagnosis of IDDCA. The same GNB5 variation was identified in his brother, who was 4 years and 8 months old and had developed the similar clinical manifestations after birth. There were only 7 papers reporting this disease in the literature review, with a total of 27 patients from 14 families. Including these 2 cases, there were 29 patients in total, whose age of diagnosis ranged from 5.5 months to 23 years. Among all the patients, 20 cases (69%) were diagnosed as IDDCA, while 8 cases (28%) as LADCI; and 11 (38%) were males while 18 (62%) females. Regarding the clinical features, 66% (19/29) had mental retardation, 41% (12/29) had seizures, 79% (23/29) developed language delay and 62%（18/29） had sinus node dysfunction. Genetic tests showed that 4 patients from 3 families had complex heterozygous variation, and 25 patients (86%) from 12 families had homozygous variation. Seventeen patients from 8 families were consanguineous. Among the total 12 variations, there were 4 nonsense, 3 frameshift, 2 missense and 2 shear mutations, and 1 shear disorder caused by synonymous mutation.Conclusions:IDDCA caused by GNB5 gene variations mainly manifests as general developmental delay or severe mental retardation, and sinus node dysfunction. GNB5 associated syndromes have phenotypic heterogeneity and are inherited in an autosomal recessive manner.

OBJECTIVETo evaluate the results of autologous hematopoietic stem cell transplantation (auto-HSCT) in adults with Philadelphia chromosome-negative acute lymphoblastic leukemia (Ph-ALL).

METHODSFrom January 2000 to December 2007, the clinical data of auto-HSCT in adults Ph-ALL with complete remession (CR) 1 according to BDHALL2000/02 protocol were analyzed.

RESULTSA total of 56 patients were enrolled and the probabilities of standard risk, intermediated risk and high-risk group were 41.1%, 33.9%, and 25.0%, respectively. After a median follow-up of 75 months (range 7-177 months), the 5-year overall survival (OS), events free survival (EFS) and relapse free survival (RFS) were (51.8 ± 6.7)%, (51.8 ± 6.7)%, and (60.5 ± 6.9)%, respectively. And the 5-year accumulative relapse rate was (39.1 ± 6.9)%. The 5-year OS of standard risk, intermediate risk, high-risk group were (60.9 ± 10.2)%, (52.6 ± 11.5)%, and (35.7 ± 2.8)%, respectively. The 5-year RFS among three groups were (68.3 ± 9.9)%, (62.5 ± 12.1)%, and (44.9 ± 14.1)%, respectively. The 5-year EFS among three groups were (60.9 ± 10.2)%, (52.6 ± 11.5)%, and (35.7 ± 12.8)%, respectively. The 5-year accumulative relapse rate among three groups were (31.7 ± 9.9)%, (37.5 ± 12.1)%, and (55.1 ± 14.1)%, respectively. There was no statistical significance of any survival rates between standard and intermediate risk groups, just as intermediate and high-risk groups. The OS and EFS in standard risk group were superior to those in high-risk group (P=0.040 and P=0.029, respectively), while there was no statistical significance of RFS and accumulative relapse rate between the two groups. The clinical factors listed below did not influenced the prognosis in the univariate analysis (P>0.05), including more than 5 weeks reaching to CR, WBC count at diagnosis, different immunophenotype (T or B cells), myeloid antigen expression, hyperdiploid chromosome karyotype, complex chromosome abnormality, conditioning regimen with or without TBI, duration between transplantation and diagnosis.

CONCLUSIONPh-ALL adults could achieve a satisfactory CR and better survial according to BDHALL2000/02 protocol followed by auto-HSCT, especially for the standard or intermediate risk group, and no-donors high-risk patients.

Adult ; Autografts ; Disease-Free Survival ; Hematopoietic Stem Cell Transplantation ; Humans ; Immunophenotyping ; Philadelphia Chromosome ; Precursor Cell Lymphoblastic Leukemia-Lymphoma ; Prognosis ; Recurrence ; Survival Rate