Post-implantation analysis of genomic variations in the progeny from developing fetus to birth.

The analysis of genomic variations in offspring after implantation has been infrequently studied. In this study, we aim to investigate the extent of de novo mutations in humans from developing fetus to birth. Using high-depth whole-genome sequencing, 443 parent-offspring trios were studied to compare the results of de novo mutations (DNMs) between different groups. The focus was on fetuses and newborns, with DNA samples obtained from the families' blood and the aspirated embryonic tissues subjected to deep sequencing. It was observed that the average number of total DNMs in the newborns group was 56.26 (54.17-58.35), which appeared to be lower than that the multifetal reduction group, which was 76.05 (69.70-82.40) (F = 2.42, P = 0.12). However, after adjusting for parental age and maternal pre-pregnancy body mass index (BMI), significant differences were found between the two groups. The analysis was further divided into single nucleotide variants (SNVs) and insertion/deletion of a small number of bases (indels), and it was discovered that the average number of de novo SNVs associated with the multifetal reduction group and the newborn group was 49.89 (45.59-54.20) and 51.09 (49.22-52.96), respectively. No significant differences were noted between the groups (F = 1.01, P = 0.32). However, a significant difference was observed for de novo indels, with a higher average number found in the multifetal reduction group compared to the newborn group (F = 194.17, P < 0.001). The average number of de novo indels among the multifetal reduction group and the newborn group was 26.26 (23.27-29.05) and 5.17 (4.82-5.52), respectively. To conclude, it has been observed that the quantity of de novo indels in the newborns experiences a significant decrease when compared to that in the aspirated embryonic tissues (7-9 weeks). This phenomenon is evident across all genomic regions, highlighting the adverse effects of de novo indels on the fetus and emphasizing the significance of embryonic implantation and intrauterine growth in human genetic selection mechanisms.

Prevalence of Polypharmacy in Elderly Population Worldwide: A Systematic Review and Meta-Analysis.

BACKGROUND: Polypharmacy (PP) is common in elderly population and associated with some adverse clinical outcomes and increases healthcare burdens. We performed this systemic review and meta-analysis to estimate worldwide prevalence of PP and explore associated factors in the elderly. METHODS: The PubMed, Web of Science, Cochrane Library, and Ovid EMBASE databases were searched for studies published until May 30, 2022. We included observational studies representative of general patients aged ≥60 in which PP was defined as multiple drugs ≥5. Studies were excluded if only a particular group of the elderly population (e.g., with diabetes) were included. The primary outcome was the prevalence of PP. Random-effect models were employed to estimate the overall or variable-specific pooled estimates of PP. Secondary outcomes were hyperpolypharmacy (HPP, defined as multiple drugs ≥10) and PP prevalence based on different study years, genders, locations, populations, and so forth. RESULTS: We included 122 original observational studies with an overall population of 57 328 043 individuals in the meta-analysis. The overall prevalence of PP and HPP in the elderly population worldwide was 39.1% (95% confidence interval [CI], 35.5%-42.7%) and 13.3% (95% CI, 10.4%-16.5%), respectively. The prevalence of PP in Europe, Oceania, North America, Asia, and South America was 45.8% (95% CI, 41.5%-50.2%), 45.5% (95% CI, 26.7%-64.3%), 40.8% (95% CI, 29.8%-51.6%), 29.0% (95% CI, 20.0%-38.0%), and 28.4% (95% CI, 24.0%-32.8%), respectively (p < 0.01). Multivariate meta-regressions showed geographical regions of Europe or North America, age ≥70, and residence from nursing homes were independently associated with higher PP prevalence. CONCLUSIONS: Nearly 40% of the elderly population is exposed to PP. The prevalence of PP is significantly higher in elderly individuals aged 70 or older, in developed regions and in nursing homes. It is important to focus on avoiding inappropriate PP in this population to address the growing burden of PP.

Low-dose of magnesium sulfate solution was not inferior to standard regime of polyethylene glycol for bowel preparation in elderly patients: a randomized, controlled study.

BACKGROUND: Large polyethylene glycol (PEG) is a standard regimen for bowel preparation. However, elderly patients suffered from adverse events. This study was to compare the efficacy and safety of oral magnesium sulfate solution (MSS) vs standard PEG in elderly patients undergoing colonoscopy. METHODS: Elderly patients aged 60-90 years, from two endoscopic centers, were enrolled in China. Patients were randomized to take a low dose of MSS or a standard PEG regime in a split-dose regime. The primary endpoint was the proportion of patients with adequate bowel preparation, which was defined as the total Boston Bowel Preparation Scale (BBPS) ≥6 and each segmental BBPS was ≥2. Secondary outcomes included adenoma detection rate (ADR), safety, adverse events, cecal intubation rate, willingness to repeat BP, and so on. RESULTS: 1174 elderly patients were randomly allocated to the MSS group (n = 588) or the standard group (n = 586). Adequate BP was achieved in 94.0% of patients in the MSS group and 92.5% in the control (p = .287). ADR was also comparable between the two groups (43.0% and 39.9%, p = .282). Compared with the standard group, MSS group reported less abdominal discomfort (1.7% vs 6.0%), less nausea (13.6% vs 21.0%) and vomiting (1.2% vs 4.2%). The change in serum potassium levels after preparation in the standard group was significantly lower than that in the MSS group (-0.19 ± 0.08 vs -0.41 ± 0.11, p = .037). CONCLUSIONS: Low dose of MSS was not inferior to the standard PEG regime in terms of bowel preparation quality for elderly patients. Low-dose MSS offered fewer adverse events and better tolerability. It is a preferable choice for the elderly to undergo bowel preparation for colonoscopy. CLINICAL TRIAL REGISTRATION NUMBER: NCT04948567.

The effect of intravenous immunoglobulin passive immunotherapy on unexplained recurrent spontaneous abortion: a meta-analysis.

The aim of this study was to investigate the effect of passive immunotherapy using intravenous immunoglobulin (IVIG) on unexplained recurrent spontaneous abortion (RSA). Live birth rates were analysed and binary data were calculated using risk ratio and 95% confidence interval. Meta-analysis of 11 studies showed that the difference in the live birth rate between the IVIG treatment and placebo groups was on the margin of significance (RR = 1.25, 95% CI 1.00 to 1.56, P = 0.05). Both cumulative and trial sequential meta-analyses indicated potential beneficial effect of IVIG but the evidence was inconclusive. Subgroup analysis showed that the live birth rate in primary (RR = 0.88, 95% CI 0.71 to 1.07) and secondary (RR = 1.26, 95% CI 0.99 to 1.61) RSA patients was not significantly different between the IVIG and placebo groups. Live birth rate was significantly different when IVIG was administered before conception (RR = 1.67, 95% CI 1.30 to 2.14, P < 0.0001) but not after implantation (RR = 1.10, 95% CI 0.93 to 1.29). Evidence is insufficient to support the beneficial effects of IVIG on an unexplained RSA. Further high quality studies are needed to elucidate the effectiveness of IVIG.

The role of DNA damage response in human embryonic stem cells exposed to atmospheric oxygen tension: Implications for embryo development and differentiation.

Previous retrospective cohort studies have found that, compared with oxygen tension in the uterus and fallopian tubes (2 %-8 %), exposure of pre-implantation embryos to atmospheric oxygen tension (AtmO2, 20 %) during assisted reproductive technology(ART) can affect embryo quality, pregnancy outcomes and offspring health. However, current research on the effects and mechanisms of AtmO2 on the development of embryos and offspring is mainly limited to animal experiments. Human embryonic stem cells (hESCs) play a special and irreplaceable role in the study of early human embryonic development. In this study, we used hESCs as a model to elucidate the possible effects and mechanisms of AtmO2 exposure on human embryonic development. We found that exposure to AtmO2 can reduce cell viability, produce oxidative stress, increase DNA damage, initiate DNA repair, activate autophagy, and increase cell apoptosis. We also noticed that approximately 50 % of hESCs survived, adapted and proliferated through high expression of self-renewal and pluripotency regulatory factors, and affected embryoid body differentiation. These data indicate that hESCs experience oxidative stress, accumulation of DNA damage, and activate DNA damage response under the selective pressure of AtmO2.Some hESCs undergo cell death, whereas other hESCs adapt and proliferate through increased expression of self-renewal genes. The current findings provide in vitro evidence that exposure to AtmO2 during the early preimplantation stage negatively affects hESCs.

Prolonged cannulation time is an independent risk factor for moderate-to-severe post-endoscopic retrograde cholangiopancreatography (ERCP) pancreatitis: a large cohort study.

Background: Moderate-to-severe post-endoscopic retrograde cholangiopancreatography (ERCP) pancreatitis contributes to most of the poor outcomes of patients with post-ERCP pancreatitis (PEP). However, it remains unclear which part of the patient is more vulnerable to moderate-to-severe PEP (MS PEP). In this study, we aimed to identify the risk factors independently associated with MS PEP. Methods: Consecutive patients with native papilla who had undergone ERCP were included in this study. The patient-related and procedure-related variables were retrieved from a prospectively maintained ERCP database. The primary outcome was the incidence of PEP. MS PEP was defined as a prolonged hospital stay of ≥4 days (as per the Cotton criteria) or the presence of organ failure (as per the revised Atlanta criteria). A logistic regression analysis was conducted to identify the risk factors. Results: A total of 6,944 patients with native papilla who had undergone elective ERCP from January 2010 to February 2022 were included in this study. Among these 6,944 patients, 362 (5.2%) patients developed PEP. Among these 362 patients, 76 (1.1%) or 17 (0.2%) had MS PEP as per the Cotton criteria and the revised Atlanta criteria, respectively. The logistic analysis revealed that the independent risk factors for overall and mild PEP were similar, and included being female and inadvertent pancreatic duct (PD) cannulation. A total cannulation time >15 min was also found to be an independent risk factor for MS PEP as defined by both the Cotton criteria and the revised Atlanta criteria. Conclusions: This study found that female patients and those who had inadvertent PD cannulation were at risk of mild PEP. A total cannulation time >15 min was also found to be a risk factor for developing MS PEP.

[Study on the bending strength of cast porcelain material of different linker sizes].

PURPOSE: To investigate the relationship between size of different connectors and bending strength of cast porcelain materials. METHODS: The samples were divided into 5 groups according to the area of all-porcelain materials and simulated connector. In group A, simulated connector with cast porcelain material with a cross-section of 2 mm×3 mm was selected; In group B, simulated connector with cast porcelain material with a cross-section of 2 mm×4 mm was selected; In group C, simulated connector with cast porcelain material with a cross-section of 3 mm×3 mm was selected; In group D, simulated connector with cast porcelain material with a cross-section of 3 mm×4 mm was selected; In group E, simulated connector with zirconium oxide material with a cross-section of 2 mm×3 mm was selected. The fracture load was tested using classical three-point bending experiment, statistical analysis was performed using SPSS 18.0 software package. RESULTS: For lithium disilicate cast porcelain, the fracture load increased with increasing cross section area, but both below the shear zirconia fracture load with a cross section of 2 mm×3 mm(P＜0.05).The increase in width increased the fracture load of porcelain samples compared to the length. CONCLUSIONS: It is suitable to increase linker area when cast porcelain is applied to single-end bridge, which is especially achieved by increasing the width at the linker.

The Incidence and Severity of Post-ERCP Pancreatitis in Patients Receiving Standard Administration of NSAIDs: a Systematic Review and Meta-analysis.

BACKGROUND: Routine rectal administration of 100 mg of diclofenac or indomethacin was demonstrated to be an effective prevention method to prevent post-endoscopic retrograde cholangiopancreatography (ERCP) pancreatitis. The systematic review and meta-analysis aimed to estimate the incidence and severity of post-ERCP pancreatitis (PEP) and explore the discrepancies of PEP incidences among different subgroups. METHODS: The PubMed, Web of Science, and Ovid EMBASE databases were searched for studies published until December 2020. Only randomized controlled trials (RCTs) reported rectal administration of 100 mg or higher doses of diclofenac or indomethacin, with PEP as the primary outcomes were eligible for inclusion. The overall and severity of PEP were estimated. Subgroup analysis was performed based on geographic regions, risk level, study beginning time, type of NSAIDs, administration time, and sample size. RESULTS: There were 26 randomized controlled trials (RCTs) with 7954 patients in 31 NSAIDs arms. The pooled incidences were 7.2% for overall PEP (95% confidence interval (CI) 5.9-8.5%), 5.0% for mild PEP (95% CI, 4.0-6.0%), and 1.5% for moderate and severe PEP (0.8-2.3%). PEP rate were higher in patients receiving rectal indomethacin than that of patients receiving rectal diclofenac (7.8% (95% CI, 6.4-9.3%) vs 3.8% (95% CI, 2.2-5.3%), p = 0.009). The PEP rates of high-risk patients and average-risk patients were 8.9% (95% CI, 5.6-12.2%) and 6.4% (95% CI, 5.1-7.6%), respectively (p = 0.160). CONCLUSIONS: The incidence of PEP was higher in patients receiving 100 mg rectal indomethacin than patients receiving 100 mg diclofenac. The effect of 100 mg diclofenac versus indomethacin on preventing PEP requires further study.

Comparative proteomic profiling reveals a pathogenic role for the O-GlcNAcylated AIMP2-PARP1 complex in aging-related hepatic steatosis in mice.

The prevalence of non-alcoholic fatty liver disease (NAFLD) increases with aging. However, the mechanism of aging-related NAFLD remains unclear. Herein, we constructed an aging-related hepatic steatosis model and analyzed the differentially expressed proteins (DEPs) in livers from young and old mice using liquid chromatography-mass spectrometry. Five hundred and eighty-eight aging-related DEPs and novel pathways were identified. Aminoacyl tRNA synthetase complex-interacting multifunctional protein 2 (AIMP2), the most significantly upregulated protein, promoted poly(ADP-ribose) polymerase 1 (PARP1) activation in aging-related hepatic steatosis. Additionally, mice liver-specific O-GlcNAcase knockout promoted AIMP2 and PARP1 expression. O-GlcNAc transferase (OGT) overexpression and O-GlcNAcase inhibition by genetic or pharmaceutical manipulations increased AIMP2 and PARP1 levels in vitro. Mechanistically, O-GlcNAcylation increased AIMP2 protein stability, leading to its aggregation. Our study reveals O-GlcNAcylated AIMP2 as a novel pathogenic regulator of aging-related hepatic steatosis.

[A study on correlation between sperm DNA fragmentation index and age of male, various parameters of sperm and in vitro fertilization outcome].

OBJECTIVE: To study the correlation between sperm DNA fragmentation index (DFI), age of male, various parameters of sperm, rates of fertilization, high quality embryo and pregnancy and implantation rates. METHODS: One hundred and eleven infertile couples were selected randomly, and DFI was tested by flow cytometry for the sperm used for IVF. The patients were divided into different groups according to the DFI scores. The results of each group were analyzed. RESULTS: The IVF normal fertilization was significantly lower in couples with sperm DFI over 10% (60.5%) than that in couples with DFI below 10% (70.1%) (P<0.05). Significantly positive correlation was found between DFI and the age of male (r=0.624, P<0.05). DFI was also significantly negatively correlated with the percentage of linearly progressive sperm (r=-0.360, P<0.05). There was no significant correlation between the rates of high quality cleaved embryos, pregnancy and implantation rate and sperm DFI. CONCLUSION: DFI scores are increased with male's age, and it can influence the sperm motility. DFI=10% can be considered as a critical point which can be used to estimate the clinical fertility rate of IVF. But it could not provide relative information about the rates of high quality embryos and pregnancy for infertile couples undergoing IVF procedure.

Neohesperidin enhances PGC-1α-mediated mitochondrial biogenesis and alleviates hepatic steatosis in high fat diet fed mice.

BACKGROUNDS: Mitochondria plays a critical role in the development and pathogenesis of nonalcoholic fatty liver disease (NAFLD). Neohesperidin (NHP) could lower blood glucose and prevent obesity in mice. However, the direct effect of NHP on hepatic steatosis has not been reported. METHODS: Mice were fed with either a chow diet or HFD with or without oral gavage of NHP for 12 weeks. A variety of biochemical and histological indicators were examined. In vitro cell culture model was utilized to demonstrate underlying molecular mechanism of the effect induced by NHP treatment. RESULTS: NHP increases mitochondrial biogenesis, improves hepatic steatosis and systematic insulin resistance in high fat diet (HFD) fed mice. NHP elevates hepatic mitochondrial biogenesis and fatty acid oxidation by increasing PGC-1α expression. Mechanistically, the activation of AMP-activated protein kinase (AMPK) is involved in NHP induced PGC-1α expression. CONCLUSIONS: PGC-1α-mediated mitochondrial biogenesis plays a vital role in the mitigation of hepatic steatosis treated by NHP. Our result suggests that NHP is a good candidate to be dietary supplement for the auxiliary treatment of NAFLD.

The flavonoid-rich Quzhou Fructus Aurantii extract modulates gut microbiota and prevents obesity in high-fat diet-fed mice.

BACKGROUND: Flavonoids are reported to modulate the composition of gut microbiota, which play an important role in preventing obesity and associated metabolic diseases. In this study, we investigated the effect of Total Flavonoids of Quzhou Fructus Aurantii Extract (TFQ) on gut microbial community in mice fed with a high-fat diet (HFD). METHODS: C57BL/6J mice were fed with either a chow diet or HFD with or without oral gavage of TFQ (300 mg/kg/day) for 12 weeks. RESULTS: Our data indicate TFQ significantly reduced obesity, inflammatio,n and liver steatosis. TFQ elevates the expression of tight junction proteins and reduces metabolic endotoxemia. In addition, TFQ treatment reverses HFD-induced gut dysbiosis, as indicated by the reduction of Firmicutes to Bacteroidetes ratio, the increase of genera Akkermansia and Alistipes, and the decrease of genera Dubosiella, Faecalibaculum, and Lactobacillus. CONCLUSION: These findings support a prebiotic role of TFQ as a dietary supplement for the intervention of gut dysbiosis and obesity-related metabolic disorders.

Astilbin ameliorates cisplatin-induced nephrotoxicity through reducing oxidative stress and inflammation.

Oxidative stress and inflammation are considered to be the main pathogenesis of cisplatin nephrotoxicity. Astilbin, a flavonoid with anti-oxidation and anti-inflammation function, has been used to treat heavy metal induced kidney injury. In this study, we investigated the protective effects of astilbin on cisplatin-induced nephrotoxicity and its underlying mechanisms. Our results showed that astilbin markedly inhibited cisplatin-induced cell apoptosis and recovered cell growth. Astilbin significantly decreased reactive oxygen species (ROS) accumulation and alleviated ROS-induced activation of p53, MAPKs and AKT signaling cascades, which in turn attenuated cisplatin-induced HEK-293 cell apoptosis. Astilbin effectively enhanced NRF2 activation and transcription of its targeting antioxidant genes to reduce ROS accumulation in cisplatin-induced HEK-293 cells. Furthermore, we found that astilbin obviously suppressed tumor necrosis factor alpha (TNF-α) expression and NF-κB activation, and also inhibited the expression of induced nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2). Finally, we confirmed that the effect of astilbin to improve renal oxidative stress and inflammation in cisplatin induced acute nephrotoxic mice. In conclusion, our study suggests that astilbin could ameliorate the cisplatin-induced nephrotoxicity by reducing oxidative stress and inflammation.