Lower extremity function and cardiovascular disease risk in hemodialysis patients: A multicenter cross-sectional study.

Physical performance in hemodialysis patients declines and serves as a cardiovascular disease (CVD) incidence and mortality predictor. However, lower extremity function's role remains unclear. This study aimed to quantify the association between lower extremity function and CVD risk in hemodialysis patients. This was a multicenter cross-sectional study enrolling 868 participants (532 males, 336 females) from seven hemodialysis centers in Shanghai, China. Patients were divided into three groups per lower extremity function, evaluated by short physical performance battery (SPPB) scores: 0-6, 7-9, and 10-12. Upper extremity function was quantified through grip strength assessment. CVD risk was assessed using the Framingham Risk Score. Approximately 35% of hemodialysis patients had impaired lower extremity function (SPPB score < 10). Participants with high SPPB scores had stronger handgrip and lower Framingham CVD risk scores than those with low and moderate SPPB scores (p < 0.05). After adjusting clinical confounders, SPPB was independently associated with CVD risk, as a categorized variable (odds ratio: 0.577, 95% confidence interval [CI]: 0.388-0.857, p = 0.006) and as a continuous variable (odds ratio: 0.858, 95% CI: 0.772-0.953, p = 0.004). An SPPB score < 10 predicted an increased CVD risk (area under curve: 0.649, 95% CI: 0.599-0.699, p < 0.001). Causality between physical performance and CVD risk was not considered. Some upper limb results may not be generalizable to peritoneal dialysis and kidney transplant patients. Lower extremity function was significantly associated with CVD risk in hemodialysis patients. Further studies are needed to explore the long-term relationship between lower extremity function and CVD risk.

BI-7273, a BRD9 inhibitor, reduces lipid accumulation by downregulating the AKT/mTOR/SREBP1 signaling pathway.

Increases in de novo lipogenesis that disturbed lipid homeostasis and caused lipid accumulation are a major cause of NAFLD and obesity. SREBP1 is a crucial regulatory factor controlling the expression of rate-limiting enzymes of lipid synthesis. A reduction in SREBP1expression can reduce lipid accumulation. Thus, we utilized an SREBP1-luciferase-KI HEK293 cell line constructed by our lab to screen 200 kinds of epigenetic drugs for their ability to downregulate SREBP1expression. BI-7273, an inhibitor of bromodomain-containing protein 9 (BRD9), was screened and found to decrease SREBP1 expression. What is more, BI-7273 has been confirmed that it could reduce lipid accumulation in HepG2 cells by BODIPY staining, and significantly decrease the protein expression of SREBP1 and FASN. To explore the potential mechanism BI-7273 reducing lipid accumulation, RNA sequencing (RNA-seq) was performed and demonstrated that BI-7273 reduced lipid accumulation by downregulating the AKT/mTOR/SREBP1 pathway in vitro. Finally, these results were verified in NAFLD and obesity mouse model induced by high fat diet (HFD). The results indicated that BI-7273 could decrease mouse body weight and improve insulin sensitivity, but also exhibited a strong negative correlation with serum lipid levels, and also demonstrated that BI-7273 reduced lipid accumulation via AKT/mTOR/SREBP1 pathway in vivo. In conclusion, our results revealed that BI-7273 decreases lipid accumulation by downregulating the AKT/mTOR/SREBP1 pathway in vivo and in vitro. This is the first report demonstrating the protective effect of this BRD9 inhibitor against NAFLD and obesity. BRD9 may be a novel target for the discovery of effective drugs to treat lipid metabolism disorders.

Association of physical performance with cognitive impairment in middle-aged to older haemodialysis patients: a multicentre cross-sectional observational study.

OBJECTIVE: To determine the prevalence of cognitive impairment (CI) among middle-aged to older patients receiving maintenance haemodialysis (MHD) and to investigate the potential association between CI and physical performance. METHODS: This cross-sectional observational study enrolled participants aged 55-85 years who received MHD. Cognitive status was assessed using the Mini Mental State Examination (MMSE). Physical performance was measured by hand grip strength, the Timed Up and Go Test (TUGT) and the 4-m walking speed. Sociodemographic, clinical and laboratory parameters were recorded for each patient. RESULTS: The study included 592 patients (363 males); and of these, 126 (21.3%) were diagnosed with CI. Compared with patients with normal cognitive function, those with CI were significantly older and had significantly longer dialysis duration, lower educational level, higher Malnutrition Inflammation Score, higher depression and higher Charlson Comorbidity Index score. After adjustment for covariates, multiple regression analysis suggested that grip strength (odds ratio [OR] = 0.959, 95% confidence interval [CI] = 0.924, 0.996) and 4-m walking speed (OR = 0.161, 95% CI = 0.070, 0.368) were protective factors. TUGT (OR = 1.037, 95%CI = 1.003, 1.071) was a risk factor. CONCLUSION: Physical performance was correlated with CI and might be a significant indicator for the early identification of CI in middle-aged to older MHD patients.

Production and characterization of novel monoclonal antibodies against pathological human TDP-43 proteins.

The RNA/DNA-binding protein TDP-43 plays a pivotal role in the ubiquitinated inclusions characteristic of TDP-43 proteinopathies, including most cases of frontotemporal lobar degeneration (FTLD-TDP) and Alzheimer disease (AD). To understand the mechanisms of pathological TDP-43 processing and identify potential biomarkers, we generated novel phosphorylation-independent monoclonal antibodies (MAbs) using bacteria-expressed human full-length recombinant TDP-43. Remarkably, we identified a distinctive MAb, No. 9, targeting an epitope in amino acid (aa) region 311-360 of the C-terminus. This antibody showed preferential reactivity for pathological TDP-43 inclusions, with only mild reactivity for normal nuclear TDP-43. MAb No. 9 revealed more pathology in FTLD-TDP type A and type B brains and in AD brains compared to the commercial p409/410 MAb. Using synthetic phosphorylated peptides, we also obtained MAbs targeting the p409/410 epitope. Interestingly, MAb No. 14 was found to reveal additional pathology in AD compared to the commercial p409/410 MAb, specifically, TDP-43-immunopositive deposits with amyloid plaques in AD brains. These unique immunopositivities observed with MAbs No. 9 and No. 14 are likely attributed to their conformation-dependent binding to TDP-43 inclusions. We expect that this novel set of MAbs will prove valuable as tools for future patient-oriented investigations into TDP-43 proteinopathies.

BMSC-derived Exosomes Ameliorate Peritoneal Dialysis-associated Peritoneal Fibrosis via the Mir-27a-3p/TP53 Pathway.

OBJECTIVE: Peritoneal fibrosis (PF) is the main cause of declining efficiency and ultrafiltration failure of the peritoneum, which restricts the long-term application of peritoneal dialysis (PD). This study aimed to investigate the therapeutic effects and mechanisms of bone marrow mesenchymal stem cells-derived exosomes (BMSC-Exos) on PF in response to PD. METHODS: Small RNA sequencing analysis of BMSC-Exos was performed by second-generation sequencing. C57BL/6J mice were infused with 4.25% glucose-based peritoneal dialysis fluid (PDF) for 6 consecutive weeks to establish a PF model. A total of 36 mice were randomly divided into 6 groups: control group, 1.5% PDF group, 2.5% PDF group, 4.25% PDF group, BMSC-Exos treatment group, and BMSC-Exos+TP53 treatment group. Reverse transcription quantitative polymerase chain reaction (RT-qPCR) was performed to measure the expression level of miR-27a-3p in BMSC-Exos and peritoneum of mice treated with different concentrations of PDF. HE and Masson staining were performed to evaluate the extent of PF. The therapeutic potential of BMSC-Exos for PF was examined through pathological examination, RT-qPCR, Western blotting, and peritoneal function analyses. Epithelial-mesenchymal transition (EMT) of HMrSV5 was induced with 4.25% PDF. Cells were divided into control group, 4.25% PDF group, BMSC-Exos treatment group, and BMSC-Exos+TP53 treatment group. Cell Counting Kit-8 assay was used to measure cell viability, and transwell migration assay was used to verify the capacity of BMSC-Exos to inhibit EMT in HMrSV5 cells. RESULTS: Small RNA sequencing analysis showed that miR-27a-3p was highly expressed in BMSC-derived exosomes compared to BMSCs. The RT-qPCR results showed that the expression of miR-27a-3p was upregulated in BMSC-Exos, but decreased in PD mice. We found that PF was glucose concentration-dependently enhanced in the peritoneum of the PD mice. Compared with the control mice, the PD mice showed high solute transport and decreased ultrafiltration volume as well as an obvious fibroproliferative response, with markedly increased peritoneal thickness and higher expression of α-SMA, collagen-I, fibronectin, and ECM1. The mice with PD showed decreased miR-27a-3p. Peritoneal structural and functional damage was significantly attenuated after BMSC-Exos treatment, while PF and mesothelial damage were significantly ameliorated. Additionally, markers of fibrosis (α-SMA, collagen-I, fibronectin, ECM1) and profibrotic cytokines (TGF-ß1, PDGF) were downregulated at the mRNA and protein levels after BMSC-Exos treatment. In HMrSV5 cells, BMSC-Exos reversed the decrease in cell viability and the increase in cell migratory capacity caused by high-glucose PDF. Western blotting and RT-qPCR analysis revealed that BMSC-Exos treatment resulted in increased expression of E-cadherin (epithelial marker) and decreased expression of α-SMA, Snail, and vimentin (mesenchymal markers) compared to those of the 4.25% PDF-treated cells. Importantly, a dual-luciferase reporter assay showed that TP53 was a target gene of miR-27a-3p. TP53 overexpression significantly reversed the decreases in PF and EMT progression induced by BMSC-Exos. CONCLUSION: The present results demonstrate that BMSC-Exos showed an obvious protective effect on PD-related PF and suggest that BMSC-derived exosomal miR-27a-3p may exert its inhibitory effect on PF and EMT progression by targeting TP53.

FAM76B regulates PI3K/Akt/NF-κB-mediated M1 macrophage polarization by influencing the stability of PIK3CD mRNA.

Macrophage polarization is closely related to inflammation development, yet how macrophages are polarized remains unclear. In our study, the number of M1 macrophages was markedly increased in Fam76b knockout U937 cells vs. wild-type U937 cells, and FAM76B expression was decreased in M1 macrophages induced from different sources of macrophages. Moreover, Fam76b knockout enhanced the mRNA and protein levels of M1 macrophage-associated marker genes. These results suggest that FAM76B inhibits M1 macrophage polarization. We then further explored the mechanism by which FAM76B regulates macrophage polarization. We found that FAM76B can regulate PI3K/Akt/NF-κB pathway-mediated M1 macrophage polarization by stabilizing PIK3CD mRNA. Finally, FAM76B was proven to protect against inflammatory bowel disease (IBD) by inhibiting M1 macrophage polarization through the PI3K/Akt/NF-κB pathway in vivo. In summary, FAM76B regulates M1 macrophage polarization through the PI3K/Akt/NF-κB pathway in vitro and in vivo, which may inform the development of future therapeutic strategies for IBD and other inflammatory diseases.

Intracytoplasmic sperm injection versus conventional in-vitro fertilisation for couples with infertility with non-severe male factor: a multicentre, open-label, randomised controlled trial.

BACKGROUND: Introduced in 1992, intracytoplasmic sperm injection (ICSI) was initially indicated for severe male infertility; however, its use has since been expanded to non-severe male infertility. We aimed to compare the efficacy and safety of ICSI versus conventional in-vitro fertilisation (IVF) in couples with infertility with non-severe male factor. METHODS: We conducted an investigator-initiated, multicentre, open-label, randomised controlled trial in ten reproductive medicine centres across China. Couples with infertility with non-severe male factor without a history of poor fertilisation were randomly assigned (1:1) to undergo either ICSI or conventional IVF. The primary outcome was live birth after first embryo transfer. We performed the primary analysis in the intention-to-treat population using log-binomial regression models for categorical outcomes or linear regression models for continuous outcomes, adjusting for centre. This trial is registered with Clinicaltrials.gov, NCT03298633, and is completed. FINDINGS: Between April 4, 2018, and Nov 15, 2021, 3879 couples were screened, of whom 2387 (61·5%) couples were randomly assigned (1184 [49·6%] to the ICSI group and 1203 [50·4%] to the conventional IVF group). After excluding couples who were ineligible, randomised twice, or withdrew consent, 1154 (97·5%) in the ICSI group and 1175 (97·7%) in the conventional IVF group were included in the primary analysis. Live birth after first embryo transfer occurred in 390 (33·8%) couples in the ICSI group and in 430 (36·6%) couples in the conventional IVF group (adjusted risk ratio [RR] 0·92 [95% CI 0·83-1·03]; p=0·16). Two (0·2%) neonatal deaths were reported in the ICSI group and one (0·1%) in the conventional IVF group. INTERPRETATION: In couples with infertility with non-severe male factor, ICSI did not improve live birth rate compared with conventional IVF. Given that ICSI is an invasive procedure associated with additional costs and potential increased risks to offspring health, routine use is not recommended in this population. FUNDING: National Natural Science Foundation of China, National Key Research and Development Program, Beijing Municipal Science & Technology Commission, and Peking University Third Hospital.

Association between hearing loss and physical performance in patients on maintenance hemodialysis.

BACKGROUND: The correlation between hearing loss (HL) and physical performance in patients receiving maintenance hemodialysis (MHD) remains poorly investigated. This study explored the association between HL and physical performance in patients on MHD. METHODS: This multicenter cross-sectional study was conducted between July 2020 and April 2021 in seven hemodialysis centers in Shanghai and Suzhou, China. The hearing assessment was performed using pure-tone average (PTA). Physical performance was assessed using the Timed Up and Go Test (TUGT), handgrip strength, and gait speed. RESULTS: Finally, 838 adult patients (male, 516 [61.6%]; 61.2 ± 2.6 years) were enrolled. Among them, 423 (50.5%) had mild to profound HL (male, 48.6% and female, 53.4%). Patients with HL had poorer physical performance than patients without HL (p < 0.001). TUGT was positively correlated with PTA (r = 0.265, p < 0.001), while handgrip strength and gait speed were negatively correlated with PTA (r = -0.356, p < 0.001 and r = -0.342, p < 0.001, respectively). Physical performance in patients aged <60 years showed significant dose-response relationships with HL. After adjusting for confounders, the odds ratios (95% confidence intervals) for HL across the TUGT quartiles (lowest to highest) were 1.00 (reference), 1.15 (0.73-1.81), 1.69 (1.07-2.70), and 2.87 (1.69-4.88) (p for trend = 0.005). CONCLUSION: Lower prevalence of HL was associated with a faster TUGT and a stronger handgrip strength in patients on MHD.

MSL-Net: Sharp Feature Detection Network for 3D Point Clouds.

As a significant geometric feature of 3D point clouds, sharp features play an important role in shape analysis, 3D reconstruction, registration, localization, etc. Current sharp feature detection methods are still sensitive to the quality of the input point cloud, and the detection performance is affected by random noisy points and non-uniform densities. In this paper, using the prior knowledge of geometric features, we propose a Multi-scale Laplace Network (MSL-Net), a new deep-learning-based method based on an intrinsic neighbor shape descriptor, to detect sharp features from 3D point clouds. First, we establish a discrete intrinsic neighborhood of the point cloud based on the Laplacian graph, which reduces the error of local implicit surface estimation. Then, we design a new intrinsic shape descriptor based on the intrinsic neighborhood, combined with enhanced normal extraction and cosine-based field estimation function. Finally, we present the backbone of MSL-Net based on the intrinsic shape descriptor. Benefiting from the intrinsic neighborhood and shape descriptor, our MSL-Net has simple architecture and is capable of establishing accurate feature prediction that satisfies the manifold distribution while avoiding complex intrinsic metric calculations. Extensive experimental results demonstrate that with the multi-scale structure, MSL-Net has a strong analytical ability for local perturbations of point clouds. Compared with state-of-the-art methods, our MSL-Net is more robust and accurate.

Investigation of androgen receptor CAG repeats length in polycystic ovary syndrome diagnosed using the new international evidence-based guideline.

BACKGROUND: To study whether CAG repeat polymorphism of androgen receptor (AR) contributes to the risk of polycystic ovarian morphology (PCOM) with antral follicle count (AFC) ≥ 20 in the context of new international guideline of polycystic ovary syndrome (PCOS). METHODS: Blood of 109 PCOS cases and 61 controls were collected for the measurement of AR CAG repeats length by sequencing. The mean number and frequency distribution of CAG repeats length were observed. Detailed analysis was conducted by dividing PCOS cases into low AFC group (L-AFC, AFC < 20) and high AFC group (H-AFC, AFC ≥ 20) according to the new international evidence-based guideline. RESULTS: The portion of individuals with lower CAG repeats length in H-AFC group was significantly larger than those with higher CAG repeats length. Logistic model revealed individuals with lower CAG length tended to develop H-AFC. CONCLUSION: Lower CAG repeats length in the AR gene of PCOS cases increases risk of PCOM.

Oral micronized progesterone versus vaginal progesterone for luteal phase support in fresh embryo transfer cycles: a multicenter, randomized, non-inferiority trial.

STUDY QUESTION: Does oral micronized progesterone result in a non-inferior ongoing pregnancy rate compared to vaginal progesterone gel as luteal phase support (LPS) in fresh embryo transfer cycles? SUMMARY ANSWER: The ongoing pregnancy rate in the group administered oral micronized progesterone 400 mg per day was non-inferior to that in the group administered vaginal progesterone gel 90 mg per day. WHAT IS KNOWN ALREADY: LPS is an integrated component of fresh IVF, for which an optimal treatment regimen is still lacking. The high cost and administration route of the commonly used vaginal progesterone make it less acceptable than oral micronized progesterone; however, the efficacy of oral micronized progesterone is unclear owing to concerns regarding its low bioavailability after the hepatic first pass. STUDY DESIGN, SIZE, DURATION: This non-inferiority randomized trial was conducted in eight academic fertility centers in China from November 2018 to November 2019. The follow-up was completed in April 2021. PARTICIPANTS/MATERIALS, SETTING, METHODS: A total of 1310 infertile women who underwent their first or second IVF cycles were enrolled. On the day of hCG administration, the patients were randomly assigned to one of three groups for LPS: oral micronized progesterone 400 mg/day (n = 430), oral micronized progesterone 600 mg/day (n = 440) or vaginal progesterone 90 mg/day (n = 440). LPS was started on the day of oocyte retrieval and continued till 11-12 weeks of gestation. The primary outcome was the rate of ongoing pregnancy. MAIN RESULTS AND THE ROLE OF CHANCE: In the intention-to-treat analysis, the rate of ongoing pregnancy in the oral micronized progesterone 400 mg/day group was non-inferior to that of the vaginal progesterone gel group [35.3% versus 38.0%, absolute difference (AD): -2.6%; 95% CI: -9.0% to 3.8%, P-value for non-inferiority test: 0.010]. There was insufficient evidence to support the non-inferiority in the rate of ongoing pregnancy between the oral micronized progesterone 600 mg/day group and the vaginal progesterone gel group (31.6% versus 38.0%, AD: -6.4%; 95% CI: -12.6% to -0.1%, P-value for non-inferiority test: 0.130). In addition, we did not observe a statistically significant difference in the rate of live births between the groups. LIMITATIONS, REASONS FOR CAUTION: The primary outcome of our trial was the ongoing pregnancy rate; however, the live birth rate may be of greater clinical interest. Although the results did not show a difference in the rate of live births, they should be confirmed by further trials with larger sample sizes. In addition, in this study, final oocyte maturation was triggered by hCG, and the findings may not be extrapolatable to cycles with gonadotropin-releasing hormone agonist triggers. WIDER IMPLICATIONS OF THE FINDINGS: Oral micronized progesterone 400 mg/day may be an alternative to vaginal progesterone gel in patients reluctant to accept the vaginal route of administration. However, whether a higher dose of oral micronized progesterone is associated with a poorer pregnancy rate or a higher rate of preterm delivery warrants further investigation. STUDY FUNDING/COMPETING INTEREST(S): This research was supported by a grant from the National Natural Science Foundation of China (82071718). None of the authors have any conflicts of interest to declare. TRIAL REGISTRATION NUMBER: This trial was registered at the Chinese Clinical Trial Registry (http://www.chictr.org.cn/) with the number ChiCTR1800015958. TRIAL REGISTRATION DATE: May 2018. DATE OF FIRST PATIENT'S ENROLMENT: November 2018.

Expression and functional analysis of fam76b in zebrafish.

FAM76B is nuclear speckle-localized protein with a molecular weight of 39 kDa. The amino sequence of FAM76B protein is highly conserved among species, suggesting that FAM76B has important biological functions. However, the biological function of FAM76B is currently still unclear. To explore the biological function of FAM76B, we firstly used zebrafish as the experimental model to study the distribution and expression level of Fam76b. The results indicated that fam76b is highly expressed in hematopoiesis and immune systems of zebrafish by real-time quantitative PCR, in situ hybridization and Tg(fam76b: eGFP) transgenic zebrafish. Then, the fam76b gene was knocked out by CRISPR/Cas9 in zebrafish and fam76b rescue in fam76b-/- zebrafish was performed using the TOL2 transposable system. fam76b gene knockout zebrafish exhibit reduced thymus, excessive inflammatory response, and increased mortality. FAM76B was further found to be involved in regulating the development of hematopoiesis and immune system, and participate in the process of inflammatory response. Our findings in the study lay the groundwork for elucidating the function of the new molecule Fam76b and provide new insights into the development of zebrafish hematopoietic and immune system.

FAM76B regulates NF-κB-mediated inflammatory pathway by influencing the translocation of hnRNPA2B1.

FAM76B has been reported to be a nuclear speckle-localized protein with unknown function. In this study, FAM76B was first demonstrated to inhibit the NF-κB-mediated inflammatory pathway by affecting the translocation of hnRNPA2B1 in vitro. We further showed that FAM76B suppressed inflammation in vivo using a traumatic brain injury (TBI) mouse model. Lastly, FAM76B was shown to interact with hnRNPA2B1 in human tissues taken from patients with acute, organizing, and chronic TBI, and with different neurodegenerative diseases. The results suggested that FAM76B mediated neuroinflammation via influencing the translocation of hnRNPA2B1 in vivo during TBI repair and neurodegenerative diseases. In summary, we for the first time demonstrated the role of FAM76B in regulating inflammation and further showed that FAM76B could regulate the NF-κB-mediated inflammatory pathway by affecting hnRNPA2B1 translocation, which provides new information for studying the mechanism of inflammation regulation.

Expression and Activity of the Transcription Factor CCAAT/Enhancer-Binding Protein ß (C/EBPß) Is Regulated by Specific Pulse-Modulated Radio Frequencies in Oligodendroglial Cells.

The rapid growth of wireless electronic devices has raised concerns about the harmful effects of leaked electromagnetic radiation (EMR) on human health. Even though numerous studies have been carried out to explore the biological effects of EMR, no clear conclusions have been drawn about the effect of radio frequency (RF) EMR on oligodendrocytes. To this end, we exposed oligodendroglia and three other types of brain cells to 2.4 GHz EMR for 6 or 48 h at an average input power of 1 W in either a continuous wave (CW-RF) or a pulse-modulated wave (PW-RF, 50 Hz pulse frequency, 1/3 duty cycle) pattern. RNA sequencing, RT-qPCR, and Western blot were used to examine the expression of C/EBPß and its related genes. Multiple reaction monitoring (MRM) was used to examine the levels of expression of C/EBPß-interacting proteins. Our results showed that PW-RF EMR significantly increased the mRNA level of C/EBPß in oligodendroglia but not in other types of cells. In addition, the expression of three isoforms and several interacting proteins and targeted genes of C/EBPß were markedly changed after 6-h PW-RF but not CW-RF. Our results indicated that RF EMR regulated the expression and functions of C/EBPß in a waveform- and cell-type-dependent manner.

PD-L1/PD-1 checkpoint pathway regulates hippocampal neuronal excitability and learning and memory behavior.

Programmed death protein 1 (PD-1) and its ligand PD-L1 constitute an immune checkpoint pathway. We report that neuronal PD-1 signaling regulates learning/memory in health and disease. Mice lacking PD-1 (encoded by Pdcd1) exhibit enhanced long-term potentiation (LTP) and memory. Intraventricular administration of anti-mouse PD-1 monoclonal antibody (RMP1-14) potentiated learning and memory. Selective deletion of PD-1 in excitatory neurons (but not microglia) also enhances LTP and memory. Traumatic brain injury (TBI) impairs learning and memory, which is rescued by Pdcd1 deletion or intraventricular PD-1 blockade. Conversely, re-expression of Pdcd1 in PD-1-deficient hippocampal neurons suppresses memory and LTP. Exogenous PD-L1 suppresses learning/memory in mice and the excitability of mouse and NHP hippocampal neurons through PD-1. Notably, neuronal activation suppresses PD-L1 secretion, and PD-L1/PD-1 signaling is distinctly regulated by learning and TBI. Thus, conditions that reduce PD-L1 levels or PD-1 signaling could promote memory in both physiological and pathological conditions.

Immunotherapies in chronic pain through modulation of neuroimmune interactions.

It is generally believed that immune activation can elicit pain through production of inflammatory mediators that can activate nociceptive sensory neurons. Emerging evidence suggests that immune activation may also contribute to the resolution of pain by producing distinct pro-resolution/anti-inflammatory mediators. Recent research into the connection between the immune and nervous systems has opened new avenues for immunotherapy in pain management. This review provides an overview of the most utilized forms of immunotherapies (e.g., biologics) and highlight their potential for immune and neuronal modulation in chronic pain. Specifically, we discuss pain-related immunotherapy mechanisms that target inflammatory cytokine pathways, the PD-L1/PD-1 pathway, and the cGAS/STING pathway. This review also highlights cell-based immunotherapies targeting macrophages, T cells, neutrophils and mesenchymal stromal cells for chronic pain management.

Nirmatrelvir/Ritonavir for hemodialysis patients with COVID-19.

Background: Hemodialysis patients have a high risk of severe/critical COVID-19 and related high mortality, but nirmatrelvir/ritonavir is not recommended for hemodialysis patients with COVID-19 infection because of lack of evidence of safety. Objectives: Our study aims to evaluate the minimum plasma concentration (Cmin) of nirmatrelvir and its safety of different doses of nirmatrelvir/ritonavir in hemodialysis patients with mild COVID-19. Method: This was a prospective, two step, nonrandomized, open-label study. Participants were treated with nirmatrelvir 150 mg or 300 mg once a day (another 75 mg or 150 mg supplied after hemodialysis) and ritonavir 100 mg twice daily for 5 days, respectively. The primary outcome was the safety of nirmatrelvir/ritonavir, including the Cmin of nirmatrelvir and the number of adverse events (AE). The secondary outcome was the time of viral elimination in hemodialysis patients. Results: Adverse events were happened in 3 and 7 participants in the step 1 and step 2 group, respectively (p = 0.025). Among them, 2 and 6 participants were identified as drug-related adverse events (p = 0.054). No SAE or liver function damage happened. The Cmin of nirmatrelvir in step 1 and step 2 group were 5,294.65 ± 2,370.59 ng/mL and 7,675.67 ± 2,745.22 ng/mL (p = 0.125). The Cmin of the control group was 2,274.10 ± 1,347.25 ng/mL (p = 0.001 compared to step 2 and p = 0.059 compared to step 1). Compared to hemodialysis patients without nirmatrelvir/ritonavir, there were no statistical differences in overall viral elimination time (p = 0.232). Conclusion: In our study, two doses of nirmatrelvir/ritonavir appeared to be excessive for hemodialysis patients. Although all of the patients tolerated 5-day administration, nearly half of the patients experienced drug-related adverse events. In addition, the medication group did not show a significant advantage in the time of viral elimination.

Systematical assessment of digit ratio in a female masculinization disease: polycystic ovary syndrome.

Background: In recent years, the right ratio of 2nd and 4th digit length (2D:4D) is regarded as an anatomical marker of prenatal testosterone exposure. Polycystic ovary syndrome (PCOS) is a female masculinized disease and is determined by prenatal testosterone exposure. Whether the ratio in the right hand of PCOS women is reduced or not compared with non-PCOS women is under debate. To further investigate the relationship between PCOS and digit ratio, we systematically measured all the digit ratios. Methods: We recruited 34 non-PCOS women, 116 PCOS women, and 40 men and systematically measured all the ratios of digit length (2D:3D, 2D:4D, 2D:5D, 3D:4D, 3D:5D, and 4D:5D) of right hands and left hands. Results: Left 2D:3D, 2D:4D, and 2D:5D in men were significantly lower than those in non-PCOS women. Significantly lower digit ratios of left 2D:3D and 2D:4D were observed in PCOS compared with non-PCOS women. In the subgroup analysis, the left ratio of digit length in 2D:3D and 2D:5D of the hyperandrogenism subgroup was lower than that of the non-hyperandrogenism subgroup without statistical significance. The logistic regression model of PCOS revealed that 2D:3D, 2D:4D, 2D:5D, and 3D:4D of left hands were statistically related to the diagnosis of PCOS among all the digit ratios. Conclusion: Not only 2D:4D but also other digit ratios, such as 2D:3D and 2D:5D, are a marker of prenatal testosterone exposure and may be an anatomical marker of PCOS. The majority of these significant differences included left 2D, with the following order: non-PCOS women > PCOS women > men.

Lycium barbarum polysaccharide alleviates dextran sodium sulfate-induced inflammatory bowel disease by regulating M1/M2 macrophage polarization via the STAT1 and STAT6 pathways.

Disruption of colonic homeostasis caused by aberrant M1/M2 macrophage polarization contributes to the development of inflammatory bowel disease (IBD). Lycium barbarum polysaccharide (LBP) is the primary active constituent of traditional Chinese herbal Lycium barbarum L., which has been widely demonstrated to have important functions in regulating immune activity and anti-inflammatory. Thus, LBP may protect against IBD. To test this hypothesis, the DSS-induced colitis model was established in mice, then the mice were treated with LBP. The results indicated that LBP attenuated the weight loss, colon shortening, disease activity index (DAI), and histopathological scores of colon tissues in colitis mice, suggesting that LBP could protect against IBD. Besides, LBP decreased the number of M1 macrophages and the protein level of Nitric oxide synthase 2(NOS2) as a marker of M1 macrophages and enhanced the number of M2 macrophages and the protein level of Arginase 1(Arg-1) as a marker of M2 macrophages in colon tissues from mice with colitis, suggesting that LBP may protect against IBD by regulating macrophage polarization. Next, the mechanistic studies in RAW264.7 cells showed that LBP inhibited M1-like phenotype by inhibiting the phosphorylation of STAT1, and promoted M2-like phenotype by promoting the phosphorylation of STAT6. Finally, immunofluorescence double-staining results of colon tissues showed that LBP regulated STAT1 and STAT6 pathways in vivo. The results in the study demonstrated that LBP could protect against IBD by regulating macrophage polarization through the STAT1 and STAT6 pathways.