TSA-seq reveals a largely conserved genome organization relative to nuclear speckles with small position changes tightly correlated with gene expression changes.

TSA-seq mapping suggests that gene distance to nuclear speckles is more deterministic and predictive of gene expression levels than gene radial positioning. Gene expression correlates inversely with distance to nuclear speckles, with chromosome regions of unusually high expression located at the apex of chromosome loops protruding from the nuclear periphery into the interior. Genomic distances to the nearest lamina-associated domain are larger for loop apexes mapping closest to nuclear speckles, suggesting the possibility of conservation of speckle-associated regions. To facilitate comparison of genome organization by TSA-seq, we reduced required cell numbers 10- to 20-fold for TSA-seq by deliberately saturating protein-labeling while preserving distance mapping by the still unsaturated DNA-labeling. Only ∼10% of the genome shows statistically significant shifts in relative nuclear speckle distances in pair-wise comparisons between human cell lines (H1, HFF, HCT116, K562); however, these moderate shifts in nuclear speckle distances tightly correlate with changes in cell type-specific gene expression. Similarly, half of heat shock-induced gene loci already preposition very close to nuclear speckles, with the remaining positioned near or at intermediate distance (HSPH1) to nuclear speckles but shifting even closer with transcriptional induction. Speckle association together with chromatin decondensation correlates with expression amplification upon HSPH1 activation. Our results demonstrate a largely "hardwired" genome organization with specific genes moving small mean distances relative to speckles during cell differentiation or a physiological transition, suggesting an important role of nuclear speckles in gene expression regulation.

Effectiveness and pregnancy outcomes of ultrasound-indicated and physical examination-indicated cervical cerclage: a retrospective study from a single centre.

OBJECTIVE: Preterm birth (PTB) is the leading cause of neonatal morbidity and mortality worldwide, and cervical incompetence (CIC) is a significant contribution. Cervical cerclage (CC) is an effective obstetric intervention. However, many clinical factors affect the success rate of surgery. The objective was to investigate and compare the pregnancy and neonatal outcomes of patients who underwent ultrasound- and physical examination-indicated cervical cerclage and to explore the influencing factors of preterm delivery before 34 weeks. METHODS: The sociodemographic characteristics and clinical data of patients with a diagnosis of cervical incompetence who underwent ultrasound- and physical examination-indicated transvaginal cervical cerclage at Nanjing Maternal and Child Health Hospital from January 2020 to December 2022 were retrospectively analyzed. The pregnancy and neonatal outcomes of the patients were evaluated. Continuous variables were compared using Student's t test (for normally distributed data) or the Mann-Whitney U test (for nonnormally distributed data). Categorical variables were analysed using the chi-square test or Fisher's exact test. Additionally, logistic regression analyses and receiver operating characteristic curves were used to evaluate the associations of inflammatory markers with maternal and neonatal outcomes. RESULTS: This study included 141 participants who underwent cervical cerclage, including 71 with ultrasound-indicated cerclage and 70 with physical examination-indicated cerclage. Compared to those in the ultrasound-indicated cerclage group, the duration from cerclage to delivery, birth weight, and APGAR score in the physical examination-indicated cerclage group were significantly lower, and the rates of delivery at < 28 weeks, < 32 weeks, < 34 weeks, and < 37 weeks of gestation and neonatal mortality were significantly higher (all P < 0.05). Compared to those in the physical ultrasound-indicated cerclage group, in the physical examination-indicated cerclage group, maternal blood inflammatory markers, such as C-reactive protein (CRP), the systemic immune-inflammation index (SII) and the systemic inflammation response index (SIRI) were significantly higher (P < 0.05). Additionally, maternal blood inflammatory markers, such as the CRP, white blood cell count, platelet to lymphocyte ratio (PLR), SII, and SIRI were significantly higher in the group with delivery before 34 weeks of gestation. Furthermore, the results demonstrated that twin pregnancy had the highest OR for preterm delivery before 34 weeks of gestation (OR = 3.829; 95% CI 1.413-10.373; P = 0.008), as well as the following: the SII level (OR = 1.001; 95% CI 1.000-1.002; P = 0.003) and CRP level (OR = 1.083; 95% CI 1.038-1.131; P = 0.022). The risk factors for preterm delivery before 34 weeks of gestation were twin gestation, an increased SII level and an increased CRP level, which had good combined predictive value. CONCLUSION: In patients with cervical insufficiency, ultrasound-indicated cervical cerclage appears to lead to better pregnancy outcomes than physical examination-indicated cerclage. Twin pregnancy and maternal blood inflammatory markers, such as the CRP level and the SII, are associated with preterm delivery before 34 weeks of gestation.

Risk Factors for Postpartum Hemorrhage in Severe Pre-Eclampsia: A Retrospective Single-Centre Study of 1953 Cases.

BACKGROUND Severe pre-eclampsia (sPE) and postpartum hemorrhage (PPH) in pregnancy have serious impact on maternal and fetal health and life. Co-occurrence of sPE and PPH often leads to poor pregnancy outcomes. We explored risk factors associated with PPH in women with sPE. MATERIAL AND METHODS This retrospective study included 1953 women with sPE who delivered at the Women's Hospital of Nanjing Medical University between April 2015 and April 2023. Risk factors for developing PPH in sPE were analyzed, and subgroups were analyzed by delivery mode (cesarean and vaginal). RESULTS A total of 197 women with PPH and 1756 women without PPH were included. Binary logistic regression results showed twin pregnancy (P<0.001), placenta accreta spectrum disorders (P=0.045), and placenta previa (P<0.001) were independent risk factors for PPH in women with sPE. Subgroup analysis showed risk factors for PPH in cesarean delivery group were the same as in the total population, but vaginal delivery did not reduce risk of PPH. Spinal anesthesia reduced risk of PPH relative to general anesthesia (P=0.034). Vaginal delivery group had no independent risk factors for PPH; however, magnesium sulfate (P=0.041) reduced PPH incidence. CONCLUSIONS Women with twin pregnancy, placenta accreta spectrum disorders, placenta previa, and assisted reproduction with sPE should be alerted to the risk of PPH, and spinal anesthesia should be preferred in cesarean delivery. Magnesium sulfate should be used aggressively in women with sPE; however, the relationship between magnesium sulfate and PPH risk needs further investigation.

Molecular hydrogen promotes retinal vascular regeneration and attenuates neovascularization and neuroglial dysfunction in oxygen-induced retinopathy mice.

BACKGROUND: Retinopathy of Prematurity (ROP) is a proliferative retinal vascular disease occurring in the retina of premature infants and is the main cause of childhood blindness. Nowadays anti-VEGF and retinal photocoagulation are mainstream treatments for ROP, but they develop a variety of complications. Hydrogen (H2) is widely considered as a useful neuroprotective and antioxidative therapeutic method for hypoxic-ischemic disease without toxic effects. However, whether H2 provides physiological angiogenesis promotion, neovascularization suppression and glial protection in the progression of ROP is largely unknown.This study aims to investigate the effects of H2 on retinal angiogenesis, neovascularization and neuroglial dysfunction in the retinas of oxygen-induced retinopathy (OIR) mice. METHODS: In this study, mice that were seven days old and either wild-type (WT) or Nrf2-deficient (Nrf2-/-) were exposed to 75% oxygen for 5 days and then returned to normal air conditions. Different stages of hydrogen gas (H2) inhalation were administered. Vascular obliteration, neovascularization, and blood vessel leakage were analyzed and compared. To count the number of neovascularization endothelial nuclei, routine HE staining of retinal sections was conducted. Immunohistochemistry was performed using DyLight 594 labeled GSL I-isolectin B4 (IB4), as well as primary antibodies against proliferating cell nuclear antigen (PCNA), glial fibrillary acidic protein (GFAP), and Iba-1. Western blots were used to measure the expression of NF-E2-related factor 2 (Nrf2), vascular endothelial growth factor (VEGF), Notch1, Dll4, and HIF-1α. Additionally, the expression of target genes such as NQO1, HO-1, Notch1, Hey1, Hey2, and Dll4 was measured. Human umbilical vein endothelial cells (HUVECs) treated with H2 under hypoxia were used as an in vitro model. RT-PCR was used to evaluate the mRNA expression of Nrf2, Notch/Dll4, and the target genes. The expression of reactive oxygen species (ROS) was observed using immunofluorescence staining. RESULTS: Our results indicate that 3-4% H2 does not disturb retinal physiological angiogenesis, but ameliorates vaso-obliteration and neovascularization in OIR mice. Moreover, H2 prevents the decreased density and reverses the morphologic and functional changes in retinal astrocytes caused by oxygen-induced injury. In addition, H2 inhalation reduces microglial activation, especially in the area of neovascularization in OIR mice. H2 plays a protective role in vascular regeneration by promoting Nrf2 activation and suppressing the Dll4-induced Notch signaling pathway in vivo. Also, H2 promotes the proliferation of HUVECs under hypoxia by negatively regulating the Dll4/Notch pathway and reducing ROS levels through Nrf2 pathway aligning with our findings in vivo.Moreover, the retinal oxygen-sensing mechanisms (HIF-1α/VEGF) are also involved in hydrogen-mediated retinal revascularization and neovascularization suppression. CONCLUSIONS: Collectively, our results indicate that H2 could be a promising therapeutic agent for POR treatment and that its beneficial effect in human ROP might involve the activation of the Nrf2-Notch axis as well as HIF-1α/VEGF pathways.

The Diagnostic Value of the Modified STdmax/MET Criterion in Treadmill Exercise Electrocardiographic Test for Coronary Artery Disease in an Aged Population.

Objective: The primary objective of this study is to assess the diagnostic value of treadmill exercise electrocardiographic test (EET) for coronary artery disease (CAD) in the aged population, emphasizing the need for improved diagnostic criteria due to the limitations of traditional EET in accurately diagnosing CAD among elderly patients. This focus is critical as the aged population has a higher prevalence of CAD, and early and accurate diagnosis is essential for effective management and treatment. Methods: This study comprised two stages. Initially, we retrospectively analyzed data from patients aged > 60 years who underwent treadmill EET within two weeks of coronary angiography (CAG) during hospitalization from June 1, 2014, to May 31, 2017. We evaluated the diagnostic value of treadmill EET using both the standard criterion (ST depression > 0.1 mV) and a modified criterion (the ratio of ST depression to metabolic equivalent [STdmax/MET]), explaining our choice of the modified criterion as it potentially offers a more nuanced assessment by considering the patient's exercise capacity. A subgroup analysis was also conducted. Subsequently, a prospective study to further investigate the modified criterion was carried out. Results: In the retrospective analysis, 190 patients were enrolled, with 71.5% confirmed to have CAD. The sensitivity, specificity, and accuracy of the standard criterion were 66.2%, 42.6%, and 59.5%, respectively. With a cut-off value for STdmax/MET set at 0.255 mV·W/m2, these metrics improved to 79.4%, 55.7%, and 72.4%, respectively, for the modified criterion. The prospective study, involving 47 patients, confirmed significant improvements in sensitivity (85.7% vs. 64.3%, P = .041) and specificity (68.4% vs. 31.6%, P = .046) when applying the modified criterion. Conclusions: The introduction of the novel modified diagnostic criterion, STdmax/MET, significantly enhances the diagnostic value of treadmill EET for detecting CAD in elderly patients. The adoption of this modified criterion could potentially improve clinical outcomes by facilitating more accurate and timely diagnosis of CAD in this high-risk group.

Outcomes after ORIF are similar in young and elderly patients with tibial plateau fractures: A minimum 2-year follow-up study.

BACKGROUND: This study aimed to compare the outcomes of open reduction internal fixation in young and elderly patients with tibial plateau fractures. METHODS: A total of 224 patients with tibial plateau fractures treated with open reduction internal fixation at a level I trauma center from 2014 to 2019 were reviewed. The patients with a minimum follow-up of 2 years were divided into two groups, with those aged 60 years and older divided into the elderly group and those under 60 years divided into the young group. The mean follow-up time was 55 months (range: 24-80), and the primary outcomes were quality of reduction and function. The secondary outcomes included complications, fracture healing time, and conversion to total knee arthroplasty. RESULTS: The elderly group had a higher proportion of women than the young group (61.1% vs. 23.9%, p < 0.001). Diabetes was more prevalent in the elderly cohort than in the young cohort (18.9% vs. 9.0%, p = 0.030). The rate of bone grafts was higher in the elderly group (57.8% vs. 41.8%, p = 0.019), but no significant differences were found between the groups regarding fracture characteristics, the operative time or intraoperative blood loss. The reduction quality, knee function, postoperative complications, healing time, and total knee arthroplasty conversion rate were not significantly different (p > 0.05) between the groups. CONCLUSIONS: Open reduction internal fixation remains a satisfactory technique to treat tibial plateau fractures in the elderly. Although the rate of bone grafts is higher in elderly patients, they had comparable outcomes compared with their younger counterparts.

Compartmentalization with nuclear landmarks yields random, yet precise, genome organization.

The 3D organization of eukaryotic genomes plays an important role in genome function. While significant progress has been made in deciphering the folding mechanisms of individual chromosomes, the principles of the dynamic large-scale spatial arrangement of all chromosomes inside the nucleus are poorly understood. We use polymer simulations to model the diploid human genome compartmentalization relative to nuclear bodies such as nuclear lamina, nucleoli, and speckles. We show that a self-organization process based on a cophase separation between chromosomes and nuclear bodies can capture various features of genome organization, including the formation of chromosome territories, phase separation of A/B compartments, and the liquid property of nuclear bodies. The simulated 3D structures quantitatively reproduce both sequencing-based genomic mapping and imaging assays that probe chromatin interaction with nuclear bodies. Importantly, our model captures the heterogeneous distribution of chromosome positioning across cells while simultaneously producing well-defined distances between active chromatin and nuclear speckles. Such heterogeneity and preciseness of genome organization can coexist due to the nonspecificity of phase separation and the slow chromosome dynamics. Together, our work reveals that the cophase separation provides a robust mechanism for us to produce functionally important 3D contacts without requiring thermodynamic equilibration that can be difficult to achieve.

Tafenoquine and its derivatives as inhibitors for the severe acute respiratory syndrome coronavirus 2.

The pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has severely affected human lives around the world as well as the global economy. Therefore, effective treatments against COVID-19 are urgently needed. Here, we screened a library containing Food and Drug Administration (FDA)-approved compounds to identify drugs that could target the SARS-CoV-2 main protease (Mpro), which is indispensable for viral protein maturation and regard as an important therapeutic target. We identified antimalarial drug tafenoquine (TFQ), which is approved for radical cure of Plasmodium vivax and malaria prophylaxis, as a top candidate to inhibit Mpro protease activity. The crystal structure of SARS-CoV-2 Mpro in complex with TFQ revealed that TFQ noncovalently bound to and reshaped the substrate-binding pocket of Mpro by altering the loop region (residues 139-144) near the catalytic Cys145, which could block the catalysis of its peptide substrates. We also found that TFQ inhibited human transmembrane protease serine 2 (TMPRSS2). Furthermore, one TFQ derivative, compound 7, showed a better therapeutic index than TFQ on TMPRSS2 and may therefore inhibit the infectibility of SARS-CoV-2, including that of several mutant variants. These results suggest new potential strategies to block infection of SARS-CoV-2 and rising variants.

Arginase-1 promotes lens epithelial-to-mesenchymal transition in different models of anterior subcapsular cataract.

BACKGROUND: Arginase-1 (ARG1) promotes collagen synthesis and cell proliferation. ARG1 is highly expressed in various tumour cells. The mechanisms of ARG1 in epithelial-to-mesenchymal transition (EMT)-associated cataracts were studied herein. METHODS: C57BL/6 mice, a human lens epithelial cell line (HLEC-SRA01/04), and human lens capsule samples were used in this study. The right lens anterior capsule of the mouse eye was punctured through the central cornea with a 26-gauge hypodermic needle. Human lens epithelial cells (HLECs) were transfected with ARG1-targeted (siARG1) or negative control siRNA (siNC). For gene overexpression, HLECs were transfected with a plasmid bearing the ARG1 coding sequence or an empty vector. Medium containing 0.2% serum with or without transforming growth factor beta-2 (TGF-ß2) was added for 6 or 24 h to detect mRNA or protein, respectively. The expression of related genes was measured by quantitative real-time polymerase chain reaction (RT-qPCR), western blotting, and immunohistochemical staining. Transwell assays and wound healing assays were used to determine cell migration. Cell proliferation, superoxide levels, nitric oxide (NO) levels, and arginase activity were estimated using Cell Counting Kit-8 assays, a superoxide assay kit, an NO assay kit, and an arginase activity kit. RESULTS: ARG1, alpha-smooth muscle actin (α-SMA), fibronectin, and Ki67 expression increased after lens capsular injury, while zonula occludens-1 (ZO-1) expression decreased. Fibronectin and collagen type I alpha1 chain (collagen 1A1) expression increased, and cell migration increased significantly in ARG1-overexpressing HLECs compared with those transfected with an empty vector after TGF-ß2 treatment. These effects were reversed by ARG1 knockdown. The arginase-related pathway plays an important role in EMT. mRNAs of enzymes of the arginase-related pathway were highly expressed after ARG1 overexpression. ARG1 knockdown suppressed these expression changes. Numidargistat (CB-1158) dihydrochloride (CB-1158), an ARG1 inhibitor, suppressed TGF-ß2-induced anterior subcapsular cataract (ASC) by reducing the proliferation of lens epithelial cells (LECs) and decreasing fibronectin, α-SMA, collagen 1A1, and vimentin expression. Compared with that in nonanterior subcapsular cataract (non-ASC) patients, the expression of ARG1, collagen 1A1, vimentin, fibronectin, and Ki67 was markedly increased in ASC patients. CONCLUSIONS: ARG1 can regulate EMT in EMT-associated cataracts. Based on the pathogenesis of ASC, these findings are expected to provide new therapeutic strategies for patients.

Fibrotic cataracts can be classified as anterior subcapsular cataract or posterior capsular opacification depending on where fibrosis occurs. The mechanism of fibrotic cataracts is not fully understood. Fibrotic opacities induced by trauma, inflammation, or radiation can accumulate underneath the anterior lens capsule, causing anterior subcapsular cataract. Posterior capsular opacification is one of the most common complications of phacoemulsification with intraocular lens implantation, with a high incidence in young patients. We show for the first time that ARG1 can regulate EMT in fibrotic cataracts. TGF-ß2 is the main cause of fibrosis in LECs. The expression of ARG1 and fibronectin in LECs increased after TGF-ß2 treatment or mouse lens capsular injury. We investigated the specific molecular mechanisms by which ARG1 regulates EMT in fibrotic cataracts. The mRNA expression of enzymes of the arginase-related pathway was decreased due to knockdown of ARG1 expression in HLECs. These effects were reversed by ARG1 overexpression. Additionally, knockdown of ARG1 decreased collagen 1A1, fibronectin, and vimentin expression; superoxide levels; and cell migration and increased NO levels. These effects were reversed by ARG1 overexpression. Pharmacological blockade of the ARG1 pathway with CB-1158 reduced the proliferation of LECs and decreased fibronectin, α-SMA, collagen 1A1, and vimentin expression in mouse lenses. We believe that ARG1 promotes the production of collagen 1A1 by directly activating the arginase pathway and leads to lens fibrosis by reducing NO production and increasing superoxide levels, providing a new mechanism for the prevention and treatment of fibrotic cataracts. Video Abstract.

Effectiveness of Needle Aspiration versus Surgical Excision for Symptomatic Synovial Cysts of the Hip: A Single-Center, Retrospective Study.

BACKGROUND This study was performed to evaluate the clinical effectiveness of needle aspiration vs surgical excision for symptomatic synovial cysts of the hip. MATERIAL AND METHODS This retrospective study analyzed the clinical data of patients diagnosed with synovial cysts of the hip and treated in a single-center hospital from January 2012 to April 2022. Patients receiving needle aspiration were assigned to group A and those treated with surgery were assigned to group B. Demographic characteristics, etiology, symptoms, cyst location, postoperative complications and recurrence, Harris Hip Score (HHS) and Visual Analog Scale of Pain (VAS) scores before treatment and at 3, 6, and 12 months after treatment were recorded to assess hip function in both groups. RESULTS This study recruited 44 patients, with 18 patients in group A and 26 in group B, and the 2 arms were well-balanced in terms of baseline patient profiles. Needle aspiration resulted in significantly better pain mitigation for patients at 24 h, 48 h, and 72 h after treatment vs surgical interventions (P<0.05). Needle joint aspiration resulted in significantly better function restoration of the hip joint than surgery at 3 months after treatment, as evidenced by the lower HHS score of 85.31±13.16 in group A vs 78.51±11.66 in group B (P=0.002). Surgery was associated with a significantly lower incidence of disease relapse (0.00%) vs needle aspiration (27.7%) (P=0.004). CONCLUSIONS Needle aspiration in the treatment of symptomatic synovial cysts of the hip causes less damage to the soft tissue and leads to faster recovery in the short term than surgical resection. Surgical resection has a lower recurrence rate and better long-term efficacy.

Tri-Lock Bone Preservation Stem Versus Conventional Corail Stem in Primary Total Hip Arthroplasty via Direct Anterior Approach: A Short-Term, Retrospective, Comparative Study.

BACKGROUND he present study was performed to evaluate the clinical efficacy of Tri-Lock bone preservation stems vs conventional Corail stems in primary total hip arthroplasty via direct anterior approach. MATERIAL AND METHODS In this retrospective analysis, patients receiving THA via DAA in a single-center hospital from January 2019 to March 2020 were assessed for eligibility and assigned to either a Tri-Lock BPS group or a Corail group based on the use of prostheses. Outcome measures for the efficiency evaluation of the 2 prostheses included perioperative outcomes, imaging results, Harris Hip Score, Western Ontario and McMaster University Osteoarthritis Index, and visual analog scale scores at 3, 6, 12, and 24 months postoperatively. RESULTS A total of 204 patients were included, including 98 patients (98 hips) in the Tri-Lock BPS group and 106 patients (106 hips) in the Corail group. Patients receiving Tri-Lock BPS exhibited better pain relief than those with Coral stems. Tri-Lock BPS had a higher safety profile vs Corail stems by significantly reducing the risk of complications (P=0.004). A markedly increased HHS score (84.42±16.27 vs 78.61±12.78, P=0.002) and a lower WOMAC score (25.08±15.39 vs 32.14±11.56, P=0.001) at 3 months postoperatively were observed in patients with Tri-Lock BPS vs those with Corail stems, indicating better restoration of hip function using Tri-Lock BPS. CONCLUSIONS During total hip arthroplasty via DAA, Tri-Lock BPS causes a smaller surgical wound, reduces the operative time and intraoperative bleeding, and produces less soft-tissue damage vs Corail stems, providing great benefits in femoral prosthesis placement.

Crystal structure and functional implication of a bacterial cyclic AMP-AMP-GMP synthetase.

Mammalian cyclic GMP-AMP synthase (cGAS) and its homologue dinucleotide cyclase in Vibrio cholerae (VcDncV) produce cyclic dinucleotides (CDNs) that participate in the defense against viral infection. Recently, scores of new cGAS/DncV-like nucleotidyltransferases (CD-NTases) were discovered, which produce various CDNs and cyclic trinucleotides (CTNs) as second messengers. Here, we present the crystal structures of EcCdnD, a CD-NTase from Enterobacter cloacae that produces cyclic AMP-AMP-GMP, in its apo-form and in complex with ATP, ADP and AMPcPP, an ATP analogue. Despite the similar overall architecture, the protein shows significant structural variations from other CD-NTases. Adjacent to the donor substrate, another nucleotide is bound to the acceptor binding site by a non-productive mode. Isothermal titration calorimetry results also suggest the presence of two ATP binding sites. GTP alone does not bind to EcCdnD, which however binds to pppApG, a possible intermediate. The enzyme is active on ATP or a mixture of ATP and GTP, and the best metal cofactor is Mg2+. The conserved residues Asp69 and Asp71 are essential for catalysis, as indicated by the loss of activity in the mutants. Based on structural analysis and comparison with VcDncV and RNA polymerase, a tentative catalytic pathway for the CTN-producing EcCdnD is proposed.

Proximal femoral bionic nail (PFBN)-an innovative surgical method for unstable femoral intertrochanteric fractures.

PURPOSE: Intertrochanteric femoral fractures (IFF) are one of the most common traumatic conditions, but there are no established treatment methods for this condition due to implant failure and re-operation rates. The proximal femoral bionic nail (PFBN), which is a new design of the cephalomedullary nail, was developed by our team. The objective of this study was to assess the clinical and radiographic outcomes of PFBN in patients with unstable IFF. METHODS: From October 2020 to August 2021, 12 patients diagnosed with unstable IFF (31-A2, 3) were treated with PFBN at the Third Hospital of Hebei Medical University. We evaluated the clinical therapeutic effects of this treatment by measuring peri-operative indicators and post-operative complications. Clinical outcomes, specific radiographic parameters, and post-operative complications were collected and analyzed within the first post-operative year. RESULTS: The average age of the patients was 72.4 ± 16.1 years (five males and seven females). The mean operation time was 90.4 ± 16.0 min, whereas the operation time of 31-A2 fractures (83.1 ± 12.2 min) was shorter than that of 31-A3 fractures (105.0 ± 12.9 min) (p < 0.05). The blood loss was 175 ml (range: 50 to 500 ml), and the length of hospitalization was 10.0 ± 1.9 days. The prognosis evaluation was assessed at three, six and 12 months after the operation; for these time points, the Harris hip scores were 69.6 ± 4.1, 77.8 ± 3.8, and 82.6 ± 4.6, respectively, and the Parker-Palmer scores were 5.3 (5.0, 7.0), 6.3 (5.3, 7.0), and 7.8 (7.0, 8.0), respectively. CONCLUSION: PFBN has shown advantages in the treatment of unstable IFF (particularly in geriatric patients) and possesses both stability and safety. This innovative method may provide a new option for treating unstable IFFs.

New Classification Based on CT and Its Value Evaluation for Fractures of the Lateral Process of the Talus.

This study aimed to develop a comprehensive classification system for fractures of the lateral process of the talus (LPTF) based on CT, and to evaluate its prognostic value, reliability and reproducibility. We retrospectively reviewed 42 patients involving LPTF with an average follow-up of 35.9 months for clinical and radiographic evaluations. In order to develop a comprehensive classification, a panel of experienced orthopedic surgeons discussed the cases. All fractures were classified according to Hawkins, McCrory-Bladin and new proposed classifications by 6 observers. The analysis of interobserver and intraobserver agreements was measured using kappa statistics. The new classification included 2 types based on presence of concomitant injuries or not, with type I consisting of 3 subtypes and type II of 5 subtypes. Average AOFAS score was 91.5 in the type Ia of new classification, 86 in type Ib, 90.5 in type Ic, 89 in type IIa, 76.7 in type IIb, 76.6 in type IIc, 91.3 in type IId, and 83.5 in type IIe. Interobserver and intraobserver reliability of the new classification system were almost perfect (κ = 0.776 and 0.837, respectively), showing a higher interobserver and intraobserver reliability compared to the Hawkins classification (κ 0.572 and 0.649, respectively) as well as McCrory-Bladin classification (κ = 0.582 and 0.685, respectively). The new classification system is a comprehensive one that takes into account concomitant injuries and shows good prognostic value with clinical outcomes. It is more reliable and reproducible and could be a useful tool for decision-making on treatment options for LPTF.

The Current Status of Bereavement Care in Chinese Emergency Departments: A Multicenter Cross-Sectional Study.

Understanding the current status and challenges of bereavement care will help facilitate the development of bereavement care in the emergency department. However, little is known about the status of bereavement care in Chinese emergency departments and nurses' perceptions of bereavement care. We used a self-made questionnaire to survey 124 head nurses and 870 emergency nurses in 21 hospitals in Jiangsu Province in September 2023. Among 124 emergency departments, 78 (62.90%) emergency departments provided bereavement care strategies, and the most frequent strategy was a waiting room, relevant information on funeral arrangements and the establishment of a relatively secluded environment conducive to the solace of the patient's family, or the provision of a dedicated farewell chamber. Emergency nurses believed that bereavement care is important but difficult to implement, with support resources, environment and human resources being the main challenges. In the future, further attention should be paid to the development of bereavement care in the emergency department, and the implementation of bereavement care should be supported in terms of policies, funds, resources and personnel.

Why Omicron Variant of SARS-CoV-2 is Less Fatal?

The article published by Nie et al. addressed one of the two key questions regarding the Omicron variant of SARS-CoV-2, while the underpinning for the less deadly nature of the variant remains unexplained. The proteins of the Omicron variant have numerous mutations, notably several substitutions of other amino acids by lysine residues. Glycine and valine attract calcium and enhance the formation of stressful, insoluble, and stiff calcium oxalate. Lysine residues in proteins build up chloride via ionic bonds which solubilizes insoluble and rigid divalent salts. The aforementioned mutations have weakened the lethalness of the Omicron variant perhaps via a biochemical mechanism. Despite net gain in favorable mutations versus deleterious mutations, the overall valine plus glycine content is still high in the proteins of Omicron variant of SARS-CoV-2, which remains a public health concern.

Biodistribution and dosimetry in human healthy volunteers of the PET radioligands [11C]CHDI-00485180-R and [11C]CHDI-00485626, designed for quantification of cerebral aggregated mutant huntingtin.

PURPOSE: Huntington's disease is caused by a trinucleotide expansion in the HTT gene, which leads to aggregation of mutant huntingtin (mHTT) protein in the brain and neurotoxicity. Direct in vivo measurement of mHTT aggregates in human brain parenchyma is not yet possible. In this first-in-human study, we investigated biodistribution and dosimetry in healthy volunteers of [11C]CHDI-00485180-R ([11C]CHDI-180R) and [11C]CHDI-00485626 ([11C]CHDI-626), two tracers designed for PET imaging of aggregated mHTT in the brain that have been validated in preclinical models. METHODS: Biodistribution and radiation dosimetry studies were performed in 3 healthy volunteers (age 25.7 ± 0.5 years; 2 F) for [11C]CHDI-180R and in 3 healthy volunteers (age 35.3 ± 6.8 years; 2 F) for [11C]CHDI-626 using sequential whole-body PET-CT. Source organs were delineated in 3D using combined PET and CT data. Individual organ doses and effective doses were determined using OLINDA 2.1. RESULTS: There were no clinically relevant adverse events. The mean effective dose (ED) for [11C]CHDI-180R was 4.58 ± 0.65 µSv/MBq, with highest absorbed doses for liver (16.9 µGy/MBq), heart wall (15.9 µGy/MBq) and small intestine (15.8 µGy/MBq). Mean ED for [11C]CHDI-626 was 5.09 ± 0.06 µSv/MBq with the highest absorbed doses for the gallbladder (26.5 µGy/MBq), small intestine (20.4 µGy/MBq) and liver (19.6 µGy/MBq). Decay-corrected brain uptake curves showed promising kinetics for [11C]CHDI-180R, but for [11C]CHDI-626 an increasing signal over time was found, probably due to accumulation of a brain-penetrant metabolite. CONCLUSION: [11C]CHDI-180R and [11C]CHDI-626 are safe for in vivo PET imaging in humans. The estimated radiation burden is in line with most 11C-ligands. While [11C]CHDI-180R has promising kinetic properties in the brain, [11C]CHDI-626 is not suitable for human in vivo mHTT PET due to the possibility of a radiometabolite accumulating in brain parenchyma. TRIAL REGISTRATION: EudraCT number 2020-002129-27. CLINICALTRIALS: gov NCT05224115 (retrospectively registered).

Deciphering molecular mechanism of silver by integrated omic approaches enables enhancing its antimicrobial efficacy in E. coli.

Despite the broad-spectrum antimicrobial activities of silver, its internal usage is restricted, owing to the toxicity. Strategies to enhance its efficacy are highly desirable but rely heavily on the understanding of its molecular mechanism of action. However, up to now, no direct silver-targeting proteins have been mined at a proteome-wide scale, which hinders systemic studies on the biological pathways interrupted by silver. Herein, we build up a unique system, namely liquid chromatography gel electrophoresis inductively coupled plasma mass spectrometry (LC-GE-ICP-MS), allowing 34 proteins directly bound by silver ions to be identified in Escherichia coli. By using integrated omic approaches, including metalloproteomics, metabolomics, bioinformatics, and systemic biology, we delineated the first dynamic antimicrobial actions of silver (Ag+) in E. coli, i.e., it primarily damages multiple enzymes in glycolysis and tricarboxylic acid (TCA) cycle, leading to the stalling of the oxidative branch of the TCA cycle and an adaptive metabolic divergence to the reductive glyoxylate pathway. It then further damages the adaptive glyoxylate pathway and suppresses the cellular oxidative stress responses, causing systemic damages and death of the bacterium. To harness these novel findings, we coadministrated metabolites involved in the Krebs cycles with Ag+ and found that they can significantly potentiate the efficacy of silver both in vitro and in an animal model. Our study reveals the comprehensive and dynamic mechanisms of Ag+ toxicity in E. coli cells and offers a novel and general approach for deciphering molecular mechanisms of metallodrugs in various pathogens and cells to facilitate the development of new therapeutics.

Iron supplementation and iron-fortified foods: a review.

About one-third of the world population is suffering from iron deficiency. Delivery of iron through diet is a practical, economical, and sustainable approach. Clinical studies have shown that the consumption of iron-fortified foods is one of the most effective methods for the prevention of iron deficiency. However, supplementing iron through diet can cause undesirable side-effects. Thus, it is essential to develop new iron-rich ingredients, iron-fortified products with high bioavailability, better stability, and lower cost. It is also essential to develop newer processing technologies for more effective fortification. This review compared the iron supplementation strategies used to treat the highly iron-deficient population and the general public. We also reviewed the efficacy of functional (iron-rich) ingredients that can be incorporated into food materials to produce iron-fortified foods. The most commonly available foods, such as cereals, bakery products, dairy products, beverages, and condiments are still the best vehicles for iron fortification and delivery.Scope of reviewThe manuscript aims at providing a comprehensive review of the latest publications that cover three aspects: administration routes for iron supplementation, iron-rich ingredients used for iron supplementation, and iron-fortified foods.

Protection effect of thymosin ß4 on ethanol injury in corneal stromal keratocyte.

PURPOSE: To investigate the protective effects of thymosin ß4 (Tß4) on ethanol injured human corneal keratocytes (HCKs). METHODS: HCKs and BALB/c mice were chosen as the study subject. Ethanol was used to treat the cells and corneal stroma of mice to build the ethanol injured model in vitro and vivo respectively. CCK-8 was used to evaluate the cell metabolic activity. DCFH-DA was used to detect the intracellular reactive oxygen species level. TUNEL was chose to detect the cell apoptosis rate. The cell proliferation and migration were investigated by using wound healing insert. Wound healing of corneal surface and stroma was observed by using fluorescein sodium eyedrop and HE stain. RT-qPCR, ELISA, and immunostaining were performed to detect gene and protein expression in keratocytes or corneal stroma tissue of mice. RESULTS: Ethanol induced oxidative stress injury and cell apoptosis on HCKs, and Tß4 can alleviate it by up-regulating the expression of Bcl-2, catalase, and CuZnSOD, and inhibiting the expression of Caspase-3. Tß4 promotes the proliferation of HCKs and the process of corneal wound healing. It may relevant to the up-regulated expression of Ki67. CONCLUSIONS: Our study established an ethanol-injured corneal stroma model in both vitro and vivo. The present study confirmed that Tß4 play a protective effect on the reconstruction process of ethanol-injured corneal stroma.