Vesical Imaging-Reporting and Data System (VI-RADS) as a grouping imaging biomarker combined with a decision-tree mode to preoperatively predict the pathological grade of bladder cancer.

AIM: To investigate whether the Vesical Imaging-Reporting and Data System (VI-RADS) could be used to develop a new non-invasive preoperative grade-prediction system to partially predict high-grade bladder cancer (HG-BC). MATERIALS AND METHODS: The present study enrolled 89 primary BC patients prospectively from March 2022 to June 2023. Receiver operating characteristic (ROC) curve analysis was performed to evaluate the diagnostic performance of VI-RADS for predicting HG-BC and muscle-invasive bladder cancer (MIBC) in the entire group. In the low VI-RADS (≤2) group, the decision tree-based method was used to obtain significant predictors and construct the decision-tree model (DT model). The performance of the DT model and low VI-RADS scores for predicting HG-BC was determined using ROC, calibration, and decision curve analyses. RESULTS: At a cut-off of ≥3, the specificity and positive predictive value of VI-RADS for predicting HG-BC in the entire group was 100%, and the area under the ROC curve (AUC) was 0.697. Among 65 patients with low VI-RADS scores, the DT model showed an AUC of 0.884 in predicting HG-BC compared to 0.506 for low VI-RADS scores. Calibration and decision curve analyses showed that the DT model performed better than the low VI-RADS scores. CONCLUSION: Most VI-RADS scores ≥3 correspond to HG-BCs. VI-RADS could be used as a grouping imaging biomarker for a pathological grade-prediction procedure, which in combination with the DT model for low VI-RADS (≤2) populations, would provide a potential preoperative non-invasive method of predicting HG-BC.

[Preparation of chitin/hyaluronic acid/collagen hydrogel loaded with mouse adipose-derived stem cells and its effects on wound healing of full-thickness skin defects in rats].

Objective: To prepare the chitin/hyaluronic acid/collagen hydrogel loaded with mouse adipose-derived stem cells and to explore its effects on wound healing of full-thickness skin defects in rats. Methods: The research was an experimental research. Chitin nanofibers were prepared by acid hydrolysis and alkaline extraction method, and then mixed with hyaluronic acid and collagen to prepare chitin/hyaluronic acid/collagen hydrogels (hereinafter referred to as hydrogels). Besides, the hydrogels loaded with mouse adipose-derived stem cells were prepared. Thirty male 12-week-old guinea pigs were divided into negative control group, positive control group, and hydrogel group according to the random number table, with 10 guinea pigs in each group. Ethanol, 4-aminobenzoic acid ethyl ester, or the aforementioned prepared hydrogels without cells were topically applied on both sides of back of guinea pigs respectively for induced contact and stimulated contact, and skin edema and erythema formation were observed at 24 and 48 h after stimulated contact. Adipose-derived stem cells from mice were divided into normal control group cultured routinely and hydrogel group cultured with the aforementioned prepared hydrogels without cells. After 3 d of culture, protein expressions of platelet-derived growth factor-D (PDGF-D), insulin-like growth factor-Ⅰ (IGF-Ⅰ), and transforming growth factor ß1 (TGF-ß1) were detected by Western blotting (n=3). Eight male 8-week-old Sprague-Dawley rats were taken and a circular full-thickness skin defect wound was created on each side of the back. The wounds were divided into blank control group without any treatment and hydrogel group with the aforementioned prepared hydrogels loaded with adipose-derived stem cells applied. Wound healing was observed at 0 (immediately), 2, 4, 8, and 10 d after injury, and the wound healing rate was calculated at 2, 4, 8, and 10 d after injury. Wound tissue samples at 10 d after injury were collected, the new tissue formation was observed by hematoxylin-eosin staining; the concentrations of interleukin-1α (IL-1α), IL-6, IL-4, and IL-10 were detected by enzyme-linked immunosorbent assay method; the expressions of CD16 and CD206 positive cells were observed by immunohistochemical staining and the percentages of positive cells were calculated. The sample numbers in animal experiment were all 8. Results: At 24 h after stimulated contact, no skin edema was observed in the three groups of guinea pigs, and only mild skin erythema was observed in 7 guinea pigs in positive control group. At 48 h after stimulated contact, skin erythema was observed in 8 guinea pigs and skin edema was observed in 4 guinea pigs in positive control group, while no obvious skin erythema or edema was observed in guinea pigs in the other two groups. After 3 d of culture, the protein expression levels of PDGF-D, IGF-I, and TGF-ß1 in adipose-derived stem cells in hydrogel group were significantly higher than those in normal control group (with t values of 12.91, 11.83, and 7.92, respectively, P<0.05). From 0 to 10 d after injury, the wound areas in both groups gradually decreased, and the wounds in hydrogel group were almost completely healed at 10 d after injury. At 4, 8, and 10 d after injury, the wound healing rates in hydrogel group were (38±4)%, (54±5)%, and (69±6)%, respectively, which were significantly higher than (21±6)%, (29±7)%, and (31±7)% in blank control group (with t values of 3.82, 3.97, and 4.05, respectively, Pvalues all <0.05). At 10 d after injury, compared with those in blank control group, the epidermis in wound in hydrogel group was more intact, and there were increases in hair follicles, blood vessels, and other skin appendages. At 10 d after injury, the concentrations of IL-1α and IL-6 in wound tissue in hydrogel group were significantly lower than those in blank control group (with tvalues of 8.21 and 7.99, respectively, P<0.05), while the concentrations of IL-4 and IL-10 were significantly higher than those in blank control group (with tvalues of 6.57 and 9.03, respectively, P<0.05). The percentage of CD16 positive cells in wound tissue in hydrogel group was significantly lower than that in blank control group (t=8.02, P<0.05), while the percentage of CD206 positive cells was significantly higher than that in blank control group (t=7.21, P<0.05). Conclusions: The hydrogel loaded with mouse adipose-derived stem cells is non-allergenic, can promote the secretion of growth factors in adipose-derived stem cells, promote the polarization of macrophages to M2 phenotype in wound tissue in rats with full-thickness skin defects, and alleviate inflammatory reaction, thereby promoting wound healing.

[Migratory pulmonary ground glass opacities caused by SARS-CoV-2 infection in a patient on B-cell depletion therapy].

In immunosuppressed individuals, the manifestation of viral pneumonia due to SARS-CoV-2 infection differs from that in healthy individuals. We reported a unique case of a 58-year-old male patient with B-cell depletion following treatment with the anti-CD20 monoclonal antibody. He presented to the Department of Pulmonary and Critical Care Medicine with complaints of intermittent fever and cough for three months, aggravated by shortness of breath for one month. He was previously diagnosed with stage IVA follicular lymphoma in April 2022 and underwent chemotherapy with Obinutuzumab (anti-CD20 monoclonal antibody). His last treatment was on November 3, 2022. On December 20, 2022, after contact with a SARS-CoV-2-infected person, he exhibited symptoms of fever peaking at 39.0 ℃, cough, and sputum production. A positive SARS-CoV-2 nucleic acid result was confirmed from a pharyngeal swab. Nine days later (December 29, 2022), the patient still had a fever. Chest CT showed multiple small pieces of ground glass opacities (GGOs) in both lower lungs. The diagnosis of viral pneumonia due to SARS-CoV-2 infection was confirmed. After five days of treatment with nirmatrelvir/ritonavir (Paxlovid) and intravenous dexamethasone (5 mg/d), his fever subsided. However, a subsequent chest CT on January 9, 2023 showed partial resorption of multiple GGOs in both lungs, accompanied by novel focal lesions. The patient developed a fever again on January 29, 2023, after which he had recurrent symptoms of fever, cough, and sputum, with intermittent short courses of antibiotics and dexamethasone, which never completely resolved. Multiple chest CTs during this period showed recurrent GGOs and consolidations in both lungs, demonstrating a migratory pattern. The patient was admitted to our hospital on March 7, 2023, with a peripheral blood test suggesting lymphocytopenia, a CD19+B lymphocyte count of zero, and negative IgG and IgM for SARS-CoV-2. A bronchoscopy and bronchoalveolar lavage fluid (BALF) analysis indicated a significantly elevated lymphocyte percentage and the presence of SARS-CoV-2 nucleic acid. Given the three-month history of chronic fever and respiratory symptoms, changing bilateral pulmonary infiltrates, and lack of SARS-CoV-2 humoral immunity, a diagnosis of persistent SARS-CoV-2 infection was considered. Subsequent treatment with Paxlovid for 15 days resulted in the resolution of all symptoms. A follow-up chest CT one month later showed almost complete normalization.

[Preliminary evaluation of immunogenicity and protective effect of multicomponent recombinant protein vaccine EPRHP014 against tuberculosis].

Objective: To evaluate the immunogenicity and protective effect of a multicomponent recombinant protein vaccine EPRHP014 constructed independently and provide a scientific basis for developing new tuberculosis (TB) vaccine and effective prevention and control of TB. Methods: Three full-length Mycobacterium (M.) tuberculosis protein antigens (EsxH, Rv2628, and HspX) and two epitope-predicted and optimized epitope-dominant protein antigens (nPPE18 and nPstS1) were selected, from which five protein antigens were used to construct a protein antigen composition EPRHP014, including a fusion expression multi-component protein antigen (EPRHP014f) and a multi-component mixed protein antigen (EPRHP014m) formed with the five single protein using clone, purification, and purification respectively. Multicomponent protein vaccines EPRHP014f and EPRHP014m were prepared with aluminum adjuvant, and the BCG vaccine was used as a control. ELISA detected the titer of serum-specific antibodies, the secretion of various cytokines was detected by ELISpot and Luminex, and immune protection was observed by the M. tuberculosis growth inhibition test in vitro. The results were statistically analyzed by t-test or rank sum test, and P<0.05 was considered a statistically significant difference. Results: Mice Immunized with EPRHP014m and EPRHP014f could produce highly effective IgG antibodies and their subtypes IgG1 and IgG2a, and the antibody titers were similar to those of mice immunized with BCG, with no statistical significance (P>0.05). The number of spot-forming cells (SFC) secreting IFN-γ and IL-4 induced by EPRHP014f group was significantly higher than those by EPRHP014m group and BCG group (P<0.05), but there was no significant difference in the number of SFC for IFN-γ and IL-4 induced between EPRHP014m group and BCG group (P>0.05). The secretion levels of GM-CSF and IL-12p70 induced by the EPRHP014m group were higher than those of the BCG group (P<0.05), but there was no significant difference in the levels of IL-6 and IL-10 induced between EPRHP014m group and BCG group (P>0.05). There was no significant difference in the secretions of IL-6, IL-10, IL-12, and GM-CSF between the EPRHP014f and BCG groups (P>0.05). EPRHP014m group, EPRHP014f group, and BCG group had obvious antibacterial effects in vitro, and the difference was insignificant (P>0.05). Conclusion: Both EPRHP014f and EPRHP014m can induce strong humoral and cellular immune responses in mice after immunization, and have a strong ability to inhibit the growth of M. tuberculosis in vitro, indicating that the antigen composition EPRHP014 has good potential in the development and application of TB vaccine.

[Immune checkpoint inhibitors induced pituitary immune-related adverse events: diagnosis and management].

Immune checkpoint inhibitors (ICIs) have been used in treating a wide variety of cancers, but they challenge clinicians with a series of special immune related adverse events (irAEs) resulting from activated immune system. Since June 2018, when the first programmed cell death 1 (PD-1) inhibitor, nivolumab, was approved by the National Medical Products Administration (NMPA), abundant experience has been accumulated in coping with irAEs from PD-1 and PD-1 ligand 1 (PD-L1) blockade therapies. In October 2021, the first CTLA-4 inhibitor, ipilimumab, which has a different spectrum of irAEs was also approved by NMPA. The discrepancy in clinical features of pituitary irAEs is obvious between these two types of ICIs. Pituitary irAEs include hypophysitis and hypopituitarism. In this review of latest literature, we have summarized the incidence, possible mechanisms, time of onset, clinical presentations, hormone test, pituitary imaging, treatment strategies and recovery patterns of pituitary irAEs. By referring to domestic and foreign clinical guidelines, we have proposed practical suggestions for screening, diagnosing and treating pituitary irAEs.

[Efficacy of recombinant human growth hormone treatment in children born small for gestational age with syndromic and non-syndromic short stature].

Objective: To analyse the efficacy of recombinant human growth hormone (rhGH) treatment in children born small for gestational age (SGA) with syndormic and non-syndormic short stature. Methods: The clinical data of 59 children born SGA who were diagnosed as short stature and admitted to the Center of Endocrinology, Genetics and Metabolism, Beijing Children's Hospital from July 2012 to June 2021 were collected and analyzed. According to the 2019 consensus on short stature, they were divided into syndromic group and non-syndromic group. Before treatment and 6, 12, 18 and 24 months after treatment, height standard deviation score (Ht-SDS), difference of height standard deviation (∆Ht-SDS) and homeostasis model assessment-insulin resistance index (HOMA-IR) were compared between groups, while Ht-SDS and HOMA-IR were compared before and after treatment. Independent t test or Kruskal-Wallis test were used for comparison between the 2 groups, and paired t test or Mann-Whitney U test were used for the intra-group comparison. Results: Among the 59 cases, 37 were males and 22 females, aged (5.5±2.3) years. There was no significant difference in Ht-SDS after 12 months of treatment between 2 groups (0.9±0.4 vs. 1.2±0.4, t=1.68, P=0.104) or in height SDS after 24 months of treatment (1.4±0.7 vs. 1.9±0.5, t=1.52, P=0.151). After 12 months of treatment, the insulin resistance index of the non-syndromic group was significantly higher than that of the syndromic group (2.29 (1.43, 2.99) vs. 0.90 (0.55, 1.40), Z=-2.95, P=0.003). There were significant differences in Ht-SDS between 6 months and before treatment, 12 months and 6 months in syndromic type (Z=7.65, 2.83 P<0.001, P=0.020), but all were significant differences in non-syndromic type between 6 months and before treatment, 12 months and 6 months, 18 months and 12 months, 24 months and 18 months (Z=11.95, 7.54, 4.26, 3.83, all P<0.001). Conclusion: The efficacy of rhGH treatment in children born SGA is comparable between syndromic and non-syndromic short stature cases, but non-syndromic children treated with rhGH need more frequent follow-up due to the risk of insulin resistance.

International Validation of a Methicillin-Resistant Staphylococcus aureus Risk Assessment Tool for Skin and Soft Tissue Infections.

INTRODUCTION: To promote judicious prescribing of methicillin-resistant Staphylococcus aureus (MRSA)-active therapy for skin and soft tissue infections (SSTI), we previously developed an MRSA risk assessment tool. The objective of this study was to validate this risk assessment tool internationally. METHODS: A multicenter, prospective cohort study of adults with purulent SSTI was performed at seven international sites from July 2016 to March 2018. Patient MRSA risk scores were computed as follows: MRSA infection/colonization history (2 points); previous hospitalization, previous antibiotics, chronic kidney disease, intravenous drug use, human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS), diabetes with obesity (1 point each). Predictive performance of MRSA surveillance percentage, MRSA risk score, and estimated MRSA probability (surveillance percentage adjusted by risk score) were quantified using the area under the receiver operating characteristic curves (aROC) and compared. Performance characteristics of different risk score thresholds across varying baseline MRSA prevalence were examined. RESULTS: Two hundred three patients were included. Common SSTI were wounds (28.6%), abscess (25.1%), and cellulitis with abscess (20.7%). Patients with higher risk scores were more likely to have MRSA (P < 0.001). The MRSA risk score aROC (95%CI) [0.748 (0.678-0.819)] was significantly greater than MRSA surveillance percentage [0.646 (0.569-0.722)] (P = 0.016). Estimated MRSA probability aROC [0.781 (0.716-0.845)] was significantly greater than surveillance percentage (P < 0.001) but not the risk score (P = 0.192). The estimated negative predictive value (NPV) of an MRSA score ≥ 1 (i.e., a score of 0) was greater than 90% when MRSA prevalence was 30% or less. CONCLUSION: The MRSA risk score and estimated MRSA probability were significantly more predictive of MRSA compared with surveillance percentage. An MRSA risk score of zero had high predictive value and could help avoid unnecessary empiric MRSA coverage in low-acuity patients. Further study, including impact of such risk assessment tools on prescribing patterns and outcomes are required before implementation.

[Clinical analysis of 4 children with hereditary hypercholesterolemia].

Objective: To investigate the clinical characteristics of hereditary hypercholesterolemia in childhood. Methods: The clinical data including general conditions, clinical manifestations, laboratory tests, and genetic testing results of 4 children with hereditary hypercholesterolemia who admitted to Henan Children's Hospital from January 2020 to December 2020 were retrospectively analyzed. Results: There were 4 female children aged 5.5,1.5,6.3,3.1 years, all presented with skin xanthoxoma as the chief complaint. Plasma total cholesterol (range 11.8 to 20.9 mmol/L) and low density lipoprotein-cholesterol (range 8.2 to 13.7 mmol/L) were significantly elevated. The serum ß-glutamate levels in case 1 (241.2 µmol/L) and case 2 (164.2 µmol/L) increased significantly. Genetic analysis revealed compound heterozygous variants of ABCG8 gene in case 1 and ABCG5 gene in case 2 who were diagnosed with sitosterolemia. Case 3 and 4 who all had family history of hypercholesterolemia and compound heterozygous variants of LDLR gene were diagnosed with familial hypercholesterolemia. After diet treatment, the blood lipids returned normal and the skin xanoma subsided in case 1 and 2. In case 3 and 4, the blood lipids gradually decreased after diet and rosuvastatin treatment. Conclusions: Xanthomatosis is the common clinical manifestation of sitosterolemia and familial hypercholesterolemia. Family history, blood plant sterol profile, genetic variation, and changes in blood lipids after early dietary treatment are helpful for disease identification.

[Cone-beam CT analysis of vertical control of mandible and changes of temporomandibular joint in adult patients with skeletal class â ¡ malocclusion with high angle].

Objective: To investigate the shape and position changes of temporomandibular joint (TMJ) in adult skeletal class Ⅱ malocclusion with high angle patients after vertical mandibular control, and the correlation between vertical mandibular changes and condylar position changes. Methods: Twenty adult skeletal class Ⅱ malocclusion with high angle patients [6 males and 14 females, aged (21.4±2.4) years] who underwent extraction treatment and active vertical control in the Department of Orthodontics, Lanzhou University Stomatological Hospital from October 2017 to November 2020 were selected. Cone-beam CT data of the patient before and after treatment were imported into Invivo Dental 5.0 software for three-dimensional reconstruction and correction, and the vertical index of mandible in reconstructed lateral cephalogram (mandibular plane angle, posterior anterior height ratio, mandibular true rotation angle) were measured. Incisal angle and variables of condyle shape, position and articular fossa shape were measured. Paired t test was performed on the results before and after treatment, and the correlation between mandibular vertical changes and condylar position changes was determined by Pearson correlation coefficient calculation. Results: After treatment, the overbite and overjet were within normal range, and the vertical height of the molars was controlled. Compared with the measurement before treatment, mandibular plane angle and mandibular true rotation angle were decreased by 2.05°±1.22° (t=7.60, P<0.001) and 1.42°±1.92° (t=3.54, P=0.002), respectively. The posterior anterior height ratio was increased by (1.89±3.32)% (t=2.56, P=0.019). After treatment, the mediolateral diameter of condyle, the anteroposterior diameter of condyle, the maximum cross-sectional area of condyle, the height of condyle head, the width of articular fossa, the depth of articular fossa and the articular nodular angle were increased by (0.55±0.76) mm (t=-2.73, P=0.015), (0.27±3.51) mm (t=-3.23, P=0.006), (6.01±7.36) mm2 (t=-2.80, P=0.013), (0.33±0.72) mm (t=-2.14, P=0.046), (0.56±0.93) mm (t=-2.37, P=0.032), 0.33 (0.14, 0.51) mm (Z=-2.76, P=0.006) and 1.50°±2.40° (t=-2.44, P=0.028), respectively. The internal condylar space and the external condylar space were decreased by (0.33±0.49) mm (t=2.31, P=0.035) and (0.20±0.23) mm (t=3.58, P=0.003), respectively. Before orthodontic treatment, 6 patients were with anterior displacement of the condyle, 7 patients with central position of the condyle, and 7 patients with posterior displacement of the condyle. After correction, patients who were with central position of the condyle have not changed much. The posterior displaced condyle in 2 patients and anterior displaced condyle in 3 patients became in central position after treatment. The joint space index was closer to the central position in 3 patients with anterior displacement and 3 patients with posterior displacement. The position of condyle in 1 patient with posterior displacement and 1 patient with anterior displacement remained basically unchanged. There was a significant negative correlation between the change of the posterior-anterior height ratio and the change of the internal condylar space in patients (r=-0.52, P=0.019), and a low correlation with the contral condylar space and the external condylar space(r=-0.48, P=0.031; r=-0.47, P=0.035). Conclusions: Skeletal class Ⅱ malocclusion with high angle adult patients achieved normal overbite and overjet and remodeling of condyle and articular fossa occurred after orthodontic treatmnet and vertical control. There was a certain negative correlation between the change of posterior-anterior height ratio and the change of condylar position.

[Consistency evaluation of 2 methods in detecting serum insulin-like growth factorâ in children].

Objective: To evaluate the consistency of mass spectrometry (MS) and chemiluminescence immunoassay (CLIA) in detecting serum insulin-like growth factor-1 (IGF-1) and IGF-1 standard deviation score (SDS). Methods: This cross-sectional parallel control study prospectively collected the serum samples of 115 children with short stature disorders who were admitted in the Department of Endocrinology, Beijing Children's Hospital, Capital Medical University from February 2020 to December 2021. The serum IGF-1 level was detected by CLIA and MS, and converted to SDS for consistency analysis. Pearson analysis was used to analyze the correlation between the 2 methods, and Deming regression equation was established. Bland-Altman diagram and weighted Kappa coefficient were used to evaluate the consistency of the 2 methods. Results: There were 46 boys (40.0%) and 69 girls (60.0%), aged (8±3) years. Among the 115 cases, 37 were Turner syndrome, 59 were small for gestational age (SGA) at term, 1 was growth hormone deficiency (GHD) and 18 were other diseases. Pearson correlation analysis showed a preferable correlation between IGF-1 measured by the 2 detection methods (r=0.94, P<0.01), and IGF-1 SDS was also significantly correlated (r=0.92, P<0.01). Bland-Altman analysis showed that the consistency of serum IGF-1 levels detected by the 2 methods was poor, and the mean difference between CLIA and MS was 33.38 µg/L. The result detected by CLIA was significantly higher than that by MS, with SDS of 43.51 µg/L (95%CI -51.89-118.7 µg/L). After converting the results to SDS and removing 3 outliers (including 1 GHD patient), the weighted Kappa showed acceptable consistency (κ=0.68). Conclusion: In clinical application, after converting to IGF-1 SDS, IGF-1 detected by MS and CLIA can be used for cross-reference, but too high or too low levels should be cautious about.

[Characteristics of overnight obstructive apnea events in patients with obstructive sleep apnea hypopnea syndrome].

Objective: To compare the overnight variation trends in the duration of obstructive apnea events, and to explore the adaptive capacity to the pathophysiological consequences of periodic sleep disordered-breathing and its underlying mechanism in patients with obstructive sleep apnea hypopnea syndrome (OSAHS). Methods: A retrospective analysis were performed of the polysomnographic (PSG) results of 89 snoring patients including 10 non-OSAHS, 15 mild, 29 moderate and 35 severe OSAHS. The total record time was divided into four equal phases, and the variation trends of the mean apnea duration (MAD) and the longest apnea duration (LAD) were compared with the progression of sleep phases in different groups. Correlation analysis was conducted with demographic indicators, pulse oxygen saturation (SpO2) and sleep related indicators. In addition, the number of apneas-time variability curve was plotted for fitting analysis. Results: In patients with severe OSAHS, both MAD [26.1(20.9, 31.4) s] and LAD [56.5(46.5, 82.0) s] were significantly higher than those of non-OSAHS, mild and moderate OSAHS (P<0.001). In addition, the MAD in the third and fourth quartiles were significantly higher than that in the first quartile [(28.4±9.0) s, (27.3±9.8) s, (22.3±9.9) s, respectively, P=0.046], and the LAD in the third quartile was significantly higher than that in the first quartile [56.5(38.5, 71.0) s, 41.0(28.0, 53.0) s, respectively, P=0.018]. In all subjects, the MAD and LAD in the third and fourth quartiles were significantly higher than those in the first quartile [MAD: 20.3(10.3, 29.2) s, 18.5(11.3, 24.2) s, 12.9(0.0, 21.8) s, respectively, P<0.001; LAD: 28.0(10.3, 50.5) s, 28.0(12.0, 44.5) s, 14.5(0.0, 32.3) s, respectively, P<0.001]. There was no statistical difference in the lowest SpO2 (LSpO2), the mean SpO2 (MSpO2), and the percent of sleep time oxygen saturation below 90% (T90%) of all subjects in different sleep phases (P>0.05). The LAD was positively correlated with obstructive apnea index (OAI, OR=1.660, P=0.025), but no correlation was observed with other indicators (P>0.05). The MAD increased 0.22 s per episode at the onset of sleep (1-31 apnea events), then dropped to 0.04 s of increase per episode, with a dynamics change of 5.5-fold slower. Conclusions: The MAD and LAD show a gradual prolongation trend with the progression of sleep phases, and the prolongation trend is the most obvious in patients with severe OSAHS, while the dynamic change trend of SpO2 is not obvious. There may be multiple adaptation mechanisms for recurrent hypoxic episodes, and the adaptation occurr in stages, with a rapid increase in MAD at the onset of sleep, follow by a markedly slower increase. Patients with severe OSAHS express the most complete pattern, suggesting the most severe pathophysiological outcomes.

[Pituitary immune-related adverse events induced by programmed cell death protein 1 inhibitors in advanced lung cancer patients: A report of 3 cases].

Pituitary immune-related adverse events induced by programmed cell death protein 1 inhibitors in advanced lung cancer patients: A report of 3 cases SUMMARY Programmed cell death protein 1 (PD-1) and its ligand 1 (PD-L1) have been widely used in lung cancer treatment, but their immune-related adverse events (irAEs) require intensive attention. Pituitary irAEs, including hypophysitis and hypopituitarism, are commonly induced by cytotoxic T lymphocyte antigen 4 inhibitors, but rarely by PD-1/PD-L1 inhibitors. Isolated adrenocorticotropic hormone(ACTH) deficiency (IAD) is a special subtype of pituitary irAEs, without any other pituitary hormone dysfunction, and with no enlargement of pituitary gland, either. Here, we described three patients with advanced lung cancer who developed IAD and other irAEs, after PD-1 inhibitor treatment. Case 1 was a 68-year-old male diagnosed with metastatic lung adenocarcinoma with high expression of PD-L1. He was treated with pembrolizumab monotherapy, and developed immune-related hepatitis, which was cured by high-dose methylprednisolone [0.5-1.0 mg/(kg·d)]. Eleven months later, the patient was diagnosed with primary gastric adenocarcinoma, and was treated with apatinib, in addition to pembrolizumab. After 17 doses of pembrolizumab, he developed severe nausea and asthenia, when methylprednisolone had been stopped for 10 months. His blood tests showed severe hyponatremia (121 mmol/L, reference 137-147 mmol/L, the same below), low levels of 8:00 a.m. cortisol (< 1 µg/dL, reference 5-25 µg/dL, the same below) and ACTH (2.2 ng/L, reference 7.2-63.3 ng/L, the same below), and normal thyroid function, sex hormone and prolactin. Meanwhile, both his lung cancer and gastric cancer remained under good control. Case 2 was a 66-year-old male with metastatic lung adenocarcinoma, who was treated with a new PD-1 inhibitor, HX008, combined with chemotherapy (clinical trial number: CTR20202387). After 5 months of treatment (7 doses in total), his cancer exhibited partial response, but his nausea and vomiting suddenly exacerbated, with mild dyspnea and weakness in his lower limbs. His blood tests showed mild hyponatremia (135 mmol/L), low levels of 8:00 a.m. cortisol (4.3 µg/dL) and ACTH (1.5 ng/L), and normal thyroid function. His thoracic computed tomography revealed moderate immune-related pneumonitis simultaneously. Case 3 was a 63-year-old male with locally advanced squamous cell carcinoma. He was treated with first-line sintilimab combined with chemotherapy, which resulted in partial response, with mild immune-related rash. His cancer progressed after 5 cycles of treatment, and sintilimab was discontinued. Six months later, he developed asymptomatic hypoadrenocorticism, with low level of cortisol (1.5 µg/dL) at 8:00 a.m. and unresponsive ACTH (8.0 ng/L). After being rechallenged with another PD-1 inhibitor, teslelizumab, combined with chemotherapy, he had pulmonary infection, persistent low-grade fever, moderate asthenia, and severe hyponatremia (116 mmol/L). Meanwhile, his blood levels of 8:00 a.m. cortisol and ACTH were 3.1 µg/dL and 7.2 ng/L, respectively, with normal thyroid function, sex hormone and prolactin. All of the three patients had no headache or visual disturbance. Their pituitary magnetic resonance image showed no pituitary enlargement or stalk thickening, and no dynamic changes. They were all on hormone replacement therapy (HRT) with prednisone (2.5-5.0 mg/d), and resumed the PD-1 inhibitor treatment when symptoms relieved. In particular, Case 2 started with high-dose prednisone [1 mg/(kg·d)] because of simultaneous immune-related pneumonitis, and then tapered it to the HRT dose. His cortisol and ACTH levels returned to and stayed normal. However, the other two patients' hypopituitarism did not recover. In summary, these cases demonstrated that the pituitary irAEs induced by PD-1 inhibitors could present as IAD, with a large time span of onset, non-specific clinical presentation, and different recovery patterns. Clinicians should monitor patients' pituitary hormone regularly, during and at least 6 months after PD-1 inhibitor treatment, especially in patients with good oncological response to the treatment.

Hyperhidrosis in Parkinson's disease: a 3-year prospective cohort study.

BACKGROUND: Although hyperhidrosis is a common symptom in patients with Parkinson's disease (PD), no study has yet examined it longitudinally. OBJECTIVES: We conducted a 3-year prospective cohort study to investigate the development, evolution and correlates of hyperhidrosis in patients with PD. METHODS: A total of 224 patients with early-stage PD were enrolled at baseline and followed up annually for three consecutive years. Hyperhidrosis was assessed using hyperhidrosis question (item 30) of the Non-Motor Symptoms Scale (NMSS). The generalized estimating equations model was applied to investigate the correlates of both presence and severity of hyperhidrosis. RESULTS: The frequency of hyperhidrosis in PD had an overall increasing tendency from 24.1% at baseline to 34.4% after 3 years, although hyperhidrosis was not always persistent in all patients over the 3-year study period. The presence of hyperhidrosis was found to be associated with dyskinesia (OR 2.27 [1.02-5.04], P = 0.045), the sexual function domain subscore of the NMSS (OR 1.04 [1.01-1.07], P = 0.016), the Hamilton Anxiety Rating Scale (HARS) score (OR 1.08 [1.03-1.13], P = 0.001) and the Unified Parkinson's Disease Rating Scale part III score (OR 1.02 [1.00-1.04], P = 0.036). Only the HARS score was associated with the severity of hyperhidrosis (B 0.08 [0.03-0.12], P = 0.001). CONCLUSIONS: Hyperhidrosis is common in PD, and its frequency increases along with disease duration. Hyperhidrosis in PD is associated not only with motor severity and motor complication such as dyskinesia, but also with non-motor symptoms such as sexual dysfunction and anxiety.

[Advances in pathogen diagnosis of respiratory infection diseases in 2021].

Respiratory tract infections (RTI) are a common and highly prevalent disease in the population, which can develop into acute respiratory distress syndrome (ARDS) in severe cases.A large variety of microorganisms can cause RTI, including bacteria, respiratory viruses, and fungi. The timely and accurate detection of these pathogens is the prerequisites of effective treatment of RTI. However, more than 50% of RTI patients failed to diagnosis of causative agents due to unavailability of qualified samples, antimicrobial treatment prior to sample collection, high variety of respiratory pathogens, and influence of the normal flora in respiratory tract. In recent years, progress on molecular diagnosis, especially the novel approaches such as clinical metagenomics and CRSIPR (Clustered regularly interspaced short palindromic repeats), has not only improved our capacity for RTI pathogen detection but also brought new challenges. In this review, we summed up the advances in RTI pathogen diagnosis in 2021 and discussed the clinical benefits and challenges from novel approaches, which provided a clinical perspective on the development and application of these diagnostic tools in the real world.

[A nomogram for predicting lymph node metastasis in early gastric cancer].

Objective: To explore the independent risk factors of lymph node metastasis (LNM) in early gastric cancer, and to use nomogram to construct a prediction model for above LNM. Methods: A retrospective cohort study was conducted. Inclusion criteria: (1) primary early gastric cancer as stage pT1 confirmed by postoperative pathology; (2) complete clinicopathological data. Exclusion criteria: (1) patients with advanced gastric cancer, stump gastric cancer or history of gastrectomy; (2) early gastric cancer patients confirmed by pathology after neoadjuvant chemotherapy; (3) other types of gastric tumors, such as lymphoma, neuroendocrine tumor, stromal tumor, etc.; (4) primary tumors of other organs with gastric metastasis. According to the above criteria, 1633 patients with early gastric cancer who underwent radical gastrectomy at the Department of General Surgery of the Chinese PLA General Hospital First Medical Center from December 2005 to December 2020 were enrolled as training set, meanwhile 239 patients with early gastric cancer who underwent gastrectomy at the Department of General Surgery of the Chinese PLA General Hospital Fourth Medical Center from December 2015 to December 2020 were enrolled as external validation set. Risk factors of LNM in early gastric cancer were identified by using univariate and multivariate logistic regression analyses. A nomogram prediction model was established with significant factors screened by multivariate analysis. Area under the receiver operating characteristic curve (AUC) was used for assessing the predictive value of the model. Calibration curve was drawn for external validation. Results: Among 1633 patients in training set, the mean number of retrieved lymph nodes was 20 (13-28), and 209 patients (12.8%) had lymph node metastasis. Univariate analysis showed that gender, resection range, tumor location, tumor morphology, lymph node clearance, vascular invasion, lymphatic cancer thrombus, tumor length, tumor differentiation, microscopic presence of signet ring cells and depth of tumor invasion were associated with LNM (all P<0.05). Multivariate analysis revealed that females, tumor morphology as ulcer type, vascular invasion, lymphatic cancer thrombus, tumor length≥3 cm, deeper invasion of mucosa, and poor differentiation were independent risk factors for LNM in early gastric cancers (all P<0.05). Receiver operating characteristic curve indicated that AUC of training set was 0.818 (95%CI: 0.790-0.847) and AUC of external validation set was 0.765 (95%CI: 0.688-0.843). The calibration curve showed that the LNM probability predicted by nomogram was consistent with the actual situation (C-index: 0.818 in training set and 0.765 in external validation set). Conclusions: Females, tumor morphology as ulcer type, vascular invasion, lymphatic cancer thrombus, tumor length≥3 cm, deeper invasion of mucosa and poor differentiation are independent risk factors for LNM of early gastric cancer. The establishment of a nomogram prediction model for LNM in early gastric cancer has great diagnostic value and can provide reference for treatment selection.

[Analysis of influence factors for short-term recurrence of retroperitoneal liposarcoma after complete resection].

Objective: To examine the influence factors of short-term recurrence after complete surgical resection of retroperitoneal liposarcoma. Methods: The clinicopathological data of retroperitoneal liposarcoma at Department of General Surgery, the First Medical Center, People's Liberation Army General Hospital from January 2000 to January 2020 were retrospectively analyzed. There were 60 males and 31 females, aged (52.1±9.9) years (range: 30 to 84 years). Tumor recurrence within 12 months after complete resection was defined as short-term recurrence, and tumor recurrence more than 12 months was defined as non-short-term recurrence. The t test, rank-sum test, χ2 test and Fisher exact test were conducted for inter-group comparison. Logistic regression analysis was used to analyze the independent influence factors for the short-term recurrence of retroperitoneal liposarcoma after complete resection. The Kaplan-Meier curve was used to calculate the recurrence-free survival, and the Log-rank test was adopted for the comparison between the groups. Results: The univariate analysis results showed that irregular tumor morphology, multiple pathological subtypes, pathological scores>3, and multiple primary tumors are influence factors for short-term recurrence after complete resection of retroperitoneal liposarcoma (χ2: 4.422 to 7.773, all P<0.05). Regression analysis of the above risk factors showed that multiple primary tumors was the independent risk factor (OR=2.918, 95%CI: 1.127 to 7.556, P=0.027). In the short-term recurrence group, Kaplan-Meier curve analysis showed that patients with multiple primary tumors had a shorter median recurrence time than patients with unifocal tumor (6 months vs. 9 months, P=0.028). Conclusions: Multiple primary tumor is an independent risk factor for short-term recurrence after complete resection of retroperitoneal liposarcoma. It suggests that the frequency of follow-up after surgery should be increased for such patients.

[Genetic and clinical analysis of X-linked hypophosphatemic rickets].

Objective: To investigate the clinical and genetic features, and treatment of X-linked hypophosphatemic rickets (XLH). Methods: In this retrospective study, we reviewed the medical records of 25 pediatric patients with XLH who were admitted to Department of Endocrinology Genetics and Metabolism,Beijing Children's Hospital from January 2010 to January 2020. The clinical characteristics, PHEX gene variants, as well as clinical outcome of the patients were summarized. To analyze the correlation between genotype and phenotype, the patients were divided into different subgroups according to the location of the variants, including N-terminal-located vs. C-terminal-located variant, and Zn-binding domain exon 17 or 19 variant vs. non-exon 17 or 19 variant. The age at onset, height standard deviation score (HtSDS), intercondylar or intermalleolar distance, fasting serum phosphorus, and HtSDS and intercondylar or intermalleolar distance at the final follow-up were compared by rank sum test or t text. Results: Among the 25 children with XLH, 8 were boys and 17 were girls. The median age of onset was 1.2 (1.0, 1.8) years, and the median age of diagnosis was 2.5 (1.5, 4.3) years. The main clinical manifestations were abnormal gait and lower limb deformity. The HtSDS was -2.0(-3.2, -0.8), and the intercondylar or intermalleolar distance was 4.5 (3.0, 6.0) cm. The fasting serum phosphorus level was 0.8 (0.7, 0.9) mmol/L, while the serum alkaline phosphatase level was (721±41) U/L and the serum calcium level was (2.5±0.1) mmol/L. Three patients (12%) had parathyroid hormone levels above the upper limit of the normal range. Twenty-five patients (100%) showed radiographic changes of active rickets. Nephrocalcinosis was found in 2 cases (9%). Twenty-four different PHEX variations were detected in 25 patients, among whom 11 (44%) had not been reported previously. No hot spot variation was found. No statistical differences (all P>0.05) were identified in clinical features and outcomes either in comparing patients with N-terminal (21 cases) and C-terminal (4 cases) variants, or in comparing patients with variant located in exon 17 or 19 (4 cases) or not (21 cases). Twenty-four cases (96%) were treated regularly with phosphate supplements and active vitamin D. After 2.7 (1.6, 5.0) years of follow-up, clinical symptoms were relieved in 96% (24/25) of the patients. The HtSDS after treatment had no significant difference compared to that before treatment (-2.0(-3.2, -0.8) vs.-2.0(-2.8, -1.1),Z =-0.156, P>0.05), while the intercondylar or intermalleolar distance after treatment was significantly reduced compared to that before treatment (4.5(3.0, 6.0) vs. 1.5(0, 3.3) cm, Z =-3.043, P<0.05). Bone X-rays were reexamined in 17 cases after treatment, and radiographic signs of rickets were improved. Eighteen cases had secondary hyperparathyroidism and 7 cases had nephrocalcinosis. Conclusions: The main clinical manifestations of XLH are abnormal gait, lower limb deformity and short stature. A high proportion of novel variations of PHEX gene but no hot spot variation neither genotype-phenotype correlation are found. Regular treatment with phosphate supplements and active vitamin D can significantly improve the symptoms except for the height. However, the rate of adverse events including secondary hyperparathyroidism and nephrocalcinosis seems to be high.

[Clinical and genetic analysis of Noonan syndrome in 20 children].

Objective: To explore the clinical and genetic characteristics of Noonan syndrome in children. Methods: The clinical characteristics,genetic analysis and follow-up data of 20 children diagnosed with Noonan syndrome who were admitted to Department of Endocrinology, Genetics and Metabolism, Beijing Children's Hospital, Capital Medical University from March 2016 to December 2020 were retrospectively analyzed. Results: Among 20 children with Noonan syndrome, 13 were males and 7 were females. The age at diagnosis was 5.9 years (1.1 years to 12.2 years). The most common clinical complaints were delayed height growth, followed by hypospadias or cryptorchidism in 2 cases, and special facial appearance in 1 case. Physical examination revealed 12 cases of Noonan syndrome with facial features, 9 cases with cryptorchidism and hypospadias, 10 cases with abnormal cardiac structure, and 10 cases with mental retardation; Twelve patients were detected with PTPN11 variations, 4 patients carried SOS2 variations, 2 cases were confirmed with variations in SHOC2 and SOS1. Six children received recombinant human growth hormone treatment, and their height increased by 4.0 (2.5-6.0) cm to varying degrees at 9 months. No adverse events occurred. Conclusions: Male Noonan syndrome is more frequently found with external genitalia. In addition to the high frequency of PTPN11 variation, the frequency of gene variation in SOS2 gene is higher than previously reported. All of the SOS2 variations are de novo. The syndrome phenotype profiles could vary with the admitted clinical departments. To understand the full picture of the syndrome, it is necessary to collect medical information from different departments.

[A clinical and pathological report of delayed encephalopathy after heat stroke].

Objective: To explore the clinical manifestations, dynamic neuroimaging changes and brain histopathologic characteristics of a patient with delayed encephalopathy after heat stroke. Methods: In October 2019, the clinical manifestations, electroencephalogram, cerebrospinal fluid, imaging changes and brain histopathological characteristics of a patient with brain damage caused by heat stroke were retrospectively analyzed. Results: The patient was a 40-year-old male who suddenly appeared dizziness, unconscious, high fever when working in the high temperature environment. The EEG showed diffuse slow wave activity. Early CT was normal, and abnormal signals gradually appeared in the basal ganglia region of the thalamus after a few days. In the late, the MRI found a large area of abnormal signals under the cerebral cortex, and white matter was involved. Pathological examination of brain biopsy showed that cortical neuron loss, loose white matter changes, and significant demyelination changes, while no inflammatory cell infiltration was observed in subarachnoid space, meninges, and dermal white matter. Conclusion: Imaging examination dynamic changes of the delayed encephalopathy is important in the heat stroke, and the main pathological manifestation is demyelination.