Tissue informative cell-free DNA methylation sites in amyotrophic lateral sclerosis.

Cell-free DNA (cfDNA) is increasingly recognized as a promising biomarker candidate for disease monitoring. However, its utility in neurodegenerative diseases, like amyotrophic lateral sclerosis (ALS), remains underexplored. Existing biomarker discovery approaches are tailored to a specific disease context or are too expensive to be clinically practical. Here, we address these challenges through a new approach combining advances in molecular and computational technologies. First, we develop statistical tools to select tissue-informative DNA methylation sites relevant to a disease process of interest. We then employ a capture protocol to select these sites and perform targeted methylation sequencing. Multi-modal information about the DNA methylation patterns are then utilized in machine learning algorithms trained to predict disease status and disease progression. We applied our method to two independent cohorts of ALS patients and controls (n=192). Overall, we found that the targeted sites accurately predicted ALS status and replicated between cohorts. Additionally, we identified epigenetic features associated with ALS phenotypes, including disease severity. These findings highlight the potential of cfDNA as a non-invasive biomarker for ALS.

[Analysis of efficacy and prognosis of allogeneic hematopoietic stem cell transplantation for the treatment of combined immunodeficiency].

Objective: To evaluate the efficacy of allogeneic hematopoietic stem cell transplantation for the treatment of combined immunodeficiency (CID) and explore prognostic risk factors. Methods: In this retrospective cohort study, clinical characteristics, laboratory tests and prognosis of 73 CID children who underwent allogeneic hematopoietic stem cell transplantation from February 2014 to April 2022 in the Children's Hospital of Fudan University were analyzed. Based on the subtypes of diseases, all patients were divided into severe combined immunodeficiency disease (SCID) group and other CID group. Based on the types of donors, all patients were divided into matched sibling donor group, matched unrelated donor group, unrelated cord blood group, and haploidentical donor group. Kaplan-Meier method and Log-Rank test were used to analyze the survival data. Cox regression was used to analyze prognostic factors. Results: Among the 73 patients, there were 61 (84%) males and 12 (16%) females. Fifty-five (75%) patients were SCID, and 18 (25%) patients were other CID. Donor source included 2 (3%) matched sibling donors (MSD), 3 (4%) matched unrelated donors (MUD), 64 (88%) unrelated cord blood (UCB), and 4 (5%) haploidentical donors. The age at transplant was 10.7 (5.9, 27.5) months, and the follow-up time was 36.2 (2.5, 62.9) months. The 3-year overall survival rate of 73 patients with CID was (67±6) %. No significant difference was found in the 3-year overall survival rates between patients with SCID (55 cases) and other CID (18 cases) ((64±7) % vs. (78±10) %, χ2=1.31, P=0.252). And no significant difference was found in the 3-year overall survival rates among patients who received MSD or MUD (5 cases), UCB (64 cases), and haploidentical donor (4 cases) transplant (100% vs. (66±6)% vs. (50±25) %, χ2=2.30, P=0.317). Cox regression analysis showed that the medical history of sepsis (HR=2.55, 95%CI 1.05-6.20, P=0.039) and hypoalbuminemia at transplant (HR=2.96, 95%CI 1.14-7.68, P=0.026) were independent risk factors for the prognosis of allogeneic hematopoietic stem cell transplantation in pediatric patients with CID. Conclusions: Allogeneic hematopoietic stem cell transplantation is an effective treatment for CID. The medical history of sepsis and hypoalbuminemia at transplant were risk factors for prognosis. Enhancing infection prevention and nutritional intervention before transplant can improve patient prognosis.

[Intraoperative neuromonitoring in surgery of cervical neurogenic tumors].

Objective: To investigate the application value of intraoperative motor nerve monitoring in cervical neurogenic tumor surgery. Methods: The efficacy of intraoperative neuromonitoring (IONM) was analyzed retrospectively in 18 patients, including 6 males and 12 females, aged from 15 to 74 years, treated in Affiliated Drum Tower Hospital, Medical School of Nanjing University from June 2019 to September 2022 who underwent total cystectomy of cervical neurogenic tumors under intraoperative nerve monitoring. Results: All 18 patients had complete tumor removal, including 8 patients with tumors from the vagus nerve and 10 patients with tumors from the brachial plexus nerve. Postoperative nerve functions were normal in patients with tumors from brachial plexus nerve, and incomplete vocal cord paralysis occurred in 2 patients with tumors from vagus vagus nerve. The total incidence of motor nerve injury was 11.1% (2/18). All patients were followed up for 6 to 45 months, with no tumor recurrence. Conclusion: Intraoperative neuromonitoring has significant values in surgery of cervical neurogenic tumors, which is helpful to remove completely the tumors on the basis of protecting the nerve functions to the maximum extent.

[Surgical treatment and prognosis analysis of hilar cholangiocarcinoma].

Objective: To investigate the surgical treatment effect and prognostic factors of hilar cholangiocarcinoma. Methods: This is an ambispective cohort study. From August 2005 to December 2022,data of 510 patients who diagnosed with hilar cholangiocarcinoma and underwent surgical resection at the Hepatobiliary Center of the First Affiliated Hospital of Nanjing Medical University were retrospectively collected. In the cohort,there were 324 males and 186 females,with an age of (M (IQR)) 63(13)years (range:25 to 85 years). The liver function at admission was Child-Pugh A (343 cases,67.3%) and Child-Pugh B (167 cases,32.7%). Three hundred and seventy-two(72.9%) patients had jaundice symptoms and the median total bilirubin was 126.3(197.6) µmol/L(range: 5.4 to 722.8 µmol/L) at admission. Two hundred and fourty-seven cases (48.4%) were treated with percutaneous transhepatic cholangial drainage or endoscopic nasobiliary drainage before operation. The median bilirubin level in the drainage group decreased from 186.4 µmol/L to 85.5 µmol/L before operation. Multivariate Logistic regression was used to identify the influencing factors for R0 resection,and Cox regression was used to construct multivariate prediction models for overall survival(OS) and disease-free survival(DFS). Results: Among 510 patients who underwent surgical resection,Bismuth-Corlett type Ⅲ-Ⅳ patients accounted for 71.8%,among which 86.1% (315/366) underwent hemi-hepatectomy,while 81.9% (118/144) underwent extrahepatic biliary duct resection alone in Bismuch-Corlett type Ⅰ-Ⅱ patients. The median OS time was 22.8 months, and the OS rates at 1-,3-,5-and 10-year were 72.2%,35.6%,24.8% and 11.0%,respectively. The median DFS time was 15.2 months,and the DFS rates was 66.0%,32.4%,20.9% and 11.0%,respectively. The R0 resection rate was 64.5% (329/510), and the OS rates of patients with R0 resection at 1-,3-,5-and 10-year were 82.5%, 48.6%, 34.4%, 15.2%,respectively. The morbidity of Clavien-Dindo grade Ⅲ-Ⅴ complications was 26.1%(133/510) and the 30-day mortality was 4.3% (22/510). Multivariate Logistic regression indicated that Bismuth-Corlett type Ⅰ-Ⅲ (P=0.009), hemi-hepatectomy and extended resection (P=0.001),T1 and T2 patients without vascular invasion (T2 vs. T1:OR=1.43 (0.61-3.35),P=0.413;T3 vs. T1:OR=2.57 (1.03-6.41), P=0.010;T4 vs. T1, OR=3.77 (1.37-10.38), P<0.01) were more likely to obtain R0 resection. Preoperative bilirubin,Child-Pugh grade,tumor size,surgical margin,T stage,N stage,nerve infiltration and Edmondson grade were independent prognostic factors for OS and DFS of hilar cholangiocarcinoma patients without distant metastasis. Conclusions: Radical surgical resection is necessary to prolong the long-term survival of hilar cholangiocarcinoma patients. Hemi-hepatectomy and extended resection,regional lymph node dissection and combined vascular resection if necessary,can improve R0 resection rate.

[Early to mid-term clinical outcomes of aortic valve repair in patients with bicuspid aortic insufficiency].

Objective: To examine the early to mid-term clinical outcomes of aortic valve repair in patients with bicuspid aortic insufficiency. Methods: This is a retrospective cohort study. The clinical data of 124 patients with BAV insufficiency who underwent aortic valve repair from January 2017 to June 2023 in the Department of Cardiovascular Surgery at Fuwai Hospital were analyzed retrospectively. There were 117 males and 7 females with an age of (38.1±12.7) years (range: 14 to 65 years). Depending on whether the aortic sinus was replaced or not, surgical approaches were divided into valve sparing root replacement (reimplantation, remodeling, modified remodeling) and isolated aortic valve repair (annuloplasty, isolated aortic valve leaflet repair). Perioperative and follow-up data were collected. Kaplan-Meier method was used to plot the curves of survival rate, free recurrence rate of massive aortic valve insufficiency and free re-operation rate, and Log-rank test was used for comparison between groups. Results: Among the surgeries, there were 47 cases of reimplantation, 8 cases of remodeling, 8 cases of modified remodeling, 48 cases of aortic annuloplasty (external annuloplasty in 22 cases, CV-0 annuloplasty in 26 cases), and 13 cases of isolated leaflet repair. Leaflet plication was the most used leaflet repair technique, used in 103 patients. The cardiopulmonary bypass time was (133.7±56.9) minutes (range: 48 to 461 minutes), and aortic cross-clamp time was (103.8±47.8) minutes (range: 25 to 306 minutes), with no surgical mortality. All patients underwent outpatient or telephone follow-up. The cumulative follow-up time was 340.3 person-years and the mean follow-up time was (M (IQR)) 34.0 (25.5) months (range: 3 to 76 months). The 5-year survival rate was 98.4%, the 5-year freedom from significant insufficiency rate was 93.4% and the 5-year freedom from aortic valve reoperation rate was 95.6%. The subgroup analysis revealed a significantly better freedom from the significant insufficiency rate in the aortic valve annular reduction group compared to the non-reduction group (P<0.01). Conclusions: Aortic valve repair in patients with bicuspid aortic insufficiency could obtain steady early to mid-term outcomes. Aortic annuloplasty can reduce the risk of recurrent aortic valve insufficiency in patients undergoing aortic repair.

[Long-term outcomes of intravascular ultrasound-guided drug-eluting stents implantation in patients with acute coronary syndrome: ULTIMATE ACS subgroup].

Objective: To explore the long-term effects of intravascular ultrasound (IVUS) guidance on patients with acute coronary syndrome (ACS) undergoing drug-eluting stents (DES) implantation. Methods: Data used in this study derived from ULTIMATE trial, which was a prospective, multicenter, randomized study. A total of 1 448 all-comer patients were enrolled between 2014 August and 2017 May. Primary endpoint of this study was target vessel failure (TVF) at 3 years, including cardiac death, target-vessel-related myocardial infarction, and clinically-driven target vessel revascularization. Results: ACS was present in 1 136 (78.5%) patients, and 3-year clinical follow-up was available in 1 423 patients (98.3%). TVF in the ACS group was 9.6% (109/1 136), which was significantly higher than 4.5% (14/312) in the non-ACS group (log-rank P=0.005). There were 109 TVFs in the ACS patients, with 7.6% (43/569) TVFs in the IVUS group and 11.6% (66/567) TVFs in the angiography group (log-rank P=0.019). Moreover, patients with optimal IVUS guidance were associated with a lower risk of 3-year TVF compared to those with suboptimal IVUS results (5.4% (16/296) vs. 9.9% (27/273),log-rank P=0.041). Conclusions: This ULTIMATE-ACS subgroup analysis showed that ACS patients undergoing DES implantation were associated with a higher risk of 3-year TVF. More importantly, the risk of TVF could be significantly decreased through IVUS guidance in patients with ACS, especially in those who had an IVUS-defined optimal procedure.

MRI-based bone marrow radiomics for predicting cytogenetic abnormalities in multiple myeloma.

AIM: To develop a radiomics signature applied to magnetic resonance imaging (MRI)-images to predict cytogenetic abnormalities in multiple myeloma (MM). MATERIALS AND METHODS: Patients with newly diagnosed MM were enrolled retrospectively from March 2019 to September 2022. They were categorised into the high-risk cytogenetics (HRC) group and standard-risk cytogenetics (SRC) group. The patients were allocated randomly at a ratio of 7:3 into training and validation cohorts. Volumes of interest (VOI) was drawn manually on fat suppression T2-weighted imaging (FS-T2WI) and copied to the same location of the T1-weighted imaging (T1WI) sequence. Radiomics features were extracted from two sequences and selected by reproducibility and redundant analysis. The least absolute shrinkage selection operation (LASSO) algorithm was applied to build the radiomics signatures. The performance of the radiomics signatures to distinguish HRC with SRC was evaluated by ROC curves. The area under the curve (AUC), specificity, and sensitivity were also calculated. RESULTS: A total of 105 MM patients were enrolled in this study. The four and 11 most significant and relevant features were selected separately from T1WI and FS-T2WI sequences to build the radiomics signatures based on the training cohort. Compared to the T1WI sequence, the radiomics signature based on the FS-T2WI sequence achieved better performance with AUCs of 0.896 and 0.729 in the training and validation cohorts respectively. A sensitivity of 0.833, specificity of 0.667, and Youden index of 0.500 were achieved for the FS-T2WI radiomics signature in the validation cohort. CONCLUSIONS: The radiomics signature based on MRI provides a non-invasive and convenient tool to predict cytogenetic abnormalities in MM patients.

[Exploring the factors affecting music-related quality of life in post-lingual deaf adults with cochlear implants].

Objective: To observe the feelings of listening to music and the importance of music in the daily life of post-lingual deaf adults with cochlear implants, and to explore the relevant influencing factors. Methods: This was a cross-sectional survey study. From January 2021 to August 2021,the Music-Related Quality of Life Scale was used to evaluate the music needs and music experiences of 63 post-lingual deaf adults who met the inclusion criteria, including 27 males and 36 females, aged (40.7±12.3) years, at the time of surgery (36.8±13.1) years, and with a preoperative hearing aid ineffective time of (3.9±5.8) years. Indicators analyzed included age, duration of ineffective preoperative hearing aid wear, preoperative music preference, duration of postoperative cochlear implant use, current hearing aid modality, and auditory rehabilitation outcomes. Whether the six factors mentioned above constituted an influence on the subjects' music listening was investigated using SPSS 25.0 statistical software. Results: All of the observations in the scale were correlated with a single factor. The two sub-dimensions of music experience section were related to the effect of auditory rehabilitation. In the importance section, the effect of auditory rehabilitation was the influential factor of the dimension of "participation importance", and the preoperative enjoyment of music was the relevant influential factor of the dimension of "perceived importance". There was a significant difference between the groups when they were grouped by the above factors (P value<0.05), while there was no statistically significance between the groups when they were grouped by other factors (P value>0.05). Conclusions: Post-lingual deaf adults show the need and attempt to listen to music after cochlear implantation. The effectiveness of auditory rehabilitation and the degree of music preference preoperatively are two important factors that influence music listening in implant recipients. Once the level of auditory communication has been restored to a certain degree, it is important to pay more attention to the needs of music for implant recipients and train them in time, especially for those with music preferences preoperatively.

[Diagnosis status and genetic characteristics analysis of Fanconi anemia in China].

Objective: To analyze the clinical and molecular diagnostic status of Fanconi anemia (FA) in China. Methods: The General situation, clinical manifestations and chromosome breakage test and genetic test results of 107 pediatric FA cases registered in the Chinese Blood and Marrow Transplantation Registry Group (CBMTRG) and the Chinese Children Blood and Marrow Transplantation Registry Group (CCBMTRG) from August 2009 to January 2022 were analyzed retrospectively. Children with FANCA gene variants were divided into mild and severe groups based on the type of variant, and Wilcoxon-test was used to compare the phenotypic differences between groups. Results: Of the 176 registered FA patients, 69 (39.2%) cases were excluded due to lack of definitive genetic diagnosis results, and the remaining 107 children from 15 hospitals were included in the study, including 70 males and 37 females. The age at transplantation treatment were 6 (4, 9) years. The enrolled children were involved in 10 pathogenic genes, including 89 cases of FANCA gene, 7 cases of FANCG gene, 3 cases of FANCB gene, 2 cases of FANCE gene and 1 case each of FANCC, FANCD1, FANCD2, FANCF, FANCJ, and FANCN gene. Compound heterozygous or homozygous of loss-of-function variants account for 69.2% (72/104). Loss-of-function variants account for 79.2% (141/178) in FANCA gene variants, and 20.8% (37/178) were large exon deletions. Fifty-five children (51.4%) had chromosome breakage test records, with a positive rate of 81.8% (45/55). There were 172 congenital malformations in 80 children.Café-au-Lait spots (16.3%, 28/172), thumb deformities (16.3%,28/172), polydactyly (13.9%, 24/172), and short stature (12.2%, 21/172) were the most common congenital malformations in Chinese children with FA. No significant difference was found in the number of congenital malformations between children with severe (50 cases) and mild FANCA variants (26 cases) (Z=-1.33, P=0.185). Conclusions: FANCA gene is the main pathogenic gene in children with FA, where the detection of its exon deletion should be strengthened clinically. There were no phenotypic differences among children with different types of FANCA variants. Chromosome break test is helpful to determine the pathogenicity of variants, but its accuracy needs to be improved.

The J-shape Association between Total Bilirubin and Stroke in Older Patients with Obstructive Sleep Apnea Syndrome: A Multicenter Study.

OBJECTIVES: To explore the relationship between total bilirubin (TBil) and stroke risk in older patients with obstructive sleep apnea syndrome (OSAS). METHODS: A total of 1,007 patients with OSAS without stroke history aged ≥ 60 years and with complete serum TBil records were enrolled in this study. The median follow-up was 42 months. Participants were divided into four groups based on the quartile of the baseline serum TBil concentration. Multivariate Cox proportional hazards analysis and restricted cubic spline (RCS) were used to investigate the association of TBil with the incidence of new-onset stroke. RESULTS: The PRIMARY part: the third quantile TBil level group had the lowest prevalence of stroke among the four groups. The RCS functions depicted a J-type curve relationship between TBil (3.3-33.3 µmol/L) and stroke (nonlinear P < 0.05). When the TBil level was in the range of 3.3 to 11.5 µmol/L, the possible protective influence of bilirubin against stroke in patients with OSAS enhanced with an increasing TBil level. However, when the TBil level exceeded 11.5 µmol/L and gradually increased, the effect of TBil on stroke risk became more and more pronounced. The SECONDARY part: for every 1 µmol/L increase in TBil levels in the range of 11.5 to 33.3 µmol/L, the risk of stroke in patients with OSAS increased by 16.2% (P < 0.001). In addition, there was a higher risk in women with OSAS (hazard ratio (HR)=1.292, 95% confidence interval (95%CI): 1.093-1.528; P = 0.003). Moreover, an increased TBil level alone was significantly associated with stroke in subjects aged < 75 years (HR: 1.190, 95%CI: 1.069-1.324), patients with mild-to-moderate OSAS (HR: 1.215, 95%CI: 1.083-1.364), and individuals without atrial fibrillation (AF) (HR: 1.179, 95%CI: 1.083-1.285) within a TBil level in the range of 11.5 to 33.3 µmol/L. CONCLUSIONS: Both lower and higher bilirubin levels may increase the risk of stroke in older persons with OSAS, and there was a J-type dose-response relationship. The risk of stroke was lowest when the TBil level was approximately 11.5 µmol/L.

Discriminating minimal residual disease status in multiple myeloma based on MRI: utility of radiomics and comparison of machine-learning methods.

AIM: To explore the possibility of discriminating minimal residual disease (MRD) status in multiple myeloma (MM) based on magnetic resonance imaging (MRI) and identify optimal machine-learning methods to optimise the clinical treatment regimen. MATERIALS AND METHODS: A total of 83 patients were analysed retrospectively. They were divided randomly into training and validation cohorts. The regions of interest were segmented and radiomics features were extracted and analysed on two sequences, including T1-weighted imaging (WI) and fat saturated (FS)-T2WI, and then radiomics models were built in the training cohort and evaluated in the validation cohort. Clinical characteristics were calculated to build a traditional model. A combined model was also built using the clinical characteristics and radiomics features. Classification accuracy was assessed using area under the curve (AUC) and F1 score. RESULTS: In the training cohort, only the bone marrow (BM) infiltrate ratio (p=0.005) was retained after univariate and multivariable logistic regression analysis. In T1WI, the linear support vector machine (SVM) achieved the best performance compared to other classifiers, with AUCs of 0.811 and 0.708 and F1 scores of 0.792 and 0.696 in the training and validation cohorts, respectively. Similarly, in FS-T2WI sequence, linear SVM achieved the best performance with AUCs of 0.833 and 0.800 and F1 score of 0.833 and 0.800. The combined model constructed by the FS-T2WI-linear SVM and BM infiltrate ratio outperformed the traditional model (p=0.050 and 0.012, Delong test), but showed no significant difference compared with the radiomics model (p=0.798 and 0.855). CONCLUSION: The linear SVM-based machine-learning method can offer a non-invasive tool for discriminating MRD status in MM.

[Pathological features and immune microenvironment in HER-2 intratumoral heterogeneous breast cancers].

Objective: To observe the clinical pathology features, and immune microenvironment of HER-2 intratumoral heterogeneity breast cancer. Methods: Thirty cases of HER-2 intratumoral heterogeneous breast cancer were retrospectively analyzed in Tianjin Medical University Cancer Institute and Hospital from November 2017 to June 2020. HER-2 expression was detected by immunohistochemistry and verified by dual color silver-enhanced in-situ hybridization (D-SISH). HER-2 intratumoral positive and negative regions were divided. The pathological characteristics, subtype, and the level of tumor infiltrating lymphocytes (TILs) and the expression of programmed cell death-ligand 1 (PD-L1) were evaluated respectively. Results: The proportion of HER-2 positive cells of the breast cancer ranged from 10% to 90%. The pathological type was mainly invasive non-special typecarcinoma. Six cases presented different pathological types between HER-2 positive and negative regions. The HER-2-positive areas included 2 cases of carcinoma with apocrine differentiation, and the negative areas included 2 cases of invasive micropapillary carcinoma, 1 case of invasive papillary carcinoma, and 1 case of carcinoma with apocrine differentiation. In HER-2 positive regions, 17 cases were Luminal B and 13 cases were HER-2 overexpressed types. There were 22 cases of Luminal B and 8 cases of triple negative tumors in the HER-2 negative areas. The levels of TILs in HER-2 positive and negative areas accounted for 53.3% (16/30) and 26.7% (8/30), respectively, with a statistically significant difference (P=0.035). The positive expression of PD-L1 in HER-2 positive area and HER-2 negative area were 6 cases and 9 cases, respectively. Among 8 cases with HER-2 negative regions containing triple negative components, 4 cases were positive for PD-L1 expression. Conclusions: In the case of HER-2 intratumoral heterogeneity, it is necessary to pay attention to both HER-2 positive and negative regions, and evaluate subtype separately as far as possible. For HER-2 intratumoral heterogeneous breast cancer containing triple negative components, the treatment mode can be optimized by refining the intratumoral expression of PD-L1.

Modifiable predictors of type 2 diabetes mellitus and roles of insulin resistance and ß-cell function over a 6-year study and 30-year follow-up.

PURPOSE: This study aimed to examine the modifiable predictors of T2DM and the roles of insulin resistance (IR) and ß-cell function over a 6-year study and 30-year follow-up. METHODS: A total of 462 non-diabetic participants, 282 with impaired glucose tolerance (IGT), and 180 with normal glucose tolerance (NGT) were enrolled in this analysis. The Matsuda IR index and area under the curve of insulin-to-glucose ratio (AUCI/G-R) were used as IR and ß-cell function indices in the analysis. RESULTS: In all participants, multivariable analysis showed that BMI, glucose status, Matsuda IR index and systolic blood pressure (SBP) at baseline were independently associated with an increased risk of T2DM over 30 years, whereas lifestyle intervention and AUCI/G-R were inversely associated with this risk. The predictive effect of the Matsuda IR index and AUCI/G-R in participants with IGT was consistent with the results of all participants, whereas in those with NGT, only the Matsuda IR index, not the AUCI/G-R, predicted the development of T2DM (HR = 1.42, 95% CI 1.07-1.89 vs HR = 1.09, 95% CI 0.76-1.56). The predictive effect of the Matsuda IR index on T2DM existed even in participants with BMI < 25 (p = 0.049). CONCLUSION: The modifiable predictors of T2DM in Chinese adults were high BMI, hypertension, mild hyperglycaemia, IR, and ß-cell dysfunction. Both IR and ß-cell function contributed to the development of T2DM in the long term; however, IR remains the initial and long-standing key risk factor for T2DM.

[Analysis of risk factors and prognosis of cytomegalovirus infection post umbilical cord blood stem cell transplantation in children with primary immunodeficiency diseases].

Objective: To investigate the risk factors and outcomes of cytomegalovirus (CMV) infection post umbilical cord blood stem cell transplantation (UCBT) in children with primary immunodeficiency diseases (PID). Methods: Clinical data of 143 PID children who received UCBT in the Children's Hospital of Fudan University from January 2015 to June 2020 were collected retrospectively. CMV-DNA in the plasma was surveilled once or twice a week within 100 days post-UCBT. According to the CMV-DNA test results, children were divided into the CMV-infected group and the CMV-uninfected group. The incidence and risk factors of CMV infection were analyzed. At 1-month post-UCBT, the absolute lymphocyte count, ratio of lymphocyte subsets and immunoglobulin levels were compared between those whose CMV infection developed 1-month later post-UCBT and those not. Mann-Whitney U test and chi-squared test were used for comparision between groups. Kaplan-Meier survival analysis was used to analyze the impact of CMV infection on survival. Results: Among 143 patients, there were 113 males and 30 females, with a age of 14 (8, 27) months at UCBT. Chronic granulomatosis disease (n=49), very-early-onset inflammatory bowel disease (n=43) and severe combined immunodefiency (n=29) were the three main kinds of PID. The rate of CMV infection was 21.7% (31/143), and the time of infection occurring was 44 (31, 49) days post-UCBT. The incidence of recurrent CMV infection was 4.2% (6/143) and refractory CMV infection was 4.9% (7/143).There was no significant difference in the first time CMV-DNA copy and peak CMV-DNA copy during treatment between the recurrent CMV infection group and the non-recurrent CMV infection group (32.8 (18.3, 63.1)×106 vs. 22.5 (13.2, 31.9)×106 copies/L, Z=-0.95, P=0.340;35.2 (20.2, 54.6)×106 vs. 28.4 (24.1, 53.5)×106copies/L, Z=-0.10, P=0.920), so were those between the refractory CMV infection group and non-refractory CMV infection group (21.8 (13.1, 32.2)×106 vs. 25.9 (14.2, 12.2)×106copies/L, Z=-1.04, P=0.299; 47.7 (27.9, 77.6)×106 vs. 27.7 (19.7,51.8)×106copies/L, Z=-1.49, P=0.137). The CMV-infected group accepted more reduced-intensity conditioning (RIC) regimen than the CMV-uninfected group (45.2% (14/31) vs. 25.0% (28/112), χ2=4.76, P<0.05). The rate of CMV-seropositive recipients and Ⅱ-Ⅳ acute graft versus host diseases (aGVHD) are significantly higher in the CMV-infected group than the CMV-uninfected group (100% (31/31) vs. 78.6% (88/112), 64.5% (20/31) vs. 26.8% (30/112), χ2=7.98,15.20, both P<0.05). The follow-up time was 31.6 (13.2, 45.9) months, CMV infection had no effect on overall survival (OS) rate (χ2=0.02, P=0.843). There was significant difference in the survival rate among three groups of refractory CMV infection, non-refractory CMV infection and the CMV-uninfected (4/7 vs.95.8% (23/24) vs. 86.6% (97/112), χ2=5.91, P=0.037), while there was no significant difference in the survival rate among three groups of recurrent CMV infection, non-recurrent CMV infection and the CMV-uninfected (5/6 vs. 88.0% (22/25) vs. 86.6% (97/112), χ2=0.43, P=0.896). Children who developed CMV infection after 30 days post-UCBT had lower absolute count and rate of CD4+ T cells and immunoglobulin G (IgG) level than those in the CMV-uninfected group (124.1 (81.5, 167.6) ×106 vs. 175.5 (108.3, 257.2) ×106/L, 0.240 (0.164, 0.404) vs. 0.376 (0.222, 0.469), 9.3 (6.2, 14.7) vs. 13.6 (10.7, 16.4) g/L, Z=-2.48, -2.12,-2.47, all P<0.05), but have higher rate of CD8+T cells than those in CMV-uninfected group (0.418 (0.281, 0.624) vs. 0.249 (0.154, 0.434), Z=-2.56, P=0.010). Conclusions: RIC regimen, grade Ⅱ-Ⅳ aGVHD and CMV-seropositive recipients are the main risk factors associated with CMV infection in PID patients post-UCBT. Survival rate of children with refractory CMV infection after UCBT is reduced. Immune reconstitution in children after UCBT should be regularly monitored, and frequency of CMV-DNA monitoring should be increased for children with delayed immune reconstitution.

[The diagnostic potential of Golgi protein 73 for cirrhosis in patients with chronic hepatitis C].

Objective: To explore the diagnostic value and model of serum Golgi protein 73 (GP73) in patients with hepatitis C cirrhosis. Methods: 271 cases with chronic hepatitis C virus infection who were treated in the Fifth Medical Center of PLA General Hospital from January 2010 to December 2017 were retrospectively collected as the research objects, including 126 cases with hepatitis and 145 cases with liver cirrhosis. Serum GP73 and liver stiffness measurement (LSM) based on transient elastography test were performed in all patients. Simultaneously, blood routine, liver function, coagulation function and other related indicators were collected. GP73 diagnostic efficiency for liver cirrhosis was evaluated by receiver operating characteristic curve (ROC). GP73 diagnostic value was clarified after comparison with aspartate aminotransferase/platelet ratio index (APRI), FIB-4 index (FIB-4) and LSM. Compensated hepatitis C virus-related cirrhosis diagnostic model based on serological index was established by logistic regression analysis. Results: The area under the receiver operating characteristic curve (AUC) of GP73, LSM, FIB-4 and APRI in the diagnosis of compensated hepatitis C virus-related cirrhosis were 0.923, 0.839, 0.836 and 0.800 respectively, and GP73 had the best diagnostic efficiency (P <0.001). LSM and GP73 combined use had improved the diagnostic sensitivity of cirrhosis to 97.24%. Multivariate logistic regression analysis revealed that GP73, age, and platelets were independent predictors of cirrhosis.Compensated hepatitis C virus-related cirrhosis diagnostic model (GAP) was established based on the result: LogitP=1/[1+exp(6.145+0.013×platelet-0.059×age-0.059×GP73)].AUC model for diagnosing compensated liver cirrhosis was 0.944, and the optimal cut-off value was 0.56, with sensitivity and specificity of 84.03% and 92.06%, respectively, and the diagnostic efficiency of this model was better than that of APRI, FIB-4, LSM and GP73 alone (P<0.05). Conclusion: GP73 is a reliable serum biomarker for the diagnosis of compensated hepatitis C virus-related cirrhosis. The GAP diagnostic model based on GP73, platelet count, and age can further improve the diagnostic efficiency and help to diagnose patients with compensated hepatitis C virus-related cirrhosis.

[The role of respiratory therapy in respiratory rehabilitation of critically ill patients].

The job description of respiratory therapists can cover emergency room, intensive care unit (ICU), post-ICU ward and specialized wards. Therefore, patient-centered respiratory rehabilitation in critically ill patients includes prevention of admission to ICU, respiratory care during ICU, and respiratory care after ICU. Respiratory therapists evaluate, diagnose and treat patients' respiratory function, forming a closed-loop management scheme of prevention, evaluation, treatment, reassessment, and adjustment.

[Efficacy and safety of neoadjuvant immunotherapy for hepatocellular carcinoma].

Objective: To study the surgical safety and efficacy of preoperative neoadjuvant therapy with immune checkpoint inhibitors combined with anti-angiogenic drugs in patients with China liver cancer staging(CNLC)-Ⅱb and Ⅲa resectable hepatocellular carcinoma. Methods: The data of 129 patients with Ⅱb and Ⅲa hepatocellular carcinoma who underwent surgery at the First Affiliated Hospital of Nanjing Medical University from January 2018 to December 2020 were analyzed. All patients were divided into two groups: the neoadjuvant therapy group(n=14,13 males and 1 female,aged (55.4±12.6)years(range:34 to 75 years)) received immune combined targeted therapy before surgery,immune checkpoint inhibitor camrelizumab was administered intravenously at a dose of 200 mg each time,every 2 weeks for 3 cycles,anti-angiogenesis drug apatinib was taken orally and continuously with a dose of 250 mg for 3 weeks and the conventional surgery group(n=115,103 males and 12 females,aged (55.8±12.0)years(range:21 to 83 years)) did not receive antitumor systemic therapy before surgery. There were 3 patients with CNLC-Ⅱb,11 with CNLC-Ⅲa in the neoadjuvant group;28 patients with CNLC-Ⅱb,87 with CNLC-Ⅲa in the conventional group. Student's t test or rank-sum test was used to compare the differences between two groups for quantitative data, Fisher's exact probability method was used to compare the differences of proportions between two groups, and Log-rank test was used to compare survival differences between two groups. Results: The 1-year recurrence rate in the neoadjuvant group was 42.9%,and the 1-year recurrence rate in the conventional group was 64.0%,with a statistically significant difference between the two groups(χ²=3.850,P=0.050);The 1-year survival rate in the neoadjuvant group was 100% and that in the conventional group was 74.2%,with a statistically significant difference between the two groups(χ²=5.170,P=0.023). According to the stratified analysis of the number of tumors,for single tumor,the 1-year recurrence rate in the neoadjuvant group was 25.0%,and that in the conventional surgery group was 71.0%,and the difference between the two groups was statistically significant(χ²=5.280, P=0.022). For multiple tumors, the 1-year recurrence rate in the neoadjuvant group was 66.7%,and the 1-year recurrence rate in the conventional surgery group was 58.9%,with no significant difference between the two groups(χ²=0.110,P=0.736). The operative time,intraoperative blood loss,and postoperative hospital stay in the neoadjuvant group were similar to those in the conventional group,and their differences were not statistically significant. Conclusions: Immune checkpoint inhibitors combined with anti-angiogenic targeted drugs as a neoadjuvant therapy for resectable hepatocellular carcinoma can reduce the 1-year recurrence rate and improve the 1-year survival rate,especially for those with solitary tumor. Limited by the sample size of the neoadjuvant group,the safety of immune combined targeted therapy before surgery cannot be observed more comprehensively,and further studies will be explored.

Association of Fear of Falling With Cognition and Physical Function in Community-Dwelling Older Adults.

BACKGROUND: Fear of falling (FOF) might be associated with physical and cognitive function, but there is a lack of understanding of the specific relationship between the three variables. OBJECTIVES: The aim of this study was to accurately investigate the association of FOF with cognitive and physical function in community-dwelling older adults. METHODS: Six hundred sixty-nine older adults (>60 years old) participated in this study. A self-report questionnaire collected information about demographic characteristics, lifestyle, and behavioral habits. FOF was evaluated through the Shortened Version of the Falls Efficacy Scale International. Global cognitive function and the subdomains of cognitive function (including memory, visual-spatial, language, attention, and executive function) were assessed using the Montreal Cognitive Assessment scale, the Auditory Verbal Learning Test, the Clock Drawing Test (CDT), the Verbal Fluency Test, and the Trail Making Test. Subjective memory complaints were assessed using the Subjective Memory Complaints Questionnaire. Physical function was evaluated by measuring muscle strength and balance ability, and muscle strength was indicated by hand grip strength. In contrast, balance was assessed using the Timed Up and Go (TUG) Test. RESULTS: After adjustment for potential confounding factors, the linear or ordinal regression analysis showed that the values of hand grip strength, Montreal Cognitive Assessment, Auditory Verbal Learning Test, and CDT were significantly and negatively correlated with the score of FOF. On the other hand, Subjective Memory Complaints Questionnaire and TUG Test values showed significant positive correlations with FOF scores. Moreover, compared with other cognitive or physical measures, the CDT and TUG Test values showed a greater association with the FOF scores. DISCUSSION: Low subjective or objective cognitive ability and low physical function, especially low visuospatial and balance ability, were positively associated with the risk of FOF in a community-dwelling older population.

[The relationship between insulin resistance and risk of long-term mortality in people without diabetes: a 30-year follow-up of the Daqing Diabetes Study].

Objective: To determine whether insulin resistance is associated with all-cause mortality in subjects without diabetes. Methods: A total of 505 participants without diabetes, 198 with normal glucose tolerance (NGT) and 307 with impaired glucose tolerance (IGT), were recruited from the Daqing Diabetes Study. The participants were followed up for 30 years. They were stratified into three groups (tertiles) according to baseline homeostasis model assessment of insulin resistance(HOMA-IR) levels, as the HOMA-IR 0, the HOMA-IR 1 and the HOMA-IR 2 groups, to assess the predictive effect of insulin resistance on risk of all-cause mortality. Results: During the 30-year follow-up, 52, 56 and 78 participants died across the three HOMA-IR groups, respectively. The corresponding mortality per 1 000 person-years (95%CI) were 12.12 (9.56-15.01), 13.10 (10.46-16.03) and 19.91 (16.73-23.15), respectively. Participants in the HOMA-IR 2 group had a significantly higher risk of death than those in the HOMA-IR 0 group after adjustment of age, sex and smoking status (HR=1.97,95%CI 1.38-2.81, P<0.001). Cox analyses showed that a one standard deviation increase in HOMA-IR was associated with a 22% increase in the mortality after adjustment of potential confounders (HR=1.22, 95%CI 1.08-1.39, P=0.002). Conclusions: Insulin resistance is associated with increased risk of all-cause death in Chinese people without diabetes, suggesting that improving insulin resistance could be beneficial for people without diabetic in reducing risk of long-term all-cause mortality.