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OBJECTIVE: The aim of the study was to systematically review and meta-analyze the available data on changes in the hormonal profile of postmenopausal women treated with hormone replacement therapy (HRT). MATERIALS AND METHODS: Full-text articles published up to April 30, 2021, were searched through PUBMED, EMBASE, the Cochrane library and Web of Science (WOS) databases and were screened strictly according to inclusion criteria. Randomized clinical trials and case control studies were enrolled. Studies not reporting steroid serum levels or not providing a control group were excluded from the analysis. Studies enrolling women with genetic defects or severe chronic systemic diseases were excluded. Data are expressed as standardized mean differences (SMDs) with 95% confidence intervals (CIs). Random effect models were used for the meta-analysis. RESULTS: HRT administration increases estradiol (E2) and reduces follicle stimulating hormone (FSH) serum levels compared with pre-treatment. Their changes are evident when oral and transdermal HRT are administered, while vaginal HRT not. No significant effect on E2 and FSH was found between 6 and 12 months, as well as between 12 and 24 months. No significant effect on E2 and FSH was shown between different regimes. No difference was observed between different HRT regarding their effect on lipid profiles, breast pain and vaginal bleeding, but oral estrogen combined synthetic progestin caused a reduction in sex hormone-binding globulin (SHGB). CONCLUSIONS: The review suggested oral and transdermal HRT could lead to a rise in E2 serum levels and a decrease in FSH. The types and doses of HRT did not seem to modify the E2 and FSH level. Also, oral estrogen combined synthetic progestin could cause a reduction in SHGB. This might be crucial when choosing the best possible treatment for each patient individually taking into consideration if potential benefits outweigh the risks. [ABSTRACT FROM AUTHOR]

The article has been corrected in the Funding section to acknowledge support from the National Natural Science Foundation of China (No. 81671421).

Cyclic purine nucleotides are important signal transduction molecules across all domains of life. 3',5'-cyclic di-adenosine monophosphate (c-di-AMP) has roles in both prokaryotes and eukaryotes, while the signals that adjust intracellular c-di-AMP and the molecular machinery enabling a network-wide homeostatic response remain largely unknown. Here, we present evidence for an acetyl phosphate (AcP)-governed network responsible for c-di-AMP homeostasis through two distinct substrates, the diadenylate cyclase D NA i ntegrity s canning protein (DisA) and its newly identified transcriptional repressor, DasR. Correspondingly, we found that AcP-induced acetylation exerts these regulatory actions by disrupting protein multimerization, thus impairing c-di-AMP synthesis via K66 acetylation of DisA. Conversely, the transcriptional inhibition of disA was relieved during DasR acetylation at K78. These findings establish a pivotal physiological role for AcP as a mediator to balance c-di-AMP homeostasis. Further studies revealed that acetylated DisA and DasR undergo conformational changes that play crucial roles in differentiation. Considering the broad distribution of AcP-induced acetylation in response to environmental stress, as well as the high conservation of the identified key sites, we propose that this unique regulation of c-di-AMP homeostasis may constitute a fundamental property of central circuits in Actinobacteria and thus the global control of cellular physiology.IMPORTANCESince the identification of c-di-AMP is required for bacterial growth and cellular physiology, a major challenge is the cell signals and stimuli that feed into the decision-making process of c-di-AMP concentration and how that information is integrated into the regulatory pathways. Using the bacterium Saccharopolyspora erythraea as a model, we established that AcP-dependent acetylation of the diadenylate cyclase DisA and its newly identified transcriptional repressor DasR is involved in coordinating environmental and intracellular signals, which are crucial for c-di-AMP homeostasis. Specifically, DisA acetylated at K66 directly inactivates its diadenylate cyclase activity, hence the production of c-di-AMP, whereas DasR acetylation at K78 leads to increased disA expression and c-di-AMP levels. Thus, AcP represents an essential molecular switch in c-di-AMP maintenance, responding to environmental changes and possibly hampering efficient development. Therefore, AcP-mediated posttranslational processes constitute a network beyond the usual and well-characterized synthetase/hydrolase governing c-di-AMP homeostasis., Competing Interests: The authors declare no conflict of interest.

Mycophenolate mofetil (MMF) is commonly utilized for the treatment of neuromyelitis optica spectrum disorders (NMOSD). However, a subset of patients experience significant gastrointestinal (GI) adverse effects following MMF administration. The present study aims to elucidate the underlying mechanisms of MMF-induced GI toxicity in NMOSD. Utilizing a vancomycin-treated mouse model, we compiled a comprehensive data set to investigate the microbiome and metabolome in the GI tract to elucidate the mechanisms of MMF GI toxicity. Furthermore, we enrolled 17 female NMOSD patients receiving MMF, who were stratified into non-diarrhea NMOSD and diarrhea NMOSD (DNM) groups, in addition to 12 healthy controls. The gut microbiota of stool samples was analyzed using 16S rRNA gene sequencing. Vancomycin administration prevented weight loss and tissue injury caused by MMF, affecting colon metabolomes and microbiomes. Bacterial β-glucuronidase from Bacteroidetes and Firmicutes was linked to intestinal tissue damage. The DNM group showed higher alpha diversity and increased levels of Firmicutes and Proteobacteria. The β-glucuronidase produced by Firmicutes may be important in causing gastrointestinal side effects from MMF in NMOSD treatment, providing useful information for future research on MMF., Importance: Neuromyelitis optica spectrum disorder (NMOSD) patients frequently endure severe consequences like paralysis and blindness. Mycophenolate mofetil (MMF) effectively addresses these issues, but its usage is hindered by gastrointestinal (GI) complications. Through uncovering the intricate interplay among MMF, gut microbiota, and metabolic pathways, this study identifies specific gut bacteria responsible for metabolizing MMF into a potentially harmful form, thus contributing to GI side effects. These findings not only deepen our comprehension of MMF toxicity but also propose potential strategies, such as inhibiting these bacteria, to mitigate these adverse effects. This insight holds broader implications for minimizing complications in NMOSD patients undergoing MMF therapy., Competing Interests: The authors declare no conflict of interest.

Objective: To investigate the efficacy and safety of protein A immunoadsorption (PAIA) combined with rituximab (RTX) in highly sensitized patients who underwent haplo-hematopoietic stem cell transplantation (haplo-HSCT) . Methods: The clinical data of 56 highly sensitized patients treated with PAIA and RTX before haplo-HSCT at the First Affiliated Hospital of Soochow University and Soochow Hopes Hematonosis Hospital between March 2021 and June 2023 were retrospectively analyzed. The number of human leukocyte antigen (HLA) antibody types and the mean fluorescence intensity (MFI), humoral immunity, adverse reactions during adsorption, and survival within 100 days before and after adsorption were measured. Results: After receiving the PAIA treatment, the median MFI of patients containing only HLA Ⅰ antibodies decreased from 7 859 (3 209-12 444) to 3 719 (0-8 275) ( P <0.001), and the median MFI of HLA Ⅰ+Ⅱ antibodies decreased from 5 476 (1 977-12 382) to 3 714 (0-11 074) ( P =0.035). The median MFI of patients with positive anti-donor-specific antibodies decreased from 8 779 (2 697-18 659) to 4 524 (0-15 989) ( P <0.001). The number of HLA-A, B, C, DR, and DQ antibodies in all patients decreased after the PAIA treatment, and the differences were statistically significant (A, B, C, DR: P <0.001, DQ: P <0.01). The humoral immune monitoring before and after the PAIA treatment showed a significant decrease in the number of IgG and complement C3 ( P <0.001 and P =0.002, respectively). Forty-four patients underwent HLA antibody monitoring after transplantation, and the overall MFI and number of antibody types decreased. However, five patients developed new antibodies with low MFI, and nine patients continued to have high MFI. The overall survival, disease-free survival, non-recurrent mortality, and cumulative recurrence rates at 100 days post-transplantation were 83.8%, 80.2%, 16.1%, and 4.5%, respectively. Conclusions: The combination of PAIA and RTX has a certain therapeutic effect and good safety in the desensitization treatment of highly sensitive patients before haplo-HSCT.

Objective: To compare the point-of-care assays for tear matrix metalloproteinase 9 (MMP-9) using domestic and InflammaDry kits, and to evaluate the feasibility of diagnosing dry eye with the domestic kit. Methods: It was a cross-sectional study. Thirty dry eye patients and 30 age-and sex-matched normal volunteers were continuously enrolled in this cross-sectional study from June 2022 to July 2022. Both domestic and InflammaDry kits were used to detect the tear MMP-9 levels. The positive rates were recorded for qualitative analysis, and the gray ratios of bands (the gray value of detection bands to that of control bands) were collected for quantitative analysis. The correlations of MMP-9 levels with age, ocular surface disease index, fluorescence tear break-up time, tear meniscus height, Schirmer's Ⅰ test score, corneal fluorescein staining score, and meibomian gland dropout were analyzed. The Mann-Whitney U test, paired Chi-square test, Kappa test, and Spearman's correlation coefficient were used for statistical analysis. Results: There were 14 males and 16 females (30 eyes) in the control group, and their age was (39.37±19.55) years. In the dry eye group, 11 males and 19 females (30 eyes), aged (46.87±17.85) years, had moderate to severe dry eye. The positive rates of MMP-9 in tear fluid were significantly different between dry eye patients (InflammaDry: 86.67%; domestic kit: 70.00%) and controls (InflammaDry: 16.67%, P <0.001; domestic kit: 6.67%, P <0.001). Although the sensitivity of the domestic kit was lower than that of the InflammaDry kit (70.0% vs . 86.7%, P =0.001), the specificity was higher (93.3% vs . 83.3%, P =0.001). In dry eye patients, the positive coincidence rate was 80.7% (21/26), the negative coincidence rate was 100% (4/4), and the total coincidence rate was 83.3% (25/30), with no significant difference between the two kits (McNemar test: χ 2 =3.20, P >0.05), and the results of both kits were consistent ( Kappa =0.001). The Spearman's correlation coefficient showed the gray ratios using both kits were positively correlated with the corneal fluorescein staining score (InflammaDry: P =0.001). The Spearman's correlation coefficient showed the gray ratios using both kits were positively correlated with the corneal fluorescein staining score (InflammaDry: ρ =0.48, P <0.05; domestic kit: ρ =0.52, P =0.003). Conclusion: The performances of the domestic and InflammaDry kits are consistent in the point-of-care assay for tear MMP-9, and the domestic kit has lower sensitivity but higher specificity.

Objective: To study the morphological pattern of single oblique complex crown fracture and its relative location to periodontal hard tissues from a three-dimensional perspective by using cone-beam CT, which provides a more intuitive and comprehensive understanding for the pathological features and rules of single oblique complex crown fracture. Methods: Primary cone-beam CT images of 56 maxillary permanent anterior teeth with oblique complex crown root fractures were collected from the Department of Integrated Emergency Dental Care, Capital Medical University School of Stomatology during January 2015 to January 2019. Fracture pattern, fracture angle, fracture depth, fracture width, and the relative location of the fracture line to the crest of the adjacent alveolar ridge were retrospectively analyzed. Independent samples t -test was used to compare the differences in angle, depth and width of fractures between sexes and tooth locations, as well as the pre-and post-fracture crown-to-root ratios between different tooth locations. Then the affected teeth were divided into juvenile group (≤18 years), young group (19-34 years) and middle-aged and elderly group (≥35 years). One-way ANOVA was applied to compare the differences in angle, depth and width of fracture between age groups, and Fisher exact test to compare the differences in fracture pattern of the teeth and the relative position of the fracture line to the crest of the adjacent alveolar ridge. Results: There were 35 males and 21 females in 56 patients, aged (28.2±13.2) years. Among the 56 affected teeth, forty-six were maxillary central incisors and 10 were lateral incisors. According to the patients' age and growing stage, they could be divided into the juvenile group (19 cases), the young group (14 cases), and the middle-aged and elderly group (23 cases). Forty-six (82%) affected teeth had an S-shaped fracture pattern, and ten (18%) had a diagonal pattern, in which the fracture angle of the S-shaped fracture line (47.85°±10.02°) was significantly greater than that of the diagonal line (28.30°±8.07°) ( P< 0.001). The fracture nadir was flush with or below the top of the alveolar crest in 98% (55/56) of cases. The fracture depth was significantly greater in the juvenile group [(1.75±0.73) mm] than in the young group [(1.21±0.68) mm]( P= 0.042) and in the middle-aged and elderly group [(1.12±0.90) mm] ( P= 0.001). The width of fractures among 56 patients was (4.75±1.44) mm, which had no statistically significant differences between different age, sex and tooth location groups ( P >0.05). There were no statistically significant differences in the crown-to-root ratios after fracture of maxillary central incisors (1.18±0.13) compared to maxillary lateral incisors (1.14±0.20) ( t= 1.90, P= 0.373). Conclusions: The fracture patterns of single oblique complex crown fracture were mainly S-shaped and oblique alignment; the fracture nadir was mostly located within 2.0 mm below the palatal alveolar crest.

Introduction: Several complications of decompensated cirrhosis are believed to result from increased intestinal permeability. However, little is known about the relationship between mucosal bacteria and epithelial permeability in cirrhosis. We aimed to assess epithelial permeability and associations with mucosal bacteria in patients with compensated cirrhosis., Methods: We obtained duodenal tissue biopsies from patients with compensated cirrhosis and controls. Patients were excluded if they used antibiotics or immunosuppression. The composition of mucosal microbiota was determined by 16S rRNA gene sequencing and epithelial permeability by transepithelial electrical resistance (TEER) and tight junction protein expression., Results: We studied 24 patients with compensated cirrhosis and 20 controls. Patients with cirrhosis were older than controls (62 vs 52 years, P = 0.02) but had a similar number of extrahepatic comorbidities (2.2 vs 1.4, P = 0.13). Patients with compensated cirrhosis had lower duodenal TEER (i.e., increased epithelial permeability; 13.3 Ω/cm 2 ± 3.4 vs 18.9 Ω/cm 2 ± 7.1; P = 0.004). Patients with compensated cirrhosis trended toward a distinct mucosal microbiota community structure relative to controls ( P = 0.09). Clustering analysis identified two unique enterotypes. These enterotypes differed in bacterial composition and also TEER. A beta-binomial model found 13 individual bacteria associated with TEER, including Lactobacillus and Bifidobacterium taxa. Thirty-six taxa were associated with tight junction protein expression, including Lactobacillus and Bifidobacterium., Discussion: Compensated cirrhosis is characterized by increased duodenal epithelial permeability with a distinct mucosal microbial community. Intriguingly, bacteria previously associated with health were protective of duodenal permeability., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of The American College of Gastroenterology.)

Objective: To evaluate the clinical outcomes of excimer laser atherectomy (ELA) in the treatment of diabetic foot with below-the-knee(BTK) lesions. Methods: The clinical data of 11 patients with diabetic foot with BTK lesions who underwent ELA at Department of Vascular Surgery,Zhongshan Hospital of Fudan University and Department of Vascular and Wound Treatment Center,Jinshan Hospital of Fudan University from September 2019 to May 2021 were retrospectively analyzed.There were 10 males and 1 female,aged 70.5 years(range:41 to 83 years).There were 20 lesions in 12 limbs,including 19 chronic total occlusion.All of the limbs were classified as Rutherford class 5 and suffered ulceration.The surgical efficacy,complications and ankle brachial index(ABI) after operation were record. Results: All patients underwent the operation successfully,the technical success rate was 12/12.No distal embolization,flow-limiting dissection,perforation or bailout stenting was occurred.The follow-up period was 8.2 months(range:3 to 13 months).The ABI increased from 0.58(range:0.24 to 1.57) before operation to 0.88(range:0.68 to 1.05) after operation.At 3 months after the operation,1 limb (1/12) underwent endovascular operation again due to restenosis,ulcers were healed in 5 limbs(5/12),and no amputation (limb/toe),death or loss of follow-up patients.Six months after the operation,2 patients were lost to follow-up and 2 died,ulcers were healed in 6 limbs(6/8),1 limb (1/8) underwent toe amputation due to prolonged healing of ulcers of toe. Conclusion: ELA is feasible and effective in the treatment of DF with BTK lesions,providing a new option of debulking atherectomy in such a group of patients.

Aims: In response to the COVID-19 pandemic, guidelines on reduced fractionation for patients treated with curative-intent radiotherapy were published, aimed at reducing the number of hospital attendances and potential exposure of vulnerable patients to minimise the risk of COVID-19 infection. We describe the changes that took place in the management of patients with stage I-III lung cancer from April to October 2020., Materials and Methods: Lung Radiotherapy during the COVID-19 Pandemic (COVID-RT Lung) is a prospective multicentre UK cohort study. The inclusion criteria were: patients with stage I-III lung cancer referred for and/or treated with radical radiotherapy between 2nd April and 2nd October 2020. Patients who had had a change in their management and those who continued with standard management were included. Data on demographics, COVID-19 diagnosis, diagnostic work-up, radiotherapy and systemic treatment were collected and reported as counts and percentages. Patient characteristics associated with a change in treatment were analysed using multivariable binary logistic regression., Results: In total, 1553 patients were included (median age 72 years, 49% female); 93 (12%) had a change to their diagnostic investigation and 528 (34%) had a change to their treatment from their centre's standard of care as a result of the COVID-19 pandemic. Age ≥70 years, male gender and stage III disease were associated with a change in treatment on multivariable analysis. Patients who had their treatment changed had a median of 15 fractions of radiotherapy compared with a median of 20 fractions in those who did not have their treatment changed. Low rates of COVID-19 infection were seen during or after radiotherapy, with only 21 patients (1.4%) developing the disease., Conclusions: The COVID-19 pandemic resulted in changes to patient treatment in line with national recommendations. The main change was an increase in hypofractionation. Further work is ongoing to analyse the impact of these changes on patient outcomes., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Objective: To investigate the relationship between plasma levels of complements before treatment and the clinicopathological feathers and prognoses of diffuse large B-cell lymphoma (DLBCL) patients treated with Rituximab (R)-CHOP or R-CHOP-like therapy. Methods: The clinicopathological data of 105 DLBCL patients treated in cancer Hospital of Chinese Academy of Medical Sciences from 2010 to 2016 were collected. The plasma samples from 105 DLBCL patients treated with R-CHOP or R-CHOP-like therapy and 80 healthy controls were used to detect 34 complement levels before treatment by utilizing antibody microarray. The relationship between plasma levels of complements and the clinicopathological feathers and prognosis of DLBCL patients were analyzed. Results: The signal values of C1QA and CR1L in patients with international prognostic index (IPI) scores of 3-5 were 1 261.43±138.9 and 2 214.69±98.58, respectively, higher than 950.79±80.19 and 984.67±121.79 in patients with IPI scores of 0~2 (both P <0.05). The levels of C1QA and CR1L in the non-complete response (CR) group were 1 165.43±98.56 and 2 263.13±145.63, respectively, higher than 914.70±100.77 and 1 821.34±84.68 in the CR group (both P <0.05). Cox regression analysis showed that elevated C1QA signal value was associated with poor progression-free survival (PFS) and poor overall survival (OS) (PFS: HR =2.063, 95% CI : 1.220-3.489, P =0.007; OS: HR =2.23, 95% CI: 1.036~4.798, P =0.040). After IPI correction by Cox multivariate model, the elevated C1QA signal value was still correlated with poor PFS ( HR =1.765, 95% CI 1.034~3.013, P =0.037). Conclusions: The baseline plasma levels of C1QA and CR1L are correlated with IPI scores and therapeutic effects of DLBCL patients treated with R-CHOP. The baseline plasma level of C1QA has a certain predictive value for the prognostic evaluation of DLBCL.