Identification of a specific APOE transcript and functional elements associated with Alzheimer's disease.

BACKGROUND: The APOE gene is the strongest genetic risk factor for late-onset Alzheimer's Disease (LOAD). However, the gene regulatory mechanisms at this locus remain incompletely characterized. METHODS: To identify novel AD-linked functional elements within the APOE locus, we integrated SNP variants with multi-omics data from human postmortem brains including 2,179 RNA-seq samples from 3 brain regions and two ancestries (European and African), 667 DNA methylation samples, and ChIP-seq samples. Additionally, we plotted the expression trajectory of APOE transcripts in human brains during development. RESULTS: We identified an AD-linked APOE transcript (jxn1.2.2) particularly observed in the dorsolateral prefrontal cortex (DLPFC). The APOE jxn1.2.2 transcript is associated with brain neuropathological features, cognitive impairment, and the presence of the APOE4 allele in DLPFC. We prioritized two independent functional SNPs (rs157580 and rs439401) significantly associated with jxn1.2.2 transcript abundance and DNA methylation levels. These SNPs are located within active chromatin regions and affect brain-related transcription factor-binding affinities. The two SNPs shared effects on the jxn1.2.2 transcript between European and African ethnic groups. CONCLUSION: The novel APOE functional elements provide potential therapeutic targets with mechanistic insight into the disease etiology.

Large-scale analysis of structural brain asymmetries during neurodevelopment: Associations with age and sex in 4265 children and adolescents.

Only a small number of studies have assessed structural differences between the two hemispheres during childhood and adolescence. However, the existing findings lack consistency or are restricted to a particular brain region, a specific brain feature, or a relatively narrow age range. Here, we investigated associations between brain asymmetry and age as well as sex in one of the largest pediatric samples to date (n = 4265), aged 1-18 years, scanned at 69 sites participating in the ENIGMA (Enhancing NeuroImaging Genetics through Meta-Analysis) consortium. Our study revealed that significant brain asymmetries already exist in childhood, but their magnitude and direction depend on the brain region examined and the morphometric measurement used (cortical volume or thickness, regional surface area, or subcortical volume). With respect to effects of age, some asymmetries became weaker over time while others became stronger; sometimes they even reversed direction. With respect to sex differences, the total number of regions exhibiting significant asymmetries was larger in females than in males, while the total number of measurements indicating significant asymmetries was larger in males (as we obtained more than one measurement per cortical region). The magnitude of the significant asymmetries was also greater in males. However, effect sizes for both age effects and sex differences were small. Taken together, these findings suggest that cerebral asymmetries are an inherent organizational pattern of the brain that manifests early in life. Overall, brain asymmetry appears to be relatively stable throughout childhood and adolescence, with some differential effects in males and females.

Generation of a human induced pluripotent stem cell line JHUi004-A with heterozygous mutation for spinocerebellar ataxia type 12 using genome editing.

Spinocerebellar ataxia type 12 (SCA12) is caused by a CAG expansion mutation in PPP2R2B, a gene encoding brain-specific regulatory units of protein phosphatase 2A (PP2A); while normal alleles carry 4 to 31 triplets, the disease alleles carry 43 to 78 triplets. Here, by CRISPR/Cas9n genome editing, we have generated a human heterozygous SCA12 iPSC line with 73 triplets for the mutant allele. The heterozygous SCA12 iPSCs have normal karyotype, express pluripotency markers and are able to differentiate into the three germ layers.

Role of Bß1 overexpression in the pathogenesis of SCA12.

BACKGROUND: Spinocerebellar ataxia type 12 (SCA12) is a neurodegenerative disease caused by a CAG/CTG repeat expansion at the PPP2R2B locus. OBJECTIVE: We investigated how the CAG repeat expansion within the PPP2R2B 7B7D transcript influences the expression of Bß1 and a potential protein containing a long polyserine tract. METHODS: Transcript and protein expression were measured using quantitative PCR (qPCR) Role of Bß1 overexpression in the pathogenesis of SCA12 and Western blot, respectively, in an SK-N-MC cell model that overexpresses the full-length PPP2R2B 7B7D transcript. The apoptotic effect of a protein containing a long polyserine tract on SK-N-MC cells was evaluated using caspase 3/7 activity. RESULTS: The CAG repeat expansion increases the expression of the PPP2R2B 7B7D transcript, as well as Bß1 protein, in an SK-N-MC cell model in which the full-length PPP2R2B 7B7D transcript is overexpressed. The CAG repeat expansion within the 7B7D transcript is translated into a long polyserine tract that triggers apoptosis in SK-N-MC cells. CONCLUSIONS: The SCA12 mutation leads to overexpression of PPP2R2B Bß1 and to expression of a protein containing a long polyserine tract; both these effects potentially contribute to SCA12 pathogenesis. © 2024 International Parkinson and Movement Disorder Society.

[Clinical analysis of 14 patients aged ≤ 50 years with high-risk multiple myeloma treated with allogeneic hematopoietic stem cell transplantation].

Objective: To evaluate the efficacy of allogeneic hematopoietic stem cell transplantation (allo-HSCT) in young patients with high-risk multiple myeloma (HRMM) and analyzed the factors affecting patient prognosis. Methods: In this retrospective study, we analyzed the clinical data of 14 patients with HRMM with cytogenetic abnormalities or high-risk biological factors who underwent allo-HSCT at the Hematopoietic Stem Cell Transplantation Center of the Institute of Hematology & Blood Diseases Hospital between November 2016 and November 2022. Results: There were seven males and seven females included in the study, with a median age of 39.5 (31-50) years at the time of allo-HSCT. The median number of treatment lines before transplantation was 2 (1-6) . Before allo-HSCT, 42.9% (6/14) of the patients did not achieve complete remission, while 35.7% (5/14) of the patients achieved measurable residual disease positivity. After transplantation, all patients were evaluated for their treatment response, and the overall response rate was 100% (14/14) . All 14 patients successfully underwent allo-HSCT, with median engraftment times for neutrophils and platelets of 11 (10-14) days and 13 (9-103) days, respectively. Acute grade Ⅱ-Ⅳ graft-versus-host disease (GVHD) occurred in five patients (35.7%) , and two patients (14.3%) developed moderate-to-severe chronic GVHD. The median follow-up time after allo-HSCT was 18.93 (4.10-72.53) months, with an expected 2-year transplant-related mortality rate of 7.1% (95% CI 0%-21.1%) and an expected 2-year overall survival rate of 92.9% (95% CI 80.3%-100.0%) . Moreover, the expected 1-year and 2-year progression-free survival rates were 92.9% (95% CI 80.3%-100.0%) and 66.0% (95% CI 39.4%-100.0%) , respectively, and the 2-year cumulative incidence of relapse was 28.9% (95% CI 0%-56.7%) . Upfront allo-HSCT following complete remission after induced therapy and the presence of chronic GVHD might be favorable prognostic factors. Conclusion: allo-HSCT is an effective treatment for improving the prognosis of young patients with HRMM.

Huntington disease-like 2: insight into neurodegeneration from an African disease.

Huntington disease (HD)-like 2 (HDL2) is a rare genetic disease caused by an expanded trinucleotide repeat in the JPH3 gene (encoding junctophilin 3) that shows remarkable clinical similarity to HD. To date, HDL2 has been reported only in patients with definite or probable African ancestry. A single haplotype background is shared by patients with HDL2 from different populations, supporting a common African origin for the expansion mutation. Nevertheless, outside South Africa, reports of patients with HDL2 in Africa are scarce, probably owing to limited clinical services across the continent. Systematic comparisons of HDL2 and HD have revealed closely overlapping motor, cognitive and psychiatric features and similar patterns of cerebral and striatal atrophy. The pathogenesis of HDL2 remains unclear but it is proposed to occur through several mechanisms, including loss of protein function and RNA and/or protein toxicity. This Review summarizes our current knowledge of this African-specific HD phenocopy and highlights key areas of overlap between HDL2 and HD. Given the aforementioned similarities in clinical phenotype and pathology, an improved understanding of HDL2 could provide novel insights into HD and other neurodegenerative and/or trinucleotide repeat expansion disorders.

Associations between Various Sleep-Wake-Related Indicators and Nutritional Status in Community-Dwelling Older Adults: The Yilan Study, Taiwan.

OBJECTIVES: To elucidate the relationship between various sleep-wake-related indicators and nutritional status. DESIGN: Cross-sectional study. SETTING: Community-based survey between 2017 and 2022 in Yilan City, Taiwan. PARTICIPANTS: 1,905 community-dwelling older adults aged ≥65 years. MEASUREMENTS: Nutritional status was evaluated using the Mini Nutritional Assessment, and participants were classified into normal nutritional status and undernutrition groups. Regarding sleep-wake-related indicators, specific items or component scores of the Pittsburgh Sleep Quality Index were used to assess sleep-wake schedule, subjective sleep quality, sleep latency, sleep duration, habitual sleep efficiency, presence of sleep disturbances, hypnotic use, and dysfunction in maintaining enthusiasm. The 5-item Athens Insomnia Scale and the Epworth Sleepiness Scale were used to evaluate insomnia and excessive daytime sleepiness, respectively. RESULTS: Of the 1,905 participants, the mean age was 75.6±7.1, with 52.2% being ≥75 years old, 58.9% were women, and 11.4% had undernutrition. After controlling for covariates, short sleepers were less likely to have undernutrition (OR: 0.63; 95% CI: 0.41-0.97); in contrast, long sleepers were more likely to exhibit undernutrition (OR: 1.52; 95% CI: 1.06-2.17). In addition, poor habitual sleep efficiency (OR:1.69; 95% CI:1.15-2.50), taking hypnotics in the past month (OR: 1.58; 95% CI: 1.12-2.24), and dysfunction in maintaining enthusiasm (OR: 1.93; 95% CI: 1.24-2.99) were associated with increased risk of undernutrition. CONCLUSIONS: Among older adults, various sleep-wake-related indicators differed in their relationships with nutritional status. Specific sleep-wake disturbances may indicate undernutrition in this population.

Identification of a specific APOE transcript and functional elements associated with Alzheimer's disease.

INTRODUCTION: The APOE gene is the strongest genetic risk factor for late-onset Alzheimer's Disease (LOAD). However, the gene regulatory mechanisms at this locus have not been fully characterized. METHODS: To identify novel AD-linked functional elements within the APOE locus, we integrated SNP variants with RNA-seq, DNA methylation, and ChIP-seq data from human postmortem brains. RESULTS: We identified an AD-linked APOE transcript (jxn1.2.2) observed in the dorsolateral prefrontal cortex (DLPFC). The APOE jxn1.2.2 transcript is associated with brain neuropathological features in DLPFC. We prioritized an independent functional SNP, rs157580, significantly associated with jxn1.2.2 transcript abundance and DNA methylation levels. rs157580 is located within active chromatin regions and predicted to affect brain-related transcriptional factors binding affinity. rs157580 shared the effects on the jxn1.2.2 transcript between European and African ethnic groups. DISCUSSION: The novel APOE functional elements provide potential therapeutic targets with mechanistic insight into the disease's etiology.

[Intelligent intensive care unit design:will it be accessible in the future].

ICU is an essential location for critically ill patients to receive comprehensive diagnosis and treatment. However, the high intensity of ICU clinical work, the difficulty of diagnosis and treatment, and the poor humanistic environment require us to accelerate the pace of ICU reform. Therefore, the use of advanced technology to create an intelligent ICU department is imperative. The modern ICU is rich in electronic data and can collect a large amount of patient data during routine care, making it an ideal place to deploy intelligent digital platforms. The vast amounts of data generated by monitoring systems and electronic medical records provide fertile ground for the development of more accurate predictive models, better Clinical Decision Support System and more personalized diagnosis and treatment. At the same time, a well-designed and well-arranged ICU department will greatly enhance the patient's sense of occupancy, as well as increase the professional pride and sense of belonging. Therefore, the establishment of an intelligent ICU department is the only way for ICU to enter the fast lane of development, which will also have a profound impact on the development of ICU.

Bidirectional Transcription at the PPP2R2B Gene Locus in Spinocerebellar Ataxia Type 12.

BACKGROUND: Spinocerebellar ataxia type 12 (SCA12) is a neurodegenerative disease caused by expansion of a CAG repeat in the PPP2R2B gene. OBJECTIVE: In this study, we tested the hypothesis that the PPP2R2B antisense (PPP2R2B-AS1) transcript containing a CUG repeat is expressed and contributes to SCA12 pathogenesis. METHODS: Expression of PPP2R2B-AS1 transcript was detected in SCA12 human induced pluripotent stem cells (iPSCs), iPSC-derived NGN2 neurons, and SCA12 knock-in mouse brains using strand-specific reverse transcription polymerase chain reaction. The tendency of expanded PPP2R2B-AS1 (expPPP2R2B-AS1) RNA to form foci, a marker of toxic processes involving mutant RNAs, was examined in SCA12 cell models by fluorescence in situ hybridization. The apoptotic effect of expPPP2R2B-AS1 transcripts on SK-N-MC neuroblastoma cells was evaluated by caspase 3/7 activity. Western blot was used to examine the expression of repeat associated non-ATG-initiated translation of expPPP2R2B-AS1 transcript in SK-N-MC cells. RESULTS: The repeat region in the PPP2R2B gene locus is bidirectionally transcribed in SCA12 iPSCs, iPSC-derived NGN2 neurons, and SCA12 mouse brains. Transfected expPPP2R2B-AS1 transcripts induce apoptosis in SK-N-MC cells, and the apoptotic effect may be mediated, at least in part, by the RNA secondary structure. The expPPP2R2B-AS1 transcripts form CUG RNA foci in SK-N-MC cells. expPPP2R2B-AS1 transcript is translated in the alanine open reading frame (ORF) via repeat-associated non-ATG translation, which is diminished by single-nucleotide interruptions within the CUG repeat and MBNL1 overexpression. CONCLUSIONS: These findings suggest that PPP2R2B-AS1 contributes to SCA12 pathogenesis and may therefore provide a novel therapeutic target for the disease. © 2023 International Parkinson and Movement Disorder Society.

[Clinical features and related factors of invasive pulmonary aspergillosis in patients with acute exacerbation of chronic obstructive pulmonary disease].

Objective: To study the clinical features and related factors of invasive pulmonary aspergillosis (IPA) in patients with acute exacerbation of chronic obstructive pulmonary disease (AECOPD). Methods: This retrospective study enrolled patients hospitalized for AECOPD in ten tertiary hospitals of China from September 2017 to July 2021. AECOPD patients with IPA were included as case group, AECOPD patients without IPA were randomly selected as control group from the same hospitals and same hospitalization period as the patients with IPA using the random function in the software of Microsoft Excel 2003, at a ratio of 2∶1. The clinical characteristics, treatment and outcome were compared between the two groups. Binary logistic regression model was used to analyze the factors associated with IPA in AECOPD patients. Results: A total of 14 007 inpatients with AECOPD were included in this study, and 300 patients were confirmed to have IPA, with an incidence rate of 2.14%. According to the above matching method, 600 AECOPD patients without aspergillus infection were enrolled as the control group. The age of the case group and the control group were (72.5±9.7) and (73.5±10.3) years old, with 78.0%(n=234) male and 76.8%(n=461) male, respectively. There were no significant differences in age and gender composition between the two groups (all P>0.05). The prognosis of case group was significantly worse than that of the control group, with longer hospital stay [M(Q1,Q3)], [14 (10-20) d vs 11 (8-15) d, P<0.001], higher ICU admission rate [16.3% (49 case) vs 10.0% (60 case), P=0.006], higher in-hospital mortality [4.0% (12 cases) vs 1.3% (8 cases), P=0.011], and higher hospitalization costs (28 000 ¥ vs 13 700 ¥, P<0.001). The smoking index of the case group and proportions of patients with diabetes mellitus, chronic pulmonary heart disease in the case group were significantly higher than those in control group (all P<0.05). In terms of clinical features, the proportions of patients with cough, expectoration, purulent sputum, hemoptysis and fever in the case group were higher than those in the control group, the serum albumin was significantly lower than that in the control group, and the proportions of patients with bronchiectasis and pulmonary bullae on imaging were significantly higher than those in the control group (all P<0.05). Diabetes (OR=1.559, 95%CI: 1.084-2.243), chronic pulmonary heart disease (OR=1.476, 95%CI: 1.075-2.028), bronchiectasis (OR=1.506, 95%CI: 1.092-2.078), pulmonary bullae (OR=1.988, 95%CI: 1.475-2.678) and serum albumin<35 g/L (OR=1.786, 95%CI: 1.325-2.406) were the related factors of IPA in patients with AECOPD. Conclusions: The incidence of IPA in AECOPD patients is relatively high and the prognosis of these patients is worse. Diabetes, chronic pulmonary heart disease, bronchiectasis, pulmonary bulla, hypoproteinemia are the related factors of IPA in patients with AECOPD.

Cost-Effectiveness Analysis of 68Ga-DOTATATE PET/MRI in Radiotherapy Planning in Patients with Intermediate-Risk Meningioma.

BACKGROUND AND PURPOSE: While contrast-enhanced MR imaging is the criterion standard in meningioma diagnosis and treatment response assessment, gallium 68Ga-DOTATATE PET/MR imaging has increasingly demonstrated utility in meningioma diagnosis and management. Integrating 68Ga-DOTATATE PET/MR imaging in postsurgical radiation planning reduces the planning target volume and organ-at-risk dose. However, 68Ga-DOTATATE PET/MR imaging is not widely implemented in clinical practice due to higher perceived costs. Our study analyzes the cost-effectiveness of 68Ga-DOTATATE PET/MR imaging for postresection radiation therapy planning in patients with intermediate-risk meningioma. MATERIALS AND METHODS: We developed a decision-analytical model based on both recommended guidelines on meningioma management and our institutional experience. Markov models were implemented to estimate quality-adjusted life-years (QALY). Cost-effectiveness analyses with willingness-to-pay thresholds of $50,000/QALY and $100,000/QALY were performed from a societal perspective. Sensitivity analyses were conducted to validate the results. Model input values were based on published literature. RESULTS: The cost-effectiveness results demonstrated that 68Ga-DOTATATE PET/MR imaging yields higher QALY (5.47 versus 5.05) at a higher cost ($404,260 versus $395,535) compared with MR imaging alone. The incremental cost-effectiveness ratio analysis determined that 68Ga-DOTATATE PET/MR imaging is cost-effective at a willingness to pay of $50,000/QALY and $100,000/QALY. Furthermore, sensitivity analyses showed that 68Ga-DOTATATE PET/MR imaging is cost-effective at $50,000/QALY ($100,000/QALY) for specificity and sensitivity values above 76% (58%) and 53% (44%), respectively. CONCLUSIONS: 68Ga-DOTATATE PET/MR imaging as an adjunct imaging technique is cost-effective in postoperative treatment planning in patients with meningiomas. Most important, the model results show that the sensitivity and specificity cost-effective thresholds of 68Ga-DOTATATE PET/MR imaging could be attained in clinical practice.

Bidirectional transcription at the PPP2R2B gene locus in spinocerebellar ataxia type 12.

OBJECTIVE: Spinocerebellar ataxia type 12 (SCA12) is a neurodegenerative disease caused by expansion of a CAG repeat in the PPP2R2B gene . Here we tested the hypothesis that the PPP2R2B antisense ( PPP2R2B-AS1 ) transcript containing a CUG repeat is expressed and contributes to SCA12 pathogenesis. METHODS: Expression of PPP2R2B-AS1 transcript was detected in SCA12 human induced pluripotent stem cells (iPSCs), iPSC-derived NGN2 neurons, and SCA12 knock-in mouse brains using strand-specific RT-PCR (SS-RT-PCR). The tendency of expanded PPP2R2B-AS1 ( expPPP2R2B-AS1 ) RNA to form foci, a marker of toxic processes involving mutant RNAs, was examined in SCA12 cell models by fluorescence in situ hybridization. The toxic effect of expPPP2R2B-AS1 transcripts on SK-N-MC neuroblastoma cells was evaluated by caspase 3/7 activity. Western blot was used to examine the expression of repeat associated non-ATG-initiated (RAN) translation of expPPP2R2B-AS1 transcript in SK-N-MC cells. RESULTS: The repeat region in PPP2R2B gene locus is bidirectionally transcribed in SCA12 iPSCs, iPSC-derived NGN2 neurons, and SCA12 mouse brains. Transfected expPPP2R2B-AS1 transcripts are toxic to SK-N-MC cells, and the toxicity may be mediated, at least in part, by the RNA secondary structure. The expPPP2R2B-AS1 transcripts form CUG RNA foci in SK-N-MC cells. expPPP2R2B-AS1 transcript is translated in the Alanine ORF via repeat-associated non-ATG (RAN) translation, which is diminished by single nucleotide interruptions within the CUG repeat, and MBNL1 overexpression. INTERPRETATION: These findings suggest that PPP2R2B-AS1 contributes to SCA12 pathogenesis, and may therefore provide a novel therapeutic target for the disease.

[Effect of hyperandrogenism on pregnancy outcomes in women with polycystic ovary syndrome undergoing in vitro fertilization/intracytoplasmic sperm injection-embryo transfer].

Objective: To explore the effects of hyperandrogenism (HA) on pregnancy outcomes in women with polycystic ovary syndrome (PCOS) undergoing in vitro fertilization/intracytoplasmic sperm injection-embryo transfer (IVF/ICSI-ET). Methods: A retrospective study was conducted on infertile women with PCOS undergoing IVF/ICSI-ET from January 2017 to June 2021 in our center. Patients were divided into HA group and NON-HA group according to the levels of testosterone. Propensity score matching (PSM) was used to balance the influence of female age and IVF/ICSI-ET for patients with gonadotropin-releasing hormone (GnRH)antagonist protocol and GnRH agonist protocol, separately. After the PSM procedure, 191 cases in HA group and 382 cases in NON-HA group, were included. Hormone levels and pregnancy outcomes were compared in the two groups. Results: The female age was comparable in two groups [HA: (29.6±3.7) vs NON-HA: (29.5±3.6), P=0.665]. The basal luteinizing hormone [(10.82±6.73) vs (7.76±5.30) IU/L], testosterone [(3.27±0.97) vs (1.60±0.59) nmol/L], free androgen index (7.13 vs 2.77), anti-mullerian hormone [(11.37±5.74) vs (9.67±4.67) ng/ml], fasting glucose [(5.18±0.49) vs (5.06±0.42) mmol/L], 1h glucose [(9.34±2.42) vs (7.99±2.21) nmol/L], 2 h glucose [(7.66±2.17) vs (6.64±1.84) nmol/L], 2 h insulin [(129.81±145.49) vs (97.51±86.92) mU/L], total cholesterol [(5.35±0.89) vs (4.92±0.92) mmol/L], triglycerides [(1.55±1.28) vs (1.33±0.77) mmol/L], and low density lipoprotein cholesterol levels [(3.38±0.66) vs (3.14±0.71) mmol/L] were significantly higher in HA group, compared with NON-HA group (P<0.05). The initiated gonadotropin dose was higher in HA group than that in NON-HA group [(126.96±33.65) vs (137.60±38.12) U, P=0.001], but moderate-severe ovarian hyperstimulation syndrome (OHSS) rate was similar in two groups (P>0.05). The rates of implantation, clinical pregnancy, miscarriage, and live birth were comparable between the two groups (P>0.05). Also, in the subgroups, the rates of implantation, clinical pregnancy, live birth, and miscarriage were similar in HA group and NON-HA group. Conclusions: The risks of hormonal abnormality and glucose-lipid metabolic disorder were higher in PCOS women with HA, whereas satisfactory pregnancy outcomes could be achieved under proper ovarian stimulation undergoing IVF/ICSI-ET.

[Intelligent intensive care unit makes medicine more accessible].

In the past half century, critical care medicine has made rapid development, and the survival rate of critically ill patients has significantly improved. However, what does not match the rapid development of the specialty is that the infrastructure of intensive care unit (ICU) has gradually appeared weaknesses and the development of humanistic care in ICU has lagged. Accelerating the digital transformation of the medical industry will help to improve the existing difficulties. The application of 5G and artificial intelligence (AI) technology to build an intelligent ICU,focusing on improving patients' comfort by strengthening humanistic care,while solve the shortcomings of the critical care dimension, such as lack of human and material resources, low alarm accuracy, insufficient response speed and ability, to better meet the needs of society and improve the level of medical services and humanistic care for critical diseases. We will review the development of ICU history, clarify the necessity of intelligent ICU construction and the core issues to be solved after the construction of intelligent ICU. Three components of the construction of intelligent ICU will be needed: intelligent space and environment management, intelligent equipment and goods management, intelligent monitoring and diagnosis and treatment. Finally, the people-oriented diagnosis and treatment concept will be realized through intelligent ICU.

[Clinical update in critical care of pulmonary medicine 2022].

In this review, we outlined the clinical studies in critical care field of pulmonary medicine from October 1, 2021 to September 30, 2022. For critically ill patients, frailty before disease onset was a predictor of mortality with increasing ICU length of stay, and the complaints of dyspnea in intubated phase was independently associated with posttraumatic stress disorder. Compared with transbronchial lung biopsy (TBLB) for patients with acute hypoxemic respiratory failure, transbronchial lung cryobiopsy (TBLC) had a positive significance to in leading to an increased chance of establishing a more accurate diagnosis, which could significantly improve the patients' prognosis. M-ROSE (microbiological rapid on-site evaluation) had high diagnostic value for lower respiratory tract pathogens, and the application of M-ROSE in the ICU could contribute to promoting a decrease in patients' inflammation levels and reducing the mortality of patients with invasive mechanical ventilation. EIT (electrical impedance tomography), DPL (transpulmonary driving pressure) and DPaw (airway driving pressure) had excellent positive values on dynamic assessment, guiding individualized respiratory support and prognostic evaluation. In critically ill hospitalized patients with COVID-19 who had received invasive mechanical ventilation or extracorporeal membrane oxygenation, treatment with baricitinib compared with placebo (in combination with standard of care, including corticosteroids) might reduce mortality. Delayed antimicrobial treatment significantly increased the incidence of severe infection and the mortality of shock patients, however, timing of antimicrobial therapy and control of the source of infection was critical. NIV (non-invasive ventilation) alternating with high-flow nasal oxygen immediately after extubation significantly decreased the risk of reintubation and death compared with high-flow nasal oxygen alone in obese or overweight patients at high risk of extubation failure. The effect of Pes-guided positive end-expiratory pressure (PEEP), compared with empirical high PEEP, was associated with lower mortality for more severe acute respiratory distress syndrome (ARDS) ventilated patients (APACHE Ⅱ>27.5). Prone-positioning during veno-venous extracorporeal membrane oxygenation was safe and effective and was associated with a higher probability of surviving and being weaned-off extracorporeal membrane oxygenation at 90 days. Therefore, individualized respiratory support strategies based on dynamic monitoring and assessment were essential for critically ill patients.

Clinical significance of CA-125 in elderly patients with active pulmonary tuberculosis: A retrospective study.

OBJECTIVES: To assess the clinical significance of serum CA-125 levels in elderly patients with pulmonary tuberculosis (PTB). METHODS: We retrospectively analyzed 1613 participants-patients (aged ≥60 years) admitted to the Beijing Shijitan Hospital, Beijing, China from February 2015 to January 2021 and healthy participants, divided into 4 groups: PTB (group 1), pulmonary malignancies (group 2), pulmonary non-malignant diseases (group 3), and healthy participants (group 4). Data concerning demographics, physical examination findings, computed tomography, histopathological examination, and laboratory tests for Mycobacterium tuberculosis and serum CA-125 levels were collected and analyzed. RESULTS: There were 720 healthy individuals and 893 patients in the study. The median levels and abnormal rates of CA-125 in groups 1 (42.5, 57.3%) and 2 (34.4, 49.5%) were higher than those in groups 3 (21.1, 29.2%) and 4 (8.6, 0.4%) (p<0.05). The ordinal logistic regression analysis model revealed significant associations between CA-125 levels and PTB (OR and 95% confidence interval [CI]: 2.749 (1.876-4.027)), hypoproteinemia [OR and 95% CI: 1.519 (1.114-2.070)], serous effusion [OR and 95% CI: 7.364 (5.346-10.143)], pulmonary malignancy [OR and 95% CI: 2.206 (1.518-3.204)], respiratory failure [OR and 95% CI: 3.216 (2.087-4.956)], and cor pulmonale [OR and 95% CI: 2.990 (1.282-6.973)]. CONCLUSION: Although elevated CA-125 levels may serve as a potential marker for diagnosing PTB in the elderly, they are affected by multiple factors, including serous effusion. Hence, caution is warranted while using this marker.

[Analysis of HIV-1 genetic subtype and pretreatment drug resistance among men who have sex with men infected with HIV-1 from 19 cities of 6 provinces in China].

Objective: To investigate the distribution of HIV-1 genetic subtypes and pretreatment drug resistance (PDR) among men who have sex with men (MSM) from 19 cities of 6 provinces in China. Methods: From April to November 2019, 574 plasma samples of ART-naive HIV-1 infected MSM were collected from 19 cities in Hebei, Shandong, Jiangsu, Zhejiang, Fujian, and Guangdong provinces, total ribonucleic acid (RNA) was extracted and amplified the HIV-1 pol gene region by nested polymerase chain reaction (PCR) after reverse transcription. Then sequences were used to construct a phylogenetic tree to determine genetic subtypes and submitted to the Stanford drug resistance database for drug resistance analysis. Results: A total of 479 samples were successfully amplified by PCR. The HIV-1 genetic subtypes included CRF01_AE, CRF07_BC, B, CRF55_01B, CRF59_01B, CRF65_cpx, CRF103_01B, CRF67_01B, CRF68_01B and unrecognized subtype, which accounted for 43.4%, 36.3%, 6.3%, 5.9%, 0.8%, 0.8%, 0.4%, 0.4%, 0.2% and 5.5%, respectively. The distribution of genetic subtypes among provinces is statistically different (χ2=44.141, P<0.001). The overall PDR rate was 4.6% (22/479), the drug resistance rate of non-nucleoside reverse transcriptase inhibitors, nucleoside reverse transcriptase inhibitors, and protease inhibitors were 3.5% (17/479), 0.8% (4/479) and 0.2% (1/479), respectively. The PDR rate of recent infections was significantly higher than that of long-term infections (χ2=4.634, P=0.031). Conclusions: The HIV-1 genetic subtypes among MSM infected with HIV-1 from 19 cities of 6 provinces in China are diverse, and the distribution of subtypes is different among provinces. The overall PDR rate is low, while the PDR rate of recent infections was significantly higher than that of long-term infections, suggesting the surveillance of PDR in recent infections should be strengthened.

[Establishment and evaluation of a model for predicting ISUP pathological grade≥2 before radical prostatectomy].

Objective: Based on the 2014 version of the International Association of Urological Pathology (ISUP) pathological classification standards, a prediction model that can predict the pathological classification of ISUP ≥2 in patients with prostate cancer (PCa) before radical prostatectomy (RP) was established and evaluated. Methods: The clinical data of 171 patients who had undergone RP from January 2017 to September 2020 in the Second Affiliated Hospital of Soochow University and obtained postoperative pathological results of all specimens were retrospectively collected. The patients were 46-83 (70±7) years old. For patients with RP ISUP pathologic stage as the gold standard, according to the pathological grading is level 2 or higher is divided into two groups(42 patients with ISUP grade=1 and 129 patients with ISUP grade ≥2). the predictors of ISUP pathology grade ≥2 after RP were screened by logistics regression analysis, predictive models were established and ROC curves were used to evaluate the efficacy of each model in diagnosing RP with pathological grade ≥2, and comparisons were conducted by DeLong test. Results: Compared with patients with ISUP grade=1, patients with ISUP grade≥2 had higher prostate specific antigen (PSA) and prostate specific antigen density (PSAD) (14.21(8.57, 24.98)ng/ml vs 7.98(5.41, 12.54)ng/ml, 0.33(0.20, 0.74)µg.L-1.ml-1 vs 0.16(0.12, 0.24)µg.L-1.ml-1), lower prostate volume (PV) (48.62(34.17,73.99)ml vs 38.94(28.15,54.84)ml)(all P<0.05). Multi-parameter magnetic resonance imaging (mp-MRI) prostate imaging and reporting system (PI-RADS) score, the positive ratio of puncture needles and the pathological grade of puncture ISUP were also significantly different between the two groups (all P<0.05). The combined mp-MRI PI-RADS score (OR=3.337, 95%CI: 1.990-5.593, P<0.001) and puncture ISUP pathological grading (OR=4.041, 95%CI: 1.960-8.334, P<0.001) had the highest diagnostic efficacy for pathological grading ≥2 after RP (AUC=0.916, P<0.05). Conclusion: The combined mp-MRI PI-RADS score and puncture ISUP pathological grading had the highest diagnostic efficacy for pathological grading ≥2 after RP.

[Risk factors associated with in-hospital mortality in hospitalized patients with acute exacerbation of chronic obstructive pulmonary disease: a multicenter retrospective study].

Objective: To investigate the risk factors associated with in-hospital mortality in hospitalized patients with acute exacerbation of chronic obstructive pulmonary disease (AECOPD). Methods: A total of 6 668 patients hospitalized for AECOPD in seven tertiary hospitals from September 2017 to January 2021 were consecutively included, and clinical data related to medical history, laboratory tests, treatment and prognosis were collected, and patients were divided into death group and survival group according to whether they died during hospitalization. After univariate analysis, multivariate logistic regression analysis was then performed to explore the independent risk factors related to in-hospital mortality. Results: Among 6 668 patients hospitalized for AECOPD, 128 patients experienced in-hospital death, with a mortality rate of 1.9%. The mean age of the death group was (81±9) years, which was significantly older than that of the survival group ((72±11) years P<0.001). The proportion of patients in the AECOPD in-hospital death group with a combination of prolonged bed rest, hypertension, myocardial infarction within 3 months, cardiac insufficiency, chronic pulmonary heart disease, pneumonia, type 2 diabetes, venous thromboembolism (VTE), and chronic renal insufficiency was also significantly higher than in the survival group (all P<0.05) The median length of stay in the in-hospital death group was 18 d, which was significantly longer than that in the survival group (9 d, P<0.001), and the proportion of patients admitted to the ICU, receiving invasive mechanical ventilation and non-invasive mechanical ventilation was also significantly higher than that in the survival group (all P<0.05). The white blood cell count, glutamic transaminase, blood creatinine, calcitoninogen, C-reactive protein, D-dimer, N-terminal B-type natriuretic and Pseudomonas aeruginosa infection rates were significantly higher than those in the survival group (all P<0.05). Multifactorial analysis showed that age>80 years (OR=3.82, 95%CI 2.36 to 6.18, P<0.001), prolonged bed rest (OR=2.95, 95%CI: 1.79 to 4.86, P<0.001), chronic pulmonary heart disease (OR=1.85, 95%CI: 1.14 to 3.00, P=0.012), and pneumonia (OR=2.75, 95%CI: 1.65 to 4.60, P<0.001), invasive mechanical ventilation (OR=7.33, 95%CI: 4.40 to 12.21, P<0.001), noninvasive mechanical ventilation (OR=3.73, 95%CI: 2.30 to 6.04, P<0.001), anemia (OR=2.03. 95%CI: 1.21 to 3.42, P=0.008), and calcitoninogen>0.5 ng/ml (OR=2.38, 95%CI: 1.41 to 4.02, P=0.001) were independent risk factors for in-hospital mortality in patients with AECOPD. Conclusion: Advanced age (>80 years), prolonged bed rest, chronic pulmonary heart disease, pneumonia, invasive mechanical ventilation, noninvasive mechanical ventilation, anemia, and calcitoninogen>0.5 ng/ml were independent risk factors for in-hospital mortality in patients hospitalized with AECOPD.