Genome sequencing reveals loci under artificial selection that underlie disease phenotypes in the laboratory rat.

Large numbers of inbred laboratory rat strains have been developed for a range of complex disease phenotypes. To gain insights into the evolutionary pressures underlying selection for these phenotypes, we sequenced the genomes of 27 rat strains, including 11 models of hypertension, diabetes, and insulin resistance, along with their respective control strains. Altogether, we identified more than 13 million single-nucleotide variants, indels, and structural variants across these rat strains. Analysis of strain-specific selective sweeps and gene clusters implicated genes and pathways involved in cation transport, angiotensin production, and regulators of oxidative stress in the development of cardiovascular disease phenotypes in rats. Many of the rat loci that we identified overlap with previously mapped loci for related traits in humans, indicating the presence of shared pathways underlying these phenotypes in rats and humans. These data represent a step change in resources available for evolutionary analysis of complex traits in disease models.

Neisseria genes required for persistence identified via in vivo screening of a transposon mutant library.

The mechanisms used by human adapted commensal Neisseria to shape and maintain a niche in their host are poorly defined. These organisms are common members of the mucosal microbiota and share many putative host interaction factors with Neisseria meningitidis and Neisseria gonorrhoeae. Evaluating the role of these shared factors during host carriage may provide insight into bacterial mechanisms driving both commensalism and asymptomatic infection across the genus. We identified host interaction factors required for niche development and maintenance through in vivo screening of a transposon mutant library of Neisseria musculi, a commensal of wild-caught mice which persistently and asymptomatically colonizes the oral cavity and gut of CAST/EiJ and A/J mice. Approximately 500 candidate genes involved in long-term host interaction were identified. These included homologs of putative N. meningitidis and N. gonorrhoeae virulence factors which have been shown to modulate host interactions in vitro. Importantly, many candidate genes have no assigned function, illustrating how much remains to be learned about Neisseria persistence. Many genes of unknown function are conserved in human adapted Neisseria species; they are likely to provide a gateway for understanding the mechanisms allowing pathogenic and commensal Neisseria to establish and maintain a niche in their natural hosts. Validation of a subset of candidate genes confirmed a role for a polysaccharide capsule in N. musculi persistence but not colonization. Our findings highlight the potential utility of the Neisseria musculi-mouse model as a tool for studying the pathogenic Neisseria; our work represents a first step towards the identification of novel host interaction factors conserved across the genus.

The use of bubble charts in analyzing second stage cesarean delivery rates.

BACKGROUND: The incidence of second stage cesarean delivery has been rising globally because of the failure or the anticipated difficulty of performing instrumental delivery. Yet, the best way to interpret the figure and its optimal rate remain to be determined. This is because it is strongly influenced by the practice of other 2 modes of birth, namely cesarean delivery performed before reaching the second stage and assisted vaginal birth during the second stage. In this regard, a bubble chart that can display 3-dimensional data through its x-axis, y-axis, and the size of each plot (presented as a bubble) may be a suitable method to evaluate the relationship between the rates of these 3 modes of births. OBJECTIVE: This study aimed to conduct an epidemiologic study on the incidence of second stage cesarean deliveries rates among >300,000 singleton term births in 10 years from 8 obstetrical units and to compare their second stage cesarean delivery rates in relation to their pre-second stage cesarean delivery rates and assisted vaginal birth rates using a bubble chart. STUDY DESIGN: The territory-wide birth data collected between 2009 and 2018 from all 8 public obstetrical units (labelled as A to H) were reviewed. The inclusion criteria were all singleton pregnancies with cephalic presentation that were delivered at term (≥37 weeks' gestation). Pre-second stage cesarean delivery rate was defined as all elective cesarean deliveries and those emergency cesarean deliveries that occurred before full cervical dilatation was achieved as a proportion of the total number of births. The second stage cesarean delivery rate and assisted vaginal birth rate were calculated according to the respective mode of delivery as a proportion of the number of cases that reached full cervical dilatation. The rates of these 3 modes of births were compared among the parity groups and among the 8 units. Using a bubble chart, each unit's second stage cesarean delivery rate (y-axis) was plotted against its pre-second stage cesarean delivery rate (x-axis) as a bubble. Each unit's second stage cesarean delivery to assisted vaginal birth ratio was represented by the size of the bubble. RESULTS: During the study period, a total of 353,434 singleton cephalic presenting term pregnancies were delivered in the 8 units, and 180,496 (51.1%) were from nulliparous mothers. When compared with the multiparous group, the nulliparous group had a significantly lower pre-second stage cesarean delivery rate (18.58% vs 21.26%; P<.001) but a higher second stage cesarean delivery rate (0.79% vs 0.22%; P<.001) and a higher assisted vaginal birth rate (17.61% vs 3.58%; P<.001). Using the bubble of their averages as a reference point in the bubble chart, the 8 units' bubbles were clustered into 5 regions indicating their differences in practice: unit B and unit H were close to the average in the center. Unit A and unit F were at the upper right corner with a higher pre-second stage cesarean delivery rate and second stage cesarean delivery rate. Unit D and unit E were at the opposite end. Unit C was at the upper left corner with a low pre-second stage cesarean delivery rate but a high second stage cesarean delivery rate, whereas unit G was at the opposite end. Unit C and unit G were also in the extremes in terms of pre-second stage cesarean delivery to assisted vaginal birth ratio (0.09 and 0.01, respectively). Although some units seemed to have very similar second stage cesarean delivery rates, their obstetrical practices were differentiated by the bubble chart. CONCLUSION: The second stage cesarean delivery rate must be evaluated in the context of the rates of pre-second stage cesarean delivery and assisted vaginal birth. A bubble chart is a useful method for analyzing the relationship among these 3 variables to differentiate the obstetrical practice between different units.

Evaluating the efficacy of standardized pressure ulcer management protocols in the prevention of pressure injuries among patients undergoing neurosurgical procedures.

Pressure injuries are a significant concern for patients undergoing neurosurgical procedures due to prolonged immobility and the complexity of care. This study evaluates the efficacy of standardized pressure ulcer management protocols in preventing pressure injuries and enhancing patient care in a neurosurgical context. A comprehensive retrospective analysis was conducted at a single institution from December 2020 to December 2023, comparing 50 patients who received standardized pressure ulcer management (intervention group) with 50 patients who received conventional care (control group). The study assessed the incidence of pressure ulcers, patient comfort levels using the Kolcaba Comfort Scale and sleep quality using the Richards-Campbell Sleep Questionnaire (RCSQ). Statistical analysis was performed using SPSS software, version 27.0, applying t-tests and chi-square tests as appropriate. The intervention group exhibited a significantly lower incidence of pressure ulcers at all measured time points post-surgery compared to the control group. Patient comfort levels in the intervention group were consistently higher across psychological, environmental, physiological and socio-cultural domains. Sleep quality metrics, including sleep depth, latency to sleep onset and overall sleep quality, were significantly improved in the intervention group. The implementation of standardized pressure ulcer management protocols in neurosurgical care significantly reduces the incidence of pressure injuries, enhances patient comfort and improves sleep quality. These findings highlight the importance of adopting structured care protocols to improve postoperative outcomes and patient well-being in neurosurgical settings.

[Tanshinone reverses androgen deprivation-induced invasion of prostate cancer cells by suppressing PI3K and AKT signaling pathways].

OBJECTIVE: To explore the effect of tanshinone on the invasion of PCa cells induced by androgen-deprivation therapy (ADT) and its possible action mechanism. METHODS: We treated human PCa LNCaP cells with tanshinone at 0 nmol/L (the control group), 5 nmol/L (tanshinone group 1), 10 nmol/L (tanshinone group 2) and 20 nmol/L (tanshinone group 3), respectively. Then we detected their cloning, angiogenesis and invasion abilities by plate cloning assay, tube-formation assay and Transwell chamber assay, respectively, examined their apoptosis using the AnnexinV-FITC/PI double staining method, and determined the protein expressions of phosphatidylinositol 3-kinase (PI3K), p-PI3K, protein kinase B (AKT) and p-AKT by Western blot. RESULTS: Compared with the control group, the PCa LNCaP cells in the tanshinone groups 1, 2 and 3 showed significant dose-dependent decreases in the clone formation rate (ï¼»25.14 ± 5.19ï¼½% vs ï¼»19.33 ± 4.12ï¼½% vs ï¼»14.69 ± 4.71ï¼½% vs ï¼»9.35 ± 2.37ï¼½%, P<0.05), number of cellular lumens (ï¼»23.20 ± 4.85ï¼½ vs ï¼»19.80 ± 5.12ï¼½ vs ï¼»14.40 ± 4.16ï¼½ vs ï¼»10.20 ± 3.21ï¼½ per microscopic field, P<0.05) and count of transmembrane cells (ï¼»62.80 ± 8.97ï¼½ vs ï¼»50.40 ± 7.62ï¼½ vs ï¼»38.60 ± 5.16ï¼½ vs ï¼»27.40 ± 4.91ï¼½ per microscopic field, P<0.05), increase in the rate of cell apoptosis (ï¼»3.58 ± 0.74ï¼½% vs ï¼»8.97 ± 1.36ï¼½% vs ï¼»14.64 ± 4.10ï¼½% vs ï¼»21.17 ± 5.37ï¼½%, P<0.05), and down-regulation of the expressions of p-PI3K, PI3K, p-AKT and AKT (P<0.05). CONCLUSION: Tanshinone can reverse ADT-induced invasion of PCa cells, reduce their clone formation and angiogenesis, promote their apoptosis, and inhibit the activity of PI3K and AKT signaling pathways.

Detecting Förster resonance energy transfer in living cells by conventional and spectral flow cytometry.

Assays based on Förster resonance energy transfer (FRET) can be used to study many processes in cell biology. Although this is most often done with microscopy for fluorescence detection, we report two ways to measure FRET in living cells by flow cytometry. Using a conventional flow cytometer and the "3-cube method" for intensity-based calculation of FRET efficiency, we measured the enzymatic activity of specific kinases in cells expressing a genetically-encoded reporter. For both AKT and protein kinase A, the method measured kinase activity in time-course, dose-response, and kinetic assays. Using the Cytek Aurora spectral flow cytometer, which applies linear unmixing to emission measured in multiple wavelength ranges, FRET from the same reporters was measured with greater single-cell precision, in real time and in the presence of other fluorophores. Results from gene-knockout studies suggested that spectral flow cytometry might enable the sorting of cells on the basis of FRET. The methods we present provide convenient and flexible options for using FRET with flow cytometry in studies of cell biology.

Subtype-specific and co-occurring genetic alterations in B-cell non-Hodgkin lymphoma.

B-cell non-Hodgkin lymphoma (B-NHL) encompasses multiple clinically and phenotypically distinct subtypes of malignancy with unique molecular etiologies. Common subtypes of B-NHL, such as diffuse large B-cell lymphoma, have been comprehensively interrogated at the genomic level, but rarer subtypes, such as mantle cell lymphoma, remain less extensively characterized. Furthermore, multiple B-NHL subtypes have thus far not been comprehensively compared using the same methodology to identify conserved or subtype-specific patterns of genomic alterations. Here, we employed a large targeted hybrid-capture sequencing approach encompassing 380 genes to interrogate the genomic landscapes of 685 B-NHL tumors at high depth, including diffuse large B-cell lymphoma, mantle cell lymphoma, follicular lymphoma, and Burkitt lymphoma. We identified conserved hallmarks of B-NHL that were deregulated in the majority of tumors from each subtype, including frequent genetic deregulation of the ubiquitin proteasome system. In addition, we identified subtype-specific patterns of genetic alterations, including clusters of co-occurring mutations and DNA copy number alterations. The cumulative burden of mutations within a single cluster were more discriminatory of B-NHL subtypes than individual mutations, implicating likely patterns of genetic cooperation that contribute to disease etiology. We therefore provide the first cross-sectional analysis of mutations and DNA copy number alterations across major B-NHL subtypes and a framework of co-occurring genetic alterations that deregulate genetic hallmarks and likely cooperate in lymphomagenesis.

Prediction of Hidden Blood Loss During Posterior Spinal Surgery.

Objective Identification of the risk factors for extraordinary hidden blood loss (HBL) could clarify the underlying causes and provide more appropriate management. This study aims to identify the predictors of HBL in spinal surgery.Methods Medical records were retrospectively retrieved to collect the data of patients who undergoing posterior thoracic and lumbar fusion surgery or scoliosis surgery. Demographic information, perioperative visible blood loss volume, as well as laboratory results were recorded. The patients receiving fusion surgery or scoliosis surgery were further divided into the HBL positive subgroup and the HBL negative subgroup. Differences in the variables between the groups were then analyzed. Binary logistic regression analysis was performed to determine independent risk factors associated with HBL.Results For patients undergoing posterior spinal surgery, the independent risk factors associated with HBL were autologous transfusion (for fusion surgery P=0.011, OR: 2.627, 95%CI: 1.574-2.782; for scoliosis surgery P<0.001, OR: 2.268, 95%CI: 2.143-2.504) and allogeneic transfusion (for fusion surgeryP<0.001, OR: 6.487, 95%CI: 2.349-17.915; for scoliosis surgery P<0.001, OR: 3.636, 95%CI: 2.389-5.231).Conclusions Intraoperative blood transfusion might be an early-warning indicator for perioperative HBL.

Genome variation and conserved regulation identify genomic regions responsible for strain specific phenotypes in rat.

BACKGROUND: The genomes of laboratory rat strains are characterised by a mosaic haplotype structure caused by their unique breeding history. These mosaic haplotypes have been recently mapped by extensive sequencing of key strains. Comparison of genomic variation between two closely related rat strains with different phenotypes has been proposed as an effective strategy for the discovery of candidate strain-specific regions involved in phenotypic differences. We developed a method to prioritise strain-specific haplotypes by integrating genomic variation and genomic regulatory data predicted to be involved in specific phenotypes. Specifically, we aimed to identify genomic regions associated with Metabolic Syndrome (MetS), a disorder of energy utilization and storage affecting several organ systems. RESULTS: We compared two Lyon rat strains, Lyon Hypertensive (LH) which is susceptible to MetS, and Lyon Low pressure (LL), which is susceptible to obesity as an intermediate MetS phenotype, with a third strain (Lyon Normotensive, LN) that is resistant to both MetS and obesity. Applying a novel metric, we ranked the identified strain-specific haplotypes using evolutionary conservation of the occupancy three liver-specific transcription factors (HNF4A, CEBPA, and FOXA1) in five rodents including rat. Consideration of regulatory information effectively identified regions with liver-associated genes and rat orthologues of human GWAS variants related to obesity and metabolic traits. We attempted to find possible causative variants and compared them with the candidate genes proposed by previous studies. In strain-specific regions with conserved regulation, we found a significant enrichment for published evidence to obesity-one of the metabolic symptoms shown by the Lyon strains-amongst the genes assigned to promoters with strain-specific variation. CONCLUSIONS: Our results show that the use of functional regulatory conservation is a potentially effective approach to select strain-specific genomic regions associated with phenotypic differences among Lyon rats and could be extended to other systems.

Skin targeted lipid vesicles as novel nano-carrier of ketoconazole: characterization, in vitro and in vivo evaluation.

Liposomal carriers for topical drug delivery have been studied since the 1980s and have evoked a considerable interest. However, the conventional liposomes do not deeply penetrate into the skin and remain confined to the outer layer of SC. In order to increase skin targeting of ketoconazole (KCZ), a hydrophobic broad-spectrum antifungal agent, this study describes novel lipid vesicles as nano-carriers for topical delivery. In this paper, lipid vesicular systems including conventional liposomes (CL), ethosomes, deformable liposomes (DL) and ethanol-containing deformable liposomes (DEL) were prepared as nano-carriers for KCZ, respectively. Sodium dodecyl sulfate [SDS, 0.08 % (W/V)] was used as edge activator for DL and DEL preparation. Characterization of the vesicles was based on particle size, zeta potential, entrapment efficiency and transmission electron microscopy (TEM). In addition, in vitro permeation profile was obtained using vertical diffusion Franz cells by porcine skin. The in vivo accumulation of KCZ was also evaluated in rat skin. Confocal microscopy was performed to visualize the penetration of fluorescently labeled vesicles into skin. All of the lipid vesicles showed almost spherical structures with low polydispersity index (PDI < 0.3) and nano-metric size (no more than 160 nm). The results demonstrated that DEL dramatically improved both in vitro and in vivo skin deposition compared to the CLs (P < 0.05), which was further confirmed by confocal laser scanning microscopy study. In vivo pharmacodynamic studies showed DEL improved antifungal activity against Candida albicans in shorter duration of time. Therefore, based on present study, the novel nano-carrier DEL capable of enhancing skin target effect and forming a micro drug-depot could serve as an effective skin targeting delivery for KCZ as an anti-fungal agent in local therapy.

Development of nanovesicular systems for dermal imiquimod delivery: physicochemical characterization and in vitro/in vivo evaluation.

The aim of the current investigation was to develop and statistically evaluate nanovesicular systems for dermal imiquimod delivery. To this purpose, transethosomes were prepared with phospholipid, ethanol and different permeation enhancers. Conventional ethosomes, with soy phospholipid and ethanol, were used as control. The prepared vesicles were characterized for size, zeta potential, stability and entrapment efficiency. The optimal transethosomal formulation with mean particle size of 82.3 ± 9.5 nm showed the higher entrapment efficiency (68.69 ± 1.7%). In vitro studies, permeation results of accumulated drug and local accumulation efficiency were significantly higher for transethosomes (24.64 µg/cm(2) and 6.70, respectively) than control (14.45 µg/cm(2) and 3.93, respectively). Confocal laser scanning microscopy of rhodamine 6G-loaded transethosomes revealed an enhanced retention into the deeper skin layers as compared to conventional ethosomes. Besides, Fourier-transform infra-red spectroscopy studies were also performed to understand the mechanism of interaction between skin and carriers. What's more, results of in vivo studies indicated the transethosomes of imiquimod providing the most effectiveness for dermal delivery among all of the formulations. These results suggested that transethosomes would be a promising dermal carrier for imiquimod in actinic keratose treatment.

Influence of Sex on Remifentanil's Cough-prevention Effect during Anesthetic Emergence.

OBJECTIVE: To investigate the influence of sex on the cough-preventing effect of target-controlled infusion(TCI)of remifentanil during anesthetic emergence. METHODS: A total of 25 female(group F)and 25 male(group M)patients undergoing thyroidectomy were recruited in the current study. Anesthesia was maintained with sevoflurane and remifentanil TCI.At the end of the surgery,inhalational anesthetics were discontinued,and remifentanil TCI at an effect-site concentration(Ce)of 2.0 ng/ml was maintained during emergence until extubation. The cough score,blood pressure,and heart rate(HR)during peri-extubation period as well as the respiratory rate,calm score,and sore throat score after extubation were evaluated. RESULTS: During extubation,the proportion of patients with no cough or just a single cough was significantly higher in group F than in group M(88% vs. 64%,P=0.047). Mean arterial pressure(P=0.025,P=0.037)and HR(P=0.035)were significantly increased during extubation compared with preoperative levels in group M. CONCLUSIONS: Sex may influence the cough-preventing effect of remifentanil TCI during anesthetic emergence. At a Ce of 2.0 ng/ml,remifentanil has better cough-preventing effect and more stable hemodynamic status in females than in males.

Genomic structure of nucleotide diversity among Lyon rat models of metabolic syndrome.

BACKGROUND: The metabolic syndrome (MetS), a complex disorder involving hypertension, obesity, dyslipidemia and insulin resistance, is a major risk factor for heart disease, stroke, and diabetes. The Lyon Hypertensive (LH), Lyon Normotensive (LN) and Lyon Low-pressure (LL) rats are inbred strains simultaneously derived from a common outbred Sprague Dawley colony by selection for high, normal, and low blood pressure, respectively. Further studies found that LH is a MetS susceptible strain, while LN is resistant and LL has an intermediate phenotype. Whole genome sequencing determined that, while the strains are phenotypically divergent, they are nearly 98% similar at the nucleotide level. Using the sequence of the three strains, we applied an approach that harnesses the distribution of Observed Strain Differences (OSD), or nucleotide diversity, to distinguish genomic regions of identity-by-descent (IBD) from those with divergent ancestry between the three strains. This information was then used to fine-map QTL identified in a cross between LH and LN rats in order to identify candidate genes causing the phenotypes. RESULTS: We identified haplotypes that, in total, contain at least 95% of the identifiable polymorphisms between the Lyon strains that are likely of differing ancestral origin. By intersecting the identified haplotype blocks with Quantitative Trait Loci (QTL) previously identified in a cross between LH and LN strains, the candidate QTL regions have been narrowed by 78%. Because the genome sequence has been determined, we were further able to identify putative functional variants in genes that are candidates for causing the QTL. CONCLUSIONS: Whole genome sequence analysis between the LH, LN, and LL strains identified the haplotype structure of these three strains and identified candidate genes with sequence variants predicted to affect gene function. This approach, merged with additional integrative genetics approaches, will likely lead to novel mechanisms underlying complex disease and provide new drug targets and therapies.

An uncommon and easily overlooked case: Delayed intraperitoneal bladder rupture following blunt trauma: A case report and review of the literature.

INTRODUCTION: Delayed intraperitoneal bladder rupture is a rare clinical occurrence, frequently overlooked and misdiagnosed due to its nonspecific clinical manifestations. However, literature provides only a limited number of cases reporting delayed intraperitoneal bladder rupture resulting from blunt abdominal injury. PATIENT CONCERNS: A 72-year-old female pedestrian was struck by a vehicle and experienced sudden, severe abdominal pain on the 8th day following the injury. Abdominal B-ultrasound revealed a significant accumulation of peritoneal effusion. The abdominal puncture retrieved serosanguinous ascites. Then the patient was promptly transferred to our hospital. Upon transfer, the physical examination revealed the patient vital signs to be stable, accompanied by mild abdominal distension, slight tenderness, tension, and an absence of rebound tenderness. Urinalysis detected microscopic hematuria, while contrast-enhanced computed tomography (CT) revealed considerable fluid accumulation in the abdominal cavity, without evidence of solid organ damage, and the bladder was adequately filled. DIAGNOSIS: The diagnosis of delayed intraperitoneal bladder rupture primarily relied on intraoperative observations. INTERVENTIONS: An emergency exploratory laparotomy was performed, revealing a linear rupture at the dome of the bladder. Subsequently, the bladder rupture was repaired. OUTCOMES: Postoperative cystography demonstrated full recovery and the patient was discharged 28 days post-surgery. The postoperative recovery was uneventful without any complications. CONCLUSIONS: A well-distended bladder observed in CT does not definitively rule out the potential for bladder injury. False negatives may occur due to incomplete bladder filling during CT cystography. Retrograde cystography can identify cases missed by CT cystography. In cases of substantial intra-abdominal free fluid, surgical intervention should be actively considered for patients with blunt abdominal trauma without concurrent solid organ damage.

Type IV pilus retraction is required for Neisseria musculi colonization and persistence in a natural mouse model of infection.

IMPORTANCE: We describe the importance of Type IV pilus retraction to colonization and persistence by a mouse commensal Neisseria, N. musculi, in its native host. Our findings have implications for the role of Tfp retraction in mediating interactions of human-adapted pathogenic and commensal Neisseria with their human host due to the relatedness of these species.

Genus-specific secondary metabolome in Allokutzneria and Kibdelosporangium.

Rare actinomycete genera are highly recognized as a promising source of structurally diverse and bioactive natural products. Among these genera, Allokutzneria and Kibdelosporangium are two phylogenetically closely related and have been reported to encode some valuable biosynthetic enzymes and secondary metabolites. However, there is currently no relevant systematic research available to outline the linkage of genomic and metabolomics for specific secondary metabolites in these two promising genera. In this study, we first investigated the genus-specific secondary metabolic potential in Allokutzneria and Kibdelosporangium by comparing the diversity and novelty of their secondary metabolite biosynthetic gene clusters (BGCs). The specific secondary metabolites produced by two representative strains of these genera were comprehensively investigated using untargeted metabolomics techniques. The findings unveiled that the majority (95.4%) of the gene cluster families (GCFs) encoded by Allokutzneria and Kibdelosporangium were genus-specific, including NRPS GCFs encoding siderophores. The untargeted metabolomics analysis revealed that the metabolic profiles of two representative strains exhibit extensive specificity, with the culture medium having a big impact on the metabolic profiles. Besides, an MS-cluster featuring a series of hydroxamate-type siderophores was identified from Allokutzneria albata JCM 9917, with two of them, including a novel one (N-deoxy arthrobactin A), being experimentally validated. The present study offers valuable insights for the targeted discovery of genus-specific natural products from microorganisms.

The use of bubble charts in analyzing the global second-stage cesarean delivery rates: a systematic review.

OBJECTIVE: This study aimed to systematically review the worldwide second-stage cesarean delivery rate concerning pre-second-stage cesarean delivery and assisted vaginal birth rates. DATA SOURCES: PubMed, Medline Ovid, EBSCOhost, Embase, Scopus, and Google Scholar were queried from inception to February 2023, with the following terms: "full dilatation," "second stage," and "cesarean," with their word variations. Furthermore, an additional cohort of 353,434 cases from our recently published study was included. STUDY ELIGIBILITY CRITERIA: Only original studies that provided sufficient information on the number of pre-second-stage cesarean deliveries, second-stage cesarean deliveries, and vaginal births were included for the calculation of different modes of delivery. Systemic reviews, meta-analyses, or case reports were excluded. METHODS: Study identification and data extraction were independently performed by 2 authors. Selected studies were categorized on the basis of parity, study period, and geographic regions for comparison. RESULTS: A total of 25 studies were included. The overall pre-second-stage cesarean delivery rate, the second-stage cesarean delivery rate, and the second-stage cesarean delivery-to-assisted vaginal birth ratio were 17.94%, 2.65%, and 0.19, respectively. Only 5 studies described singleton, term, cephalic presenting pregnancies of nulliparous women, and their second-stage cesarean delivery rates were significantly higher than those studies with cohorts of all parity groups (4.50% vs 0.83%; P<.05). In addition, the second-stage cesarean delivery rate showed a secular increase across 2009 (0.70% vs 1.05%; P<.05). Moreover, it was the highest among African studies (5.14%) but the lowest among studies from East Asia and South Asia (0.94%). The distributions of second-stage cesarean delivery rates of individual studies and subgroups were shown with that of pre-second-stage cesarean delivery and assisted vaginal birth using the bubble chart. CONCLUSION: The overall worldwide pre-second-stage cesarean delivery rate was 17.94%, the second-stage cesarean delivery rate was 2.65%, and the second-stage cesarean delivery-to-assisted vaginal birth ratio was 0.19. The African studies had the highest second-stage cesarean delivery rate (5.14%) and second-stage cesarean delivery-to-assisted vaginal birth ratio (1.88), whereas the studies from East Asia and South Asia were opposite (0.94% and 0.11, respectively).

Angiotensin II type 2 receptor is critical for the development of human fetal pancreatic progenitor cells into islet-like cell clusters and their potential for transplantation.

Local renin-angiotensin systems (RASs) regulate the differentiation of tissue progenitors. However, it is not known whether such systems can regulate the development of pancreatic progenitor cells (PPCs). To address this issue, we characterized the expression profile of major RAS components in human fetal PPC preparations and examined their effects on the differentiation of PPCs into functional islet-like cell clusters (ICCs). We found that expression of RAS components was highly regulated throughout PPC differentiation and that locally generated angiotensin II (Ang II) maintained PPC growth and differentiation via Ang II type 1 and type 2 (AT(1) and AT(2)) receptors. In addition, we observed colocalization of AT(2) receptors with critical ß-cell phenotype markers in PPCs/ICCs, as well as AT(2) receptor upregulation during differentiation, suggesting that these receptors may regulate ß-cell development. In fact, we found that AT(2) , but not AT(1) , receptor was a key mediator of Ang II-induced upregulation of transcription factors important in ß-cell development. Furthermore, lentivirus-mediated knockdown of AT(2) receptor suppressed the expression of these transcription factors in ICCs. Transplantation of AT(2) receptor-depleted ICCs into immune-privileged diabetic mice failed to ameliorate hyperglycemia, implying that AT(2) receptors are indispensable during ICC maturation in vivo. These data strongly indicate that a local RAS is involved in governing the functional maturation of pancreatic progenitors toward the endocrine lineage.

The SMAC mimetic birinapant alleviates lipopolysaccharide-induced acute lung injury by inhibiting MAPK signaling.

The second mitochondria-derived activator of caspases (SMAC) mimetic birinapant attenuated liver injury by inhibited the degradation of tumor necrosis factor receptor-associated factor 3 (TRAF3) and activation of mitogen-activated protein kinase (MAPK) signaling pathway in liver macrophage, but its role in LPS induced acute lung injury (ALI) is not understood. The present study was to investigate the effects of birinapant on ALI and its possible mechanism. A dose of birinapant (30 mg/kg) or a vehicle was administered intravenously 24 hours before LPS (100 µg) stimulation in mice. The levels of TNF-α, IL-6 and IL-1ß in bronchoalveolar lavage fluid (BALF) were measured by ELISA. The infiltrated macrophages and expression of monocyte chemoattractant protein-1 (MCP-1) was determined by immunohistochemistry staining in the lung tissues. The JNK and p38 MAPK activation, protein expression and K48-linked polyubiquitination of TRAF3 were determined in alveolar macrophage cell line (MH-S cells) after 1µg/ml LPS stimulation. The results showed that the birinapant down-regulated the levels of TNF-α, IL-6 and IL-1ß in the BALF. In addition, birinapant markedly inhibited macrophages infiltration and MCP-1 protein expression in lung tissues. At last, birinapant suppressed the MAPKsignaling pathway and K48-linked ubiquitinated degradation of TRAF3 in MH-S cells after LPS administration. In conclusion, the results proved that birinapant protected against LPS-induced ALI through inhibiting MAPK activation and K48-linked ubiquitination of TRAF3 in alveolar macrophages.

Nerve growth factor-basic fibroblast growth factor poly-lactide co-glycolid sustained-release microspheres and the small gap sleeve bridging technique to repair peripheral nerve injury.

We previously prepared nerve growth factor poly-lactide co-glycolid sustained-release microspheres to treat rat sciatic nerve injury using the small gap sleeve technique. Multiple growth factors play a synergistic role in promoting the repair of peripheral nerve injury; as a result, in this study, we added basic fibroblast growth factors to the microspheres to further promote nerve regeneration. First, in an in vitro biomimetic microenvironment, we developed and used a drug screening biomimetic microfluidic chip to screen the optimal combination of nerve growth factor/basic fibroblast growth factor to promote the regeneration of Schwann cells. We found that 22.56 ng/mL nerve growth factor combined with 4.29 ng/mL basic fibroblast growth factor exhibited optimal effects on the proliferation of primary rat Schwann cells. The successfully prepared nerve growth factor-basic fibroblast growth factor-poly-lactide-co-glycolid sustained-release microspheres were used to treat rat sciatic nerve transection injury using the small gap sleeve bridge technique. Compared with epithelium sutures and small gap sleeve bridging alone, the small gap sleeve bridging technique combined with drug-free sustained-release microspheres has a stronger effect on rat sciatic nerve transfection injury repair at the structural and functional level.