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Background: Severe mental illness (SMI), which includes schizophrenia, schizoaffective disorder and bipolar disorder, has profound health impacts, even in the elderly., Aims: To evaluate relative risk of hospital admission and length of hospital stay for physical illness in elders with SMI., Method: To construct a population-based retrospective cohort observed from April 2007 to March 2016, data from a case registry with full but de-identified electronic health records were retrieved for patients of the South London and Maudsley NHS Foundation Trust, the single secondary mental healthcare service provider in south-east London. We compared participants with SMI aged >60 years old with the general population of the same age and residing in the same areas through data linkage by age-, sex- and fiscal-year-standardised admission ratios (SARs) for primary diagnoses at hospital discharge. Furthermore, we compared the duration of hospital stay with an age-, sex- and cause-of-admission-matched random group by linear regression for major causes of admission., Results: In total, records for 4175 older people with SMI were obtained, relating to 10 342 admission episodes, showing an overall SAR for all physical illnesses of 5.15 (95% CI: 5.05, 5.25). Among the top causes of admission, SARs ranged from 3.87 for circulatory system disorders (ICD-10 codes: I00-I99) to 6.99 for genitourinary system or urinary conditions (N00-N39). Specifically, the diagnostic group of 'symptoms, signs and findings, not elsewhere classified' (R00-R99) had an elevated SAR of 6.56 (95% CI: 6.22, 6.90). Elders with SMI also had significantly longer hospital stays than their counterparts in the general population, especially for digestive system illnesses (K00-K93), after adjusting for confounding., Conclusions: Poorer overall physical health and specific patterns were identified in elders with SMI.

Background: Sepsis-associated encephalopathy (SAE) is among the most prevalent and deadly complications associated with sepsis, but satisfactory treatments and therapeutic agents are lacking. Gelsevirine, an active ingredient derived from Gelsemium elegans Benth., has shown promising effects in animal models of anxiety, ischaemic stroke and osteoarthritis. However, its protective effect against SAE and its mechanism of action are still unknown., Purpose: To elucidate the efficacy of gelsevirine against SAE and the mechanism of its protective effect through the STING signalling-mediated pyroptosis pathway., Methods: We constructed a mouse model of caecum ligation and puncture (CLP)-induced sepsis and explored the protective effects of gelsevirine in mice with SAE by assessing survival rates and behavioural alterations. To further explore its mechanism of action, we investigated the modulatory effects of gelsevirine on the levels of inflammatory factors, microglial activation and pyroptosis by Western blotting, immunohistochemistry staining and PCR. STING knockout mice were used to verify the protective effect of gelsevirine against SAE through the STING pathway., Results: Gelsevirine increased the survival rate of mice with SAE. The Morris water maze and open field tests revealed that gelsevirine significantly alleviated cognitive dysfunction and increased exploratory behaviour in mice with SAE. Gelsevirine inhibited the activation of microglia and decreased inflammatory factor levels in the hippocampus of mice with SAE. In mice with SAE and in vitro BV2 microglia, gelsevirine reduced levels of inflammatory factors and inhibited STING protein phosphorylation and microglial pyroptosis. However, after STING knockout, the inhibitory effect of gelsevirine on microglial pyroptosis was significantly weakened, and gelsevirine-mediated protective effects were abolished., Conclusions: Gelsevirine increased the survival rate, ameliorated cognitive impairment, inhibited glial cell activation and reduced inflammation in the hippocampi of mice with SAE; the mechanism may be related to the inhibition of STING signalling pathway-mediated pyroptosis in microglia., Competing Interests: Declaration of competing interest The authors have no conflicts of interest to declare., (Copyright © 2024 Elsevier GmbH. All rights reserved.)

Purpose: Periprosthetic femoral fractures (PPFs) around the hip are challenging complications in orthopaedic surgery, particularly Vancouver type B2 (VTB2) fractures. The surgical management of these fractures is crucial and depends on various factors. Cementless short taper stem with plate osteosynthesis is an alternative surgical technique. This study aims to compare the outcomes of this surgical technique with revision arthroplasty (RA) with long stem in the treatment of VTB2 PPFs., Methods: This retrospective study was conducted in a single medical institute from February 2010 to May 2019. Patients who had received either total hip arthroplasty or bipolar hemiarthroplasty and subsequently developed a VTB2 PPF were included; patients who sustained intra-operative fractures or received a cemented stem previously were excluded from the analysis. The patients were divided into two groups: group I received RA with cementless long stem, while group II underwent RA with cementless short taper stem with plate osteosynthesis. Demographic data, radiographic and functional outcomes, and complications were analyzed between the two groups., Results: A total of 85 patients diagnosed with VTB2 PPFs were included in the study. There were no significant differences between the two groups in terms of demographic data, including age, gender, mean follow-up times, estimated blood loss, and operative times. The radiographic results showed that there was no significant difference in the incidence of subsidence and implant stability between the two groups. However, group II tended to have less subsidence and periprosthetic osteolysis. Patients in group II had significantly better functional scores (mean Harris hip score: post-operative: 60.2 in group I and 66.7 in group ii; last follow-up: 77.4 in group 1 and 83.2 in group II (both p < 0.05)). There were no significant differences in the overall complication rate, including infection, dislocation, re-fracture, and revision surgery, between the two groups., Conclusions: Both surgical techniques, cementless long stem and cementless short taper stem with plate osteosynthesis, are effective in the treatment of Vancouver B2 PPFs, with no significant differences in outcomes or complications. However, patients in cementless short taper stem with plate osteosynthesis had better functional scores at both post-operative and the last follow-up., (© 2024. The Author(s).)

Objective: The study aims to explain whether or not minimal invasive surgery (MIS) would be feasible in elbow fracture-dislocation with coronoid process fracture., Methods: At Taipei Veterans General Hospital, patients who had elbow dislocations with coronoid process fractures underwent a single surgeon's MIS techniques which included the fluoroscopy-guided ulnar anteromedial (FGUAM) approach in the stage of reducing the coronoid process. When there is a proximal ulnar fracture, the posterior incision should be necessary, followed by the incision over the lateral or medial elbow for treating radial fractures or ligament injuries., Results: The Flow Diagram for approach recommendation was established on the basis of defining MIS as that which does not include cross-plane dissection. The importance of anterior rigid fixation for the coronoid process was also emphasized., Conclusions: MIS can be achieved by multiple limited surgical incisions. Although the posterior extensile approach is necessary in situations of ulnar metaphysis or ligament avulsion fracture, the FGUAM approach decreases the cross-plane dissection.

Background: Osteosarcoma (OS) usually happens in patients under 20 years old and is notorious for its low survivorship and limb loss. Personalized medicine is a viable approach to increase the efficiency of chemotherapy which is the main prognostic factor for survivorship after surgical treatment., Methods: In this five-year prospective observational study, we collected primary cells of osteosarcoma from 15 patients, and examined the correlation between clinical characters of patients and cell properties characterized using various in vitro assays. The properties including genes expression, pro-angiogenic capability and anti-cancer drug response are characterized respectively by using RT-PCR, tube formation assay, osteogenesis assay and drug testing on 3D tumor spheroid model., Result: The results suggest that OS patients with higher MMP9 expression levels have higher probability to develop skip metastasis (p = 0.041). The 3D tumor spheroid test based on the median lethal dose from 2D culture provides some prognostic value. Patients do not response well to methotrexate (MTX) show higher percentage of high pathology grade (p = 0.009) and lung metastasis (p = 0.044). Also, patients respond well to ifosfamide (IFO) have higher probability to achieve high tumor necrosis rate (p = 0.007)., Conclusion: The association between cell properties and clinical characters of patients provided by our data can act as potential prognostic factors to help physicians to develop effective personalized chemotherapy for osteosarcoma treatments., Competing Interests: Declaration of competing interest A conflict of interest occurs when an individual's objectivity is potentially compromised by a desire for financial gain, prominence, professional advancement or a successful outcome. JFMA Editors strive to ensure that what is published in the Journal is as balanced, objective and evidence-based as possible. Since it can be difficult to distinguish between an actual conflict of interest and a perceived conflict of interest, the Journal requires authors to disclose all and any potential conflicts of interest. This Authorship & Conflicts of Interest Statement is signed by the corresponding author on behalf of all the listed authors in the manuscript. The corresponding author certifies that all the information contained in this statement is true, correct and agreed on by all the listed authors., (Copyright © 2024 Formosan Medical Association. Published by Elsevier B.V. All rights reserved.)

Bone defects are a common clinical issue, but therapeutic efficiency can be challenging in cases of more considerable traumas or elderly patients with degenerated physiological metabolism. To address this issue, a more suitable cell-biomaterial construct promoting bone regeneration has been extensively investigated, with the chitosan scaffold being considered a potential candidate. In this study, chitosan was crosslinked with different doses of glucose (CTS-10~50%Glc) using a modified Maillard reaction condition to develop a more appropriate cell-biomaterial construct. Mouse MC3T3-E1 pre-osteoblasts were seeded onto the scaffolds to examine their osteoinductive capability. The results showed that CTS-Glc scaffolds with higher glucose contents effectively improved the adhesion and survival of mouse MC3T3-E1 pre-osteoblasts and promoted their differentiation and mineralization. It was further demonstrated that the membrane integrin α5 subunit of pre-osteoblasts is the primary adhesion molecule that communicates with CTS-Glc scaffolds. After that, Akt signaling was activated, and then bone morphogenetic protein 4 was secreted to initiate the osteoinduction of pre-osteoblasts. The prepared CTS-Glc scaffold, with enhanced osteoinduction capability and detailed mechanism elucidations, offers a promising candidate material for advancing bone tissue engineering and clinical regenerative medicine. As a result, this study presents a potential tool for future clinical treatment of bone defects., (© 2023 Wiley Periodicals LLC.)

Background: This study investigated the association between postoperative piriformis fossa and greater trochanter tubercle distance (distance from the deepest point of piriformis fossa to the most lateral greater trochanter tubercle [PG]) and cutout failure after cephalomedullary nail (CMN) osteosynthesis for intertrochanter fracture (ITF). A rotating femur model was designed to analyze PG variation during femur rotation., Methods: From 2005 to 2010, 311 patients diagnosed of ITF (Arbeitsgemeinschaft für Osteosynthesefragen/Orthopaedic Trauma Association [AO/OTA] 31-A2 and A3) underwent CMN fixation at our institute were reviewed. Of these, 281 (90.3%) patients achieved union without complication, 21 (6.8%) had cutout failure, six (1.9%) had femoral head osteonecrosis, and three (1%) had nonunion during postoperative 2-year follow-up. The side difference of postoperative PG compared to contralateral uninjured hip (dPG) was analyzed between patients who had cutout failure and those who did not. In the rotating femur model, the PG was measured for every 2.5° increments of internal and external rotation from 0° to 50°., Results: The dPG was significantly higher in the failure group (10.2 ± 4.2 vs 6.6 ± 3.5 mm, p <0.001). The odds ratio for lag screw cutout was 6.35 (95% CI, 1.10-11.6, p =0.003) for every 1 mm dPG increment. dPG exhibited high diagnostic performance in predicting cutout failure according to receiver operating characteristic curve analysis. The area under the curve was 0.774 (95% CI, 0.711-0.837). dPG yielded the greatest sensitivity (78.4%) and specificity (78.4%) to predict lag screw cutout when cutoff value being 8.65 mm. In rotating femur model, PG change from baseline demonstrated significant ( p <0.001) positive and negative correlation with increased external and internal rotation, respectively., Conclusion: Increased dPG is a risk factor of cutout failure for ITF osteosynthesis with CMN. In conjunction with tip-apex distance, fracture displacement, and reduction quality; dPG can help surgeons interpret postoperative radiograph and predict failure. However, it should be noticed that a proper and standard patient positioning is critical for accurate dPG measurement., Competing Interests: Conflicts of interest: Dr Yu-Ping Su, an editorial board member at Journal of the Chinese Medical Association , had no role in the peer review process of or decision to publish this article. The other authors declare that they have no conflicts of interest related to the subject matter or materials discussed in this article., (Copyright © 2023, the Chinese Medical Association.)

Ground glass hepatocytes (GGHs) have been associated with hepatocellular carcinoma (HCC) recurrence and poor prognosis. We previously demonstrated that pre-S expression in some GGHs is resistant to current hepatitis B virus (HBV) antiviral therapies. This study aimed to investigate whether integrated HBV DNA (iDNA) is the primary HBV DNA species responsible for sustained pre-S expression in GGH after effective antiviral therapy. We characterized 10 sets of micro-dissected, formalin-fixed-paraffin-embedded, and frozen GGH, HCC, and adjacent hepatitis B surface antigen-negative stained tissues for iDNA, pre-S deletions, and the quantity of covalently closed circular DNA. Eight patients had detectable pre-S deletions, and nine had detectable iDNA. Interestingly, eight patients had integrations within the TERT and CCNE1 genes, which are known recurrent integration sites associated with HCC. Furthermore, we observed a recurrent integration in the ABCC13 gene. Additionally, we identified variations in the type and quantity of pre-S deletions within individual sets of tissues by junction-specific PacBio long-read sequencing. The data from long-read sequencing indicate that some pre-S deletions were acquired following the integration events. Our findings demonstrate that iDNA exists in GGH and can be responsible for sustained pre-S expression in GGH after effective antiviral therapy., (© 2024 Wiley Periodicals LLC.)

Objectives: This study investigated the progression of pubofemoral distance (PFD) with age and assessed the correlation between PFD and late acetabular index (AI) measurements., Methods: This prospective observational study was conducted between January 2017 and December 2021. We enrolled 223 newborns who underwent the first, second, and third hip ultrasounds, and pelvis radiograph at a mean age of 18.6 days, 3.1 months, 5.2 months, and 6.8 months, respectively. The difference between PFD measured at serial ultrasounds and the correlation with AI were analyzed., Results: The PFD increased significantly (p < 0.001) at serial measurements. The mean PFD at the first, second, and third ultrasounds were 3.3 (2.0-5.7), 4.3 (2.9-7.2), and 5.1 (3.3-8.0) mm, respectively. The PFD at three ultrasounds were all significantly (p < 0.001) and positively correlated with AI, with the Pearson correlation coefficients being 0.658, 0.696, and 0.753 for the first, second, and third ultrasounds, respectively. Using AI as reference, the diagnostic ability of PFD was calculated by the areas under the receiver operating characteristic curve, which was 0.845, 0.902, and 0.938 for the first, second, and third PFD, respectively. For the first, second, and third ultrasounds, PFD cutoff values of ≥ 3.9, ≥ 5.0, and ≥ 5.7 mm, respectively, yielded the greatest sensitivity and specificity in predicting late abnormal AI., Conclusion: The PFD naturally progresses with age and is positively correlated with AI. The PFD has potential for predicting residual dysplasia. However, the cutoff for abnormal PFD values may require adjustment according to the patient's age., Key Points: • The pubofemoral distance measured in hip ultrasonography naturally increases as the infant's hips mature. • The early pubofemoral distance demonstrates a positive correlation with late acetabular index measurements. • The pubofemoral distance may help physicians predict abnormal acetabular index. However, the cutoff for abnormal pubofemoral distance values may require adjustment according to patient's age., (© 2023. The Author(s).)

Noctiluca scintillans (NS) adds an aesthetic appeal to many coastal areas because of their bioluminescence. An intense bloom of the red NS frequently occurs in the coastal aquaculture region of Pingtan Island in Southeastern China. However, when NS exceeds in abundance, it causes hypoxia which has devastating impacts on the aquaculture. This study was conducted in the Southeastern part of China with an aim to examine the relationship between the profusion of NS and its impacts on marine environment. Samples from four stations on Pingtan Island were collected for 12 months (January to December 2018) and were later analyzed in laboratory against five parameters, namely temperature, salinity, wind speed, dissolved oxygen, and chlorophyll a. Results showed that the NS blooms were particularly active during the months of May and June in the Pingtan Island area. The seawater temperatures during that time were recorded between 20 and 28.8 °C indicating the optimum survival temperature for NS. The NS bloom activity ceased above 28.8 °C. A principal component analysis (PCA) indicated that the richness of NS was positively associated with temperature and salinity, whereas there was a significant reverse correlation between NS accumulation and wind speed. NS is a heterotrophic dinoflagellate and relies on the predation of algae for reproduction; therefore, a significant correlation was observed between NS abundance and chlorophyll a concentration, and an inverse correlation was observed between NS and phytoplankton abundance. Additionally, red NS growth was observed immediately following the diatom bloom, suggesting that phytoplankton, temperature, and salinity are the essential factors in the evolution, progression, and termination of NS growth., (© 2023. The Author(s), under exclusive licence to Springer Nature B.V.)

Background: The prevalence of developmental dysplasia of the hip (DDH) has been considered to be low in East Asia, but this may be incorrect because of inconsistent diagnostic definitions and testing criteria. In 2015, the AAOS released guidelines for systematic screening for DDH in newborns. We implemented these guidelines and compared DDH incidence and outcomes before and after their implementation., Methods: We used a historic comparison cohort of newborns with DDH between July 2015 and May 2017 before guideline implementation (the preguideline group); their data were retrieved using electronic medical records. In this group, the newborns received general hip screening without systemic follow-up. The postguideline group included newborns who were screened for hip dysplasia and followed up per the AAOS guidelines between July 2017 and May 2019. Their data were prospectively collected. The primary outcome in the postguideline group was DDH incidence. Other outcomes included rates of referral, surgery, and complications, and DDH prognosis., Results: The preguideline and postguideline groups included 3534 and 2663 newborns, respectively, of whom 49 (1.1%) and 225 (8.4%), respectively, were referred to the pediatric orthopaedic clinic enrolled. In the postguideline group, 35 patients were diagnosed as having DDH (incidence: 1.3%, 95% CI: 0.8%-1.9%). Both the incidence and referral rates were significantly higher in the postguideline group than in the preguideline group. Furthermore, the mean age at referral was 6.7±10.06 months and 0.9±0.25 months in the preguideline and postguideline groups, respectively, indicating a potential for early treatment in the postguideline group. Finally, the female sex was identified as a risk factor for residual hip dysplasia at 6 months of age., Conclusion: DDH incidence in East Asia seems comparable to that in Western countries. Implementing the AAOS guidelines increased the diagnosis rate and opportunity for early treatment initiation, thus potentially avoiding surgical intervention. Nevertheless, residual DDH may be detected in some patients at 6 months of age, particularly in female infants., Level of Evidence: Level IV., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc.)

Colorectal cancers (CRCs) are prevalent worldwide, yet current treatments remain inadequate. Using chemical genetic screens, we identify that co-inhibition of topoisomerase I (TOP1) and NEDD8 is synergistically cytotoxic in human CRC cells. Combination of the TOP1 inhibitor irinotecan or its bioactive metabolite SN38 with the NEDD8-activating enzyme inhibitor pevonedistat exhibits synergy in CRC patient-derived organoids and xenografts. Mechanistically, we show that pevonedistat blocks the ubiquitin/proteasome-dependent repair of TOP1 DNA-protein crosslinks (TOP1-DPCs) induced by TOP1 inhibitors and that the CUL4-RBX1 complex (CRL4) is a prominent ubiquitin ligase acting on TOP1-DPCs for proteasomal degradation upon auto-NEDD8 modification during replication. We identify DCAF13, a DDB1 and Cullin Associated Factor, as the receptor of TOP1-DPCs for CRL4. Our study not only uncovers a replication-coupled ubiquitin-proteasome pathway for the repair of TOP1-DPCs but also provides molecular and translational rationale for combining TOP1 inhibitors and pevonedistat for CRC and other types of cancers., (© 2023. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Host-derived cellular pathways can provide an unfavorable environment for virus replication. These pathways have been a subject of interest for herpesviruses, including the betaherpesvirus human cytomegalovirus (HCMV). Here, we demonstrate that a compound, ARP101, induces the noncanonical sequestosome 1 (SQSTM1)/p62-Keap1-Nrf2 pathway for HCMV suppression. ARP101 increased the levels of both LC3 II and SQSTM1/p62 and induced phosphorylation of p62 at the C-terminal domain, resulting in its increased affinity for Keap1. ARP101 treatment resulted in Nrf2 stabilization and translocation into the nucleus, binding to specific promoter sites and transcription of antioxidant enzymes under the antioxidant response element (ARE), and HCMV suppression. Knockdown of Nrf2 recovered HCMV replication following ARP101 treatment, indicating the role of the Keap1-Nrf2 axis in HCMV inhibition by ARP101. SQSTM1/p62 phosphorylation was not modulated by the mTOR kinase or casein kinase 1 or 2, indicating ARP101 engages other kinases. Together, the data uncover a novel antiviral strategy for SQSTM1/p62 through the noncanonical Keap1-Nrf2 axis. This pathway could be further exploited, including the identification of the responsible kinases, to define the biological events during HCMV replication. IMPORTANCE Antiviral treatment for human cytomegalovirus (HCMV) is limited and suffers from the selection of drug-resistant viruses. Several cellular pathways have been shown to modulate HCMV replication. The autophagy receptor sequestosome 1 (SQSTM1)/p62 has been reported to interact with several HCMV proteins, particularly with components of HCMV capsid, suggesting it plays a role in viral replication. Here, we report on a new and unexpected role for SQSTM1/p62, in HCMV suppression. Using a small-molecule probe, ARP101, we show SQSTM1/p62 phosphorylation at its C terminus domain initiates the noncanonical Keap1-Nrf2 axis, leading to transcription of genes under the antioxidant response element, resulting in HCMV inhibition in vitro. Our study highlights the dynamic nature of SQSTM1/p62 during HCMV infection and how its phosphorylation activates a new pathway that can be exploited for antiviral intervention.

Koumine, an alkaloid, exerts therapeutic effects against rheumatoid arthritis (RA), and thus may have a potential application in novel treatment strategies against this disease. Herein, we investigated the regulatory effect of koumine on Th cell polarization using a "pyramid" structure model to elucidate the mechanism underlying its therapeutic effect on RA. The third layer of the model comprises the cytokine secretion layer, in which the effects of koumine on the balance of Th-related cytokines were investigated in mice with collagen-induced arthritis (CIA). Koumine showed significant therapeutic effects and reversed the imbalance of Th1/Th2 and Th17/Treg cytokines. In the Th cell polarization layer, the effects of koumine on the relative numbers of Th cell subsets in splenocytes of rats with CIA were examined. Koumine attenuated both of the increased Th1/Th2 and Th17/Treg subset ratios accompanied with its therapeutic effects. Finally, the primary cultured splenocytes from BALB/c mice were used to further investigate the effect of koumine on Th cell activation by evaluating cell proliferation induced by concanavalin A (Con A), lipopolysaccharides (LPS) and phytohemagglutinin (PHA). Koumine inhibited the cell proliferation responses and its effects on proliferation induced by Con A and PHA were greater than those by LPS, showing the relatively selective inhibition on the proliferation of Th cells. Our results suggest that koumine might restore the homeostasis of the network system with Th subsets and cytokines by inhibiting the activation of T cells, subsequently regulating the polarization of Th subsets and the downstream imbalance of pro/anti-inflammatory cytokines in RA., Competing Interests: Declaration of competing interest The authors have no conflicts of interest to declare., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Background: The aim of this study was to compare two techniques for the surgical treatment of diaphyseal fractures in the adult humerus: double-crossed retrograde elastic stable intramedullary nailing (DCR-ESIN) and limited-contact dynamic compression plate (LC-DCP)., Methods: This was a retrospective study conducted at a single hospital. We included 122 patients with diaphyseal fractures of the humerus who had received DCR-ESIN or LC-DCP from January 2011 to January 2017. We compared union rates, union times, disabilities of the arm, shoulder, and hand (DASH) scores at the postoperative 1-year follow-up, and complications between the two groups., Results: Plating management was performed in 63 patients, while DCR-ESIN was performed in 59 patients. The union rate was higher in the DCR-ESIN group than in the LC-DCP group (100% vs. 90.5%; p = 0.052). The union time was shorter in the DCR-ESIN group than in the LC-DCP group (12.0 weeks vs. 14.8 weeks; p < 0.001). The intraoperative blood loss and operative time were less in the DCR-ESIN group than in the LC-DCP group (76.4 min vs. 129.5 min; p < 0.001; 60.9 ml vs. 244.8 ml; p < 0.001, respectively). The DCR-ESIN had superior results for the rate of overall complications (p = 0.006). At the 1-year follow-up, the DCR-ESIN group had better DASH scores than the LC-DCP group (p = 0.014)., Conclusions: The DCR-ESIN technique, used to treat diaphyseal fractures of the humerus, has shorter operative times, less intra-operative blood loss, shorter union times, and better functional outcomes at 1-year follow-up than the LC-DCP technique. DCR-ESIN may be an alternative method for the surgical treatment of diaphyseal humeral fractures in adults., (© 2022. The Author(s).)

Background: This study investigated the association between early Graf classification and femoral head coverage (FHC) with the acetabular index (AI) at the age of 6 months., Methods: A prospective observational study was conducted between 2017-2018. Patients requiring Pavlik harness treatment and patients with syndromic dislocation or neurogenic dislocation were excluded. In total, 169 newborns with the first ultrasound performed at the mean age of 12.3 (0-15) days, the second ultrasound performed at the mean age of 3.2 (2.5-4.1) months, and the AI measured at the age of 6.6 (4.3-7.1) months were enrolled. The correlation between the AI and first and second alpha angles and FHC measurements, and the correlation of dysplasia in early ultrasound with dysplasia in the AI were analyzed., Results: At the first ultrasound, only the FHC (P = .02) demonstrated a significant negative correlation with the AI. At the second ultrasound, both the alpha angle (P < .01) and FHC (P < .01) demonstrated a significant negative correlation with the AI. With the AI as a reference, the sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were found to be 77%, 7%, 5%, and 81%, respectively, for the first Graf; 91%, 37%, 9%, and 98%, respectively, for the first FHC measurement; 82%, 90%, 35%, and 99%, respectively, for the second Graf; and 95%, 97%, 68% and 99%, respectively, for the second FHC measurement., Conclusions: FHC and alpha angle exhibited significant negative correlations with the AI at six months, both ultrasound parameters may have the potential to predict AI in DDH screening. Compared to the ultrasound measurements taken at 2 weeks, Graf and FHC at 3 months demonstrated superior sensitivity, specificity, PPV, and NPV to detect abnormal AI. The best timing to perform ultrasound examination may need further research., (© 2022. The Author(s).)

Purpose: A population-based case-control study was conducted in Yangjiang and Enping areas in South China to assess whether the risk of lens opacity induced by natural high background radiation exposure is modulated by polymorphisms of ATM and TP53 . Materials and methods: A total of 133 cases who were diagnosed with cortical and posterior subcapsular (PSC) opacity were recruited, and 419 healthy controls were selected through counter-matching in terms of radiation status. Genomic DNA from all the participants was genotyped with the Illumina platform for four single nucleotide polymorphisms of ATM (rs189037, rs373759, and rs4585) and TP53 (rs1042522). The cumulative lens dose received during the entire life was estimated based on annual indoor and outdoor radiation doses and gender- and age-specific occupancy factors. Non-conditional logistic regression was performed to calculate odds ratio (OR) and 95% confidence intervals (95% CI). Results: ATM rs189037 and TP53 rs1042522 were significantly related to cortical and PSC opacity. The risk of opacity was higher when individuals carried the A allele of ATM rs189037 and C allele of TP53 rs1042522, compared with GG genotype. ATM rs189037 A allele carriers (AG/AA) and TP53 rs1042522 C allele carriers (CG/CC) combined with a cumulative lens dose of 100 mGy or higher showed statistically significant opacity risks (OR = 5.51, 95% CI: 1.47-20.66; OR = 2.69, 95% CI: 1.10-6.60). Conclusion: The A allele of ATM rs189037 and C allele of TP53 rs1042522 increased the risk of lens opacity induced by radiation. These polymorphisms in ATM and TP53 might modify the risk of cortical and PSC opacity induced by chronic and prolonged low-dose radiation.

Background: Germinal vesicle (GV) chromatin configurations of oocytes are proposed to be related to oocyte competence and may reflect the quality of oocyte. Currently, a limited number of published studies investigated the GV chromatin configurations of guinea pig oocytes., Objective: In this study on the in vitro maturation (IVM) of guinea pig oocytes, we examined the changes in their GV chromatin configurations during meiotic progression., Methods: Based on the degree of chromatin compaction, the GV chromatin configurations of guinea pig oocytes could be divided into three categories depending on whether the nucleolus-like body (NLB) was surrounded or partly surrounded by compacted chromatin, namely the uncondensed (NSN), the intermediate type (SN-1) and the compacted type (SN-2)., Results: The percentage of cells displaying the SN-2 configuration increased with the growth of guinea pig oocytes, suggesting that this configuration presents the potential for maturation in oocytes. Oocytes derived from larger follicle exhibited increased meiotic potential. Serum starvation affected the GV chromatin configurations of guinea pig oocytes., Conclusions: Collectively, these results suggest that the SN-2 type might be a more mature form of configuration in guinea pig oocyte, whose proportion was associated with the follicle size and susceptible to the environment (e.g. serum concentration)., (© 2021 The Authors. Veterinary Medicine and Science published by John Wiley & Sons Ltd.)

Integrated hepatitis B virus (HBV) DNA, found in more than 85% of HBV-associated hepatocellular carcinomas (HBV-HCCs), can play a significant role in HBV-related liver disease progression. HBV-host junction sequences (HBV-JSs), created through integration events, have been used to determine HBV-HCC clonality. Here, we investigate the feasibility of analyzing HBV integration in a noninvasive urine liquid biopsy. Using an HBV-targeted next-generation sequencing (NGS) assay, we first identified HBV-JSs in eight HBV-HCC tissues and designed short-amplicon junction-specific polymerase chain reaction assays to detect HBV-JSs in matched urine. We detected and validated tissue-derived junctions in five of eight matched urine samples. Next, we screened 32 urine samples collected from 25 patients infected with HBV (5 with hepatitis, 10 with cirrhosis, 4 with HCC, and 6 post-HCC). Encouragingly, all 32 urine samples contained HBV-JSs detectable by HBV-targeted NGS. Of the 712 total HBV-JSs detected in urine, 351 were in gene-coding regions, 11 of which, including TERT (telomerase reverse transcriptase), had previously been reported as recurrent integration sites in HCC tissue and were found only in the urine patients with cirrhosis or HCC. The integration breakpoints of HBV DNA detected in urine were found predominantly (~70%) at a previously identified integration hotspot, HBV DR1-2 (down-regulator of transcription 1-2). Conclusion: HBV viral-host junction DNA can be detected in urine of patients infected with HBV. This study demonstrates the potential for a noninvasive urine liquid biopsy of integrated HBV DNA to monitor patients infected with HBV for HBV-associated liver diseases and the efficacy of antiviral therapy., (© 2021 The Authors. Hepatology Communications published by Wiley Periodicals LLC on behalf of American Association for the Study of Liver Diseases.)

Background: Diabetic neuropathic pain (DNP), a complication of diabetes, has serious impacts on human health. As the pathogenesis of DNP is very complex, clinical treatments for DNP is limited. Koumine (KM) is an active ingredient extracted from Gelsemium elegans Benth. that exerts an inhibitory effect on neuropathic pain (NP) in several animal models., Purpose: To clarify the anti-NP effect of KM on rats with DNP and the molecular mechanisms involving the Notch- Jκ recombination signal binding protein (RBP-Jκ) signaling pathway., Methods: Male Sprague-Dawley rats were administered streptozocin (STZ) by intraperitoneal injection to induce DNP. The effect of KM on mechanical hyperalgesia in rats with DNP was evaluated using the Von Frey test. Microglial polarization in the spinal cord was examined using western blotting and quantitative real-time PCR. The Notch-RBP-Jκ signaling pathway was analysed using western blotting., Results: KM attenuated DNP during the observation period. In addition, KM alleviated M1 microglial polarization in STZ-induced rats. Subsequent experiments revealed that Notch-RBP-Jκ signaling pathway was activated in the spinal cord of rats with DNP, and the activation of this pathways was decreased by KM. Additionally, KM-mediated analgesia and deactivation of the Notch-RBP-Jκ signaling pathway were inhibited by the Notch signaling agonist jagged 1, indicating that the anti-DNP effect of KM may be regulated by the Notch-RBP-Jκ signaling pathway., Conclusions: KM is a potentially desirable candidate treatment for DNP that may inhibit microglial M1 polarization through the Notch-RBP-Jκ signaling pathway., (Copyright © 2021. Published by Elsevier GmbH.)

Poly(ADP)-ribosylation (PARylation) regulates chromatin structure and recruits DNA repair proteins. Using single-molecule fluorescence microscopy to track topoisomerase I (TOP1) in live cells, we found that sustained PARylation blocked the repair of TOP1 DNA-protein crosslinks (TOP1-DPCs) in a similar fashion as inhibition of the ubiquitin-proteasome system (UPS). PARylation of TOP1-DPC was readily revealed by inhibiting poly(ADP-ribose) glycohydrolase (PARG), indicating the otherwise transient and reversible PARylation of the DPCs. As the UPS is a key repair mechanism for TOP1-DPCs, we investigated the impact of TOP1-DPC PARylation on the proteasome and found that the proteasome is unable to associate with and digest PARylated TOP1-DPCs. In addition, PARylation recruits the deubiquitylating enzyme USP7 to reverse the ubiquitylation of PARylated TOP1-DPCs. Our work identifies PARG as repair factor for TOP1-DPCs by enabling the proteasomal digestion of TOP1-DPCs. It also suggests the potential regulatory role of PARylation for the repair of a broad range of DPCs., (© 2021. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

The ability to characterize individual biomarker protein molecules in patient blood samples could enable diagnosis of diseases at an earlier stage, when treatment is typically more effective. Single-molecule imaging offers a promising approach to accomplish this goal. However, thus far, single-molecule imaging methods have not been translated into the clinical setting. The detection limit of these methods has been confined to the picomolar (10 -12 M) range, several orders of magnitude higher than the circulating concentrations of biomarker proteins present in many diseases. Here, we describe single-molecule augmented capture (SMAC), a single-molecule imaging technique to quantify and characterize individual protein molecules of interest down to the subfemtomolar (<10 -15 M) range. We demonstrate SMAC in a variety of applications with human blood samples, including the analysis of disease-associated secreted proteins, membrane proteins, and rare intracellular proteins. SMAC opens the door to the application of single-molecule imaging in noninvasive disease profiling., (Copyright © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC).)

To evaluate the therapeutic effect of Potentilla discolor on 2,4,6-trinitrobenzensulfonic acid(TNBS)-induced experimental ulcerative colitis(UC) in rats and to determine its therapeutic mechanism through mitochondrial autophagy, immune cells, and cytokines. A rat model of UC was established by TNBS-ethanol enema. Rats were divided into six groups: control, UC model, sulfasalazine(positive drug), and high-dose, moderate-dose, and low-dose ethanol extract groups. After 14-day continuous administration of the corresponding drugs, the disease activity index(DAI) and hematoxylin and eosin(HE) were evaluated. The morphological structure of mitochondria was observed by using transmission electron microscope(TEM), mitophagy-related mRNA expression was detected by using Real-time quantitative polymerase chain reaction(qRT-PCR), immune cell differentiation in rat serum was detected by using flow cytometry(FCM), and cytokine expression in colon tissues of rats was detected by protein microarray. The results showed that compared with the model group, each dose group of P. discolor could significantly reduce the DAI of UC model rats, and decrease the degree of inflammatory cells infiltration in the colon tissue of UC model rats. Meanwhile the expressions of T cells and Th cells in the serum increased significantly, the expression of Tc cells in the serum decreased significantly. Transmission electron microscope found that there was fusion of mitochondria and lysosomes in the colon tissue of the administration group. The expressions of mitochondrial autophagy related genes NF-κB, p62 and parkin were significantly increased in colon tissues. The results of protein chip showed that compared with the model group, the high dose group of P. discolor could significantly regulate the expression of cytokines. In conclusion, these results suggested that P. discolor improved TNBS-induced acute ulcerative colitis in rats by regulating the mitochondrial autophagy and the inflammatory factor expression.

Osteoarthritis (OA) is still a recalcitrant musculoskeletal disease on account of its complex biochemistry and mechanical stimulations. Apart from stimulation by external mechanical forces, the regulation of intracellular mechanics in chondrocytes has also been linked to OA development. Recently, visfatin has received significant attention because of the clinical finding of the positive correlation between its serum/synovial level and OA progression. However, the precise mechanism involved is still unclear. This study determined the effect of visfatin on intracellular mechanics and catabolism in human primary chondrocytes isolated from patients. The intracellular stiffness of chondrocytes was analyzed by the particle-tracking microrheology method. It was shown that visfatin damages the microtubule and microfilament networks to influence intracellular mechanics to decrease the intracellular elasticity and viscosity via glycogen synthase kinase 3β (GSK3β) inactivation induced by p38 signaling. Further, microtubule network destruction in human primary chondrocytes is predominantly responsible for the catabolic effect of visfatin on the cyclooxygenase 2 upregulation. The present study shows a more comprehensive interpretation of OA development induced by visfatin through biochemical and biophysical perspectives. Finally, the role of GSK3β inactivation, and subsequent regulation of intracellular mechanics, might be considered as theranostic targets for future drug development for OA.

Abstract: Ultrasonography is the ideal tool for assessing hip morphology in infants younger than 6-month-old. This study assessed the interobserver agreement and clinical disparities of the 2 most widely used ultrasound (US) methods, the Graf method, and femoral head coverage (FHC) measurement.A prospective observational study (STROBE compliant) of 2024 newborns was conducted between January 2017 and December 2018. Hip US was conducted on all newborns with abnormal Barlow and Ortolani maneuvers as well as on 50 randomly selected normal newborns. The physical examination and US were performed by a senior pediatric orthopedic surgeon with musculoskeletal sonography certification. Three observers with different levels of experience interpreted the images by using the Graf method and FHC. We analyzed the intraclass correlation coefficient, Cohen kappa, and the disparity between the clinical findings of the 2 methods.A total of 198 newborns (9.8%) presented with clinical instability, including 193 subluxatable hips in 168 patients (84.8%) and 45 dislocatable/dislocated hips in 30 patients (15.2%). The mean age at US examination was 11.69 days (range: 0-18 days). The intraclass correlation coefficient was .71 (95% CI: 0.55-0.83) for FHC, 0.63 (95% CI: 0.38-0.78) for the alpha angle, and 0.47 (95% CI: 0.16-0.69) for beta angle. The Cohen kappa coefficients of Graf type were 0.19 (95% CI: 0.03-0.35), 0.39 (95% CI: 0.20-0.58), and 0.17 (95% CI: 0.02-0.32) between observers 1 and 2, observers 1 and 3, and observers 2 and 3, respectively. Based on the Graf method, 14% of the stable hips had abnormal USs; by contrast, 19.2% of the subluxatable hips and 17.8% of the dislocatable/dislocated hips had normal Graf morphologies. In USs interpreted using FHC, 16% of stable hips demonstrated abnormal coverage, whereas 13.5% of subluxatable hips and 4.4% of dislocatable/dislocated hips had normal FHC.Incidence of clinically detectable hip instability was 9.8% among newborns in our series. Both alpha angle and FHC ratio revealed substantial interobserver agreement while beta angle achieved moderate agreement. FHC ratio possesses higher sensitivity and similar specificity compared with the Graf method when screening unstable hips.Level II, development of diagnostic criteria on basis of consecutive patients., Competing Interests: The authors have no funding and conflicts of interest to disclose., (Copyright © 2021 the Author(s). Published by Wolters Kluwer Health, Inc.)

Microbial mineralization of organic phosphorus is an important component of marine phosphorus cycle. The research on organic phosphate-mineralizing bacteria (OPB) is helpful to reveal microbial driving mechanism of organic phosphorus mineralization in eutrophic sea area. The diversity and community characteristics of OPB were examined by Illumina high-throughput sequencing using the primer sets phoX in the sea area between Minjiang Estuary to Pingtan in April (spring) and July (summer) 2019. The results showed that the Shannon index of OPB in the surface seawater samples ranged from 3.21 to 7.91, and that the diversity at each station was greater in spring than that in summer. Shannon index of OPB in the sediment samples ranged from 2.04 to 8.70, which was greater in summer than that in spring. Shannon index of OPB in surface seawater of each station was higher than that of sediment in spring, while it was in adverse in summer. Nine phyla of OPB were detected in surface seawater, with Proteobacteria and Cyanobacteria being the most abundant. Tweleve phyla of OPB were detected in the sediments, with Proteobacteria and Bacteroidetes being the most dominant. OPB community composition at the genus level showed obvious spatio-temporal variation. Leisingera, Phaeobacter, Thalassococcus , and Pseudomonas were the major genera in the seawater in spring, while Synechococcus , Halioglobus , Roseovarius , Phaeo-bacter , Sulfitobacter , and Hyphomonas were the major genera detected in summer. Leisingera , Phaeobacter , Vibrio , and Sulfitobacter were major genera in the sediment in spring, while Azospirillum , Aminobacter , Sulfurifustis , Burkholderia , and Thiohalobacter were the major genera in summer. A large number of unclassified OPB were detected in both surface seawater and sediment. The redundancy analysis results showed that dissolved oxygen, water temperature, pH, dissolved inorganic nitrogen, NO 2 - -N, and NO 3 - -N had great influences on community distribution of OPB in the surface seawater. The abundant OPB in the surface seawater and sediment might play an important role in phosphorus cycle in this sea area.

Objectives: This report aimed to determine whether transitional care management (TCM) services, provided by Inspira Care Connect, LLC (ICC), a Track 1 Medicare Shared Savings Program accountable care organization, were effective in reducing 30-day readmission rates, observation stay days, and emergency department visits, along with mortality rates, total costs, and frequency of primary care physician (PCP) visits among Medicare beneficiaries served by ICC., Study Design: In accordance with TCM programming, ICC contacted the majority of patients telephonically within 48 business hours after discharge from an inpatient setting and scheduled a face-to-face visit with the patient's PCP within 1 to 14 days after discharge from an inpatient setting. The patients were provided with non-face-to-face services as needed throughout the 30-day period., Methods: The effectiveness of the TCM model was measured using a retrospective propensity score matching design, which allowed for an accurate comparison between those who received TCM and similar ICC Medicare beneficiaries who did not. The analysis utilized Medicare parts A and B claims from January 1, 2016, to December 31, 2017., Results: Patients who received TCM had lower 30-day readmission rates than those who did not (P < .05)., Conclusions: The services provided to ICC Medicare patients through the TCM model may have enhanced the ability to identify problems at an earlier stage, resulting in the prevention of complications and unnecessary utilization of costly health care services.

Topoisomerases form transient covalent DNA cleavage complexes to perform their reactions. Topoisomerase I cleavage complexes (TOP1ccs) are trapped by camptothecin and TOP2ccs by etoposide. Proteolysis of the trapped topoisomerase DNA-protein cross-links (TOP-DPCs) is a key step for some pathways to repair these lesions. We describe a pathway that features a prominent role of the small ubiquitin-like modifier (SUMO) modification for both TOP1- and TOP2-DPC repair. Both undergo rapid and sequential SUMO-2/3 and SUMO-1 modifications in human cells. The SUMO ligase PIAS4 is required for these modifications. RNF4, a SUMO-targeted ubiquitin ligase (STUbL), then ubiquitylates the TOP-DPCs for their subsequent degradation by the proteasome. This pathway is conserved in yeast with Siz1 and Slx5-Slx8, the orthologs of human PIAS4 and RNF4., (Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC).)

Platelet decline is a feature of many acute viral infections, including cytomegalovirus (CMV) infection in humans and mice. Platelet sequestration in association with other cells, including endothelium and circulating leukocytes, can contribute to this decline and influence the immune response to and pathogenesis of viral infection. We sought to determine if platelet-endothelial associations (PEAs) contribute to platelet decline during acute murine CMV (mCMV) infection, and if these associations affect viral load and production. Male BALB/c mice were infected with mCMV (Smith strain), euthanized at timepoints throughout acute infection and compared to uninfected controls. An increase in PEA formation was confirmed in the salivary gland at all post-inoculation timepoints using immunohistochemistry for CD41+ platelets co-localizing with CD34+ vessels. Platelet depletion did not change amount of viral DNA or timecourse of infection, as measured by qPCR. However, platelet depletion reduced viral titer of mCMV in the salivary glands while undepleted controls demonstrated robust replication in the tissue by plaque assay. Thus, platelet associations with endothelium may enhance the ability of mCMV to replicate within the salivary gland. Further work is needed to determine the mechanisms behind this effect and if pharmacologic inhibition of PEAs may reduce CMV production in acutely infected patients.

Vascularisation efficiency plays an essential role in the success of bulk transplantation, while biocompatibility and safety are major concerns in clinical applications. Fibrin-based hydrogels have been exploited as scaffolds for their advantages in biocompatibility, degradability and mass transportation in various forms. However, the mechanical strength and degree of vascularisation remain unsatisfactory for clinical usage. An interpenetrating hydrogel was developed by adding hyaluronic acid (HA) to a fibrin-based natural hydrogel. The vasculogenesis of endothelial cells (human umbilical vein endothelial cells, HUVECs) was characterised within the gel using both in vitro and in vivo animal studies. The in vitro vascular morphology analysis showed 17.9 % longer mean tube length and 14.3 % higher average thickness in 7 d cultivation within the HA-supplemented hydrogel. The in vivo results showed 51.6 % larger total tube area, 1.8 × longer average tube length and 81.6 % higher cell number in the HA-supplemented hydrogel compared to the hydrogel without HA. The experimental results demonstrated better vascularisation and cell recruitment in the HA- supplemented hydrogel. The material properties of the hydrogels were also analysed using atomic force microscopy (AFM). The results revealed 3.7 × higher elasticity of the HA-supplemented hydrogel, which provided better mechanical strength and support for easy handling during procedures. With the demonstrated advantages, the developed hydrogels showed promise for exploitation in various practical clinical applications.

Aging leads to changes in nearly all pharmacokinetic phases. Koumine (KM), an alkaloid derived from Gelsemium elegans Benth., is effective against age-associated chronic diseases, but its dose proportionality following oral administration in aged individuals remains unknown. Herein, we established and validated a simple method that requires low sample volumes to determine KM concentration in rats using ultra-performance liquid chromatography-tandem mass spectrometry. The maximum plasma concentration (C max ) of 7 mg·kg -1 KM was ~12-fold and ~24-fold higher than that of 0.28 mg·kg -1 KM in adult and aged rats, respectively ( P < 0.01). Time to reach C max (T max ) for 7 mg·kg -1 KM was 4-fold longer in aged rats ( P < 0.05). The area under the curve (AUC) of 7 mg·kg -1 KM was >17-fold and >43-fold higher than those of 0.28 mg·kg -1 KM in adult and aged rats, respectively ( P < 0.01). The half-life (t 1/2 ) of 7 mg·kg -1 KM was over 4-fold longer than that of 0.28 mg·kg -1 KM in adult rats ( P < 0.01). The t 1/2 of 1.4 and 7 mg·kg -1 KM were 1.5~2-fold longer, than that of 0.28 mg·kg -1 KM in aged rats ( P < 0.05). The clearance rate of 7 mg·kg -1 KM was significantly lower in aged than in adult rats ( P < 0.05). For 7.0 mg·kg -1 KM, the C max in aged rats was higher than in adult rats during the T max period ( P < 0.05). In aged rats, the AUC for KM was >2.5-fold higher ( P < 0.05) and the t 1/2 was >60% longer than in adult rats ( P < 0.05). These results help interpret the pharmacokinetics of KM in aging-associated diseases., (Copyright © 2020 Ye, Xu, Zhang, Cao, Chen, Su, Huang and Yu.)

Mechanical regulation is known as an important regulator in cancer progression and malignancy. High shear force has been found to inhibit the cell cycle progression and result in cell death in various cancer cells. Stearoyl-CoA desaturase (SCD)-1, one of the important lipogenic enzymes, has recently been indicated as a potential pharmaceutical target in cancer therapy. In this study, we determined whether the cell fate control of shear force stimulation is through regulating the SCD-1 expression in cancer cells. Human MG63 osteosarcoma cells were used in this study. 2 and 20 dynes/cm 2 shear forces were defined as low and high intensities, respectively. A SCD-1 upregulation in human MG63 osteosarcoma cells under 20, but not 2, dynes/cm 2 shear force stimulation was shown, and this induction was regulated by Smad1/5 and peroxisome proliferator-activated receptor δ (PPARδ) signaling. Moreover, gene knockdown of PPARδ and SCD-1 in human MG63 osteosarcoma cells attenuated the differentiation inhibition and resulted in much more cell death of high shear force initiation. The present study finds a possible auto-protective role of SCD-1 upregulation in high shear force-damaged human MG63 osteosarcoma cells. However, its detailed regulation in the cancer fate decision of high shear force should be further examined.

Objective: To explore the imaging characteristics of large vestibular aqueduct syndrome (LVAS) patients and their relationship with the acoustically evoked short latency negative response (ANSR), so as to provide reference for the diagnosis of LVAS. Methods: Clinical data of 174 patients(334 ears) with LVAS diagnosed and treated by the Department of Otorhinolaryngology Head and Neck Surgery of the First Affiliated Hospital of Guangxi Medical University, from October 2009 to December 2017 were retrospectively analyzed, including 117 males and 57 females, aged from 5 months to 47 years old, with the median age of 4 years and 4 months. ABR and imaging data of patients were collected. Midpoint diameter and the outlet diameter of the vestibular aqueduct were measured on CT images, the midpoint diameter of the intraosseous parts and the extraosseous parts of enlarged endolymphatic sac(EES) were measured on MRI images. The correlation between the above measurements was analyzed by Pearson test using SPSS 17.0. According to whether ASNR was detected in ABR, the above data were divided into two groups, and the differences of the above imaging measurements were compared by the Independent-Sample Test. Results: The average midpoint diameter of the vestibular aqueduct was (1.87±0.58) mm ( x ± s , the following was the same), and the outlet diameter was (3.07±0.99) mm on CT; the average midpoint diameter of the intraosseous parts in enlarged endolymphatic sac(EES) was (2.39±1.37) mm, and the extraosseous parts was (2.50±2.18) mm on MRI. There was a correlation between the four measurements ( P< 0.05), among which the midpoint diameter of vestibular aqueduct was strongly positively correlated with the outlet diameter ( r= 0.760), and the remaining pairs were weakly correlated. ASNR was detected in 241 ears (72.16%,241/334) and undetected in 93 ears (27.84%, 93/334) of the 334 ears with LVAS. Midpoint diameter and the outlet diameter of the vestibular aqueduct in no ASNR group were smaller than the ASNR group, and the difference was statistically significant ( t value was 2.814 and 2.754, P< 0.05). There was no significant difference in the midpoint diameter of the intraosseous parts and the extraosseous parts of enlarged endolymphatic sac between the two groups, and the difference was no statistically significant( t value was 0.101 and 0.683, P> 0.05). Conclusions: There is a strong positive correlation between the midpoint diameter of vestibular aqueduct and the outlet diameter in LVAS patients. There is a certain correlation between the size of vestibular aqueduct and the size of endolymphatic sac. The smaller the diameter of vestibular aqueduct, the lower the occurrence rate of ASNR.

Polyphosphate accummulating organisms (PAOs) play an important role in the phosphorus metabolic cycling in the sediment of reservoir. We assessed the diversity and community structure of PAOs in the sediments by T-RFLP and clone sequencing which targeted ppk1 gene at the hearts of three reservoirs (Jiulongjiangxipi reservoir, Sanshiliujiao lake reservoir and Dongyaxi reservoir) in Fujian Province. The results showed that the diversity of PAOs varied among different reservoirs, though not statistically significant. The diversity of PAOs in the Sanshiliujiao lake reservoir was highest (Shannon index H=2.89±0.03, Simpson index D=0.06±0.01). The community structure of the PAOs in the Sanshiliujiao lake reservoir was most complicated, consistent with the results of the T-RFLP. The differences of dominant PAOs genera in three reservoirs were distinct, mainly concentrated in the Proteobacteria, Actinobacteria and Acidobacteria. The percentage of those three phylum accounted for 74.5%, 85.0% and 75.0%, respectively, of the total PAOs. The dominant groups in each reservoir sediment were Anaeromyxobacter and Solibacter. Various forms of phosphorus had certain influence on the diversity of PAOs. There were significantly correlation between Fe/Al-P and PAOs diversity and community structure. The dominant genus in the three reservoirs, Anaeromyxobacter, was positively correlated with all forms of phosphorus and significantly correlated with insoluble phosphorus such as OP and Ca-P, while Solibacter was negatively correlated with all forms of phosphorus. The results suggested that PAOs had important impacts on the phosphorus cycle of sediment in eutrophicatied reservoirs.

Background: The cephalomedullary nail is the most common device used to treat unstable intertrochanteric fractures (ITFs) (AO/OTA 31-A2 and A3) in the geriatric population. However, there is lack of radiological parameter to evaluate the entry point; hence, this study reports a new radiological parameter to evaluate the entry point of the nail. Besides, other risk factors were also examined., Methods: A retrospective study on the geriatric population with unstable ITFs was conducted from July 2011 to December 2014. A total of 136 patients were enrolled in this study; they received treatment with Gamma-3 nails (Stryker, Mahwah, NJ, USA) and were followed for at least 1 year. Demographic data, radiological parameters, and side-difference of the distance from the piriformis fossa to the greater trochanteric tubercle in the anteroposterior view (dPG) were compared between the union and failure groups. Student's t test, χ test, and multiple logistic regression were used in the statistical analyses., Results: The overall failure rate was 13.23% (18 patients). Sex, tip-apex distance (TAD), and dPG were significantly different between the failure and union groups in multivariate analyses. Using a dPG > 6 mm as a reference, patients with a dPG > 6 mm had an odds ratio of 7.64 for failure relative to a dPG < 6 mm., Conclusion: This study provides additional evidence demonstrating that sex and TAD have significant effects on the outcomes of unstable ITFs after nailing. Moreover, the newly reported radiological parameter, dPG, can be used to predict the failure of ITFs treated using cephalomedullary nails.

Background: We compared the clinical efficacy of normal C-reactive protein (CRP) expression (<1.0 mg/dL), with a 2-week drug holiday test (DHT) and no drug holiday test (DHT) as a reimplantation criterion, based on subsequent infections after a two-stage revision of a total knee arthroplasty of a periprosthetic joint infection (PJI)., Methods: In a 10-year review of 58 patients (mean age: 73.3-years-old; mean follow-up: 46.2 months), there were 31 patients in the DHT group and 27 patients in the DHT group. Primary outcome was recurrent infection rate. Secondary outcomes included length of hospital stay in the revision stage and CRP resurge one day before revision., Results: We reported that the CRP resurge rate in the DHT group (0%) was significantly (p = 0.029) lower than that in the DHT group (16.1%) one day before the revision. The DHT group also had a significantly shorter mean length of stay (LOS) in the hospital (9.6 vs 12.7 days, p = 0.015) and a nonsignificantly lower subsequent infection rate (14.8% vs 29%, p = 0.195)., Conclusion: We found that disciplined use of DHT as a reimplantation criterion reduced CRP resurges before reimplantation and yielded a shorter LOS afterward. DHT positively affected the subsequent mid-term infection rate after PJI treatment.

Background: We elucidated the effect of open reduction and internal fixation with locking plate for acute isolated displaced greater tuberosity fractures of humerus in elder adults (aged >60 years)., Methods: From 2009 to 2015, data from 32 patients, aged between 60 and 88 years, who had acute unilaterally displaced greater tuberosity fractures of humerus were collected and evaluated retrospectively. All the fractures were managed with open reduction and internal fixation with locking plate. The follow-up period was 50.8 months on an average (range 22-80 months). Finally, 25 patients were available for final evaluation of radiographic and functional results., Results: All the 32 fractures had union with the average union time of 14 weeks (range 10-18 weeks) and with no complications. The average of preoperative Visual Analogue Scale (VAS) was 6.2 (range 4-8), ASES was 30.4 (range 13-45), and Constant score was 30.4 (range 20-45). At the last follow-up, the mean VAS was 1.3 (range 0-2.5), the mean ASES score was 90.1 (range 72-100), and the mean Constant score was 90.3 (range 80-100). There were statistically significant differences between preoperative and final follow-up in VAS, ASES, and Constant score. Hundred percent of patients had good or excellent results by Constant score, with excellent results (86-100) in 17 (68%) patients and good result (71-85) in 8 (32%)., Conclusion: In conclusion, open reduction and internal fixation with locking plate is an effective treatment for acute displaced greater tuberosity fractures of humerus in elder adults.

Background: The treatment of subtrochanteric fracture nonunion is challenging. Although revision with either an intramedullary or extramedullary device had been advocated with acceptable results, complications that require secondary procedures still arise. The use of an intramedullary device with augmentation plate fixation is a well-known approach for femoral or tibial diaphyseal nonunion. However, this approach has not previously been reported for subtrochanteric fracture nonunion., Materials and Methods: A series of 21 cases of subtrochanteric fracture nonunion treated with an intramedullary device in combination with augmentation side plating were collected and retrospectively reviewed after an average of 18 months of followup. Fourteen patients with a prior well-fixed intramedullary device were treated with side plating and bone grafting. Seven patients underwent revision nailing in addition to side plating and bone grafting., Results: All fractures united well without major complication. The average time to union was 7.1 months., Conclusion: The use of an intramedullary device with augmentation plate fixation is a reliable and decisive procedure for treating subtrochanteric fracture nonunion that produces satisfactory results with a low complication rate., Competing Interests: There are no conflicts of interest.

Objective: The aim of this study was to compare clinical and radiological outcomes of elder and younger patients with comminuted proximal humerus fracture treated with osteosynthesis with locking plate., Methods: A total of 70 patients (30 males and 40 females; mean age 65.4 years) operated on for Neer 3- or 4-part proximal humeral fractures between 2010 and 2016 and followed for at least one-year were included in the study. The reduction was achieved through intraosseous window to minimize soft tissue stripping in all patients and structural allograft at metaphyseal diaphyseal junction was used aggressively to resist varus force. Group 1 consisted of 32 patients aged 70 or older (14 males and 18 females; mean age: 77.8 ± 5.1), while Group 2 consisted of 38 patients younger than 70 (16 males and 22 females; mean age: 58.2 ± 9.3). The groups were compared for their clinical and radiological outcomes., Results: There was no significant difference in clinical outcomes by Oxford score (54.8 ± 2.7 vs 56.6 ± 3.4, p = 0.13) and ASES score (89.7 ± 5.7 vs 90.8 ± 8.2, p = 0.68). Two groups had similar radiological outcomes regarding neck shaft angle, greater tip height and offset. However, group 2 had better final shoulder forward elevation (162.6 ± 8.7 vs 135.4 ± 14.7ß, p < 0.05) and shorter duration to achieve maximal range of motion (4.37 ± 2.37 vs 8.14 ± 3.25 months, p < 0.05) than group 1. Two groups had similar complication rates (9.4% vs 7.9%). All the complications were related to greater tuberosity including mal-reduction and avulsion., Conclusion: With the prerequisite of good alignment with robust medial cortical support and untouched soft tissue over medial metaphysis area via intra-osseous reduction, comminution of proximal humeral fracture can achieve satisfactory result and low complication rate by osteosynthesis with locking plate system, regardless of age. In addition, we suggested to use structural bone graft for comminuted medial cortex fracture with multiple fragments or bony defect more than 2 cm., Level of Evidence: Level III Therapeutic study., (Copyright © 2018 Turkish Association of Orthopaedics and Traumatology. Production and hosting by Elsevier B.V. All rights reserved.)

Artesunate (AS), a semisynthetic artemisinin approved for malaria therapy, inhibits human cytomegalovirus (HCMV) replication in vitro , but therapeutic success in humans has been variable. We hypothesized that the short in vivo half-life of AS may contribute to the different treatment outcomes. We tested novel synthetic ozonides with longer half-lives against HCMV in vitro and mouse cytomegalovirus (MCMV) in vivo Screening of the activities of four ozonides against a pp28-luciferase-expressing HCMV Towne recombinant identified OZ418 to have the best selectivity; its effective concentration inhibiting viral growth by 50% (EC 50 ) was 9.8 ± 0.2 µM, and cytotoxicity in noninfected human fibroblasts (the concentration inhibiting cell growth by 50% [CC 50 ]) was 128.1 ± 8.0 µM. In plaque reduction assays, OZ418 inhibited HCMV TB40 in a concentration-dependent manner as well as a ganciclovir (GCV)-resistant HCMV isolate. The combination of OZ418 and GCV was synergistic in HCMV inhibition in vitro Virus inhibition by OZ418 occurred at an early stage and was dependent on the cell density at the time of infection. OZ418 treatment reversed HCMV-mediated cell cycle progression and correlated with the reduction of HCMV-induced expression of pRb, E2F1, and cyclin-dependent kinases 1, 2, 4, and 6. In an MCMV model, once-daily oral administration of OZ418 had significantly improved efficacy against MCMV compared to that of twice-daily oral AS. A parallel pharmacokinetic study with a single oral dose of OZ418 or AS showed a prolonged plasma half-life and higher unbound concentrations of OZ418 than unbound concentrations of AS. In summary, ozonides are proposed to be potential therapeutics, alone or in combination with GCV, for HCMV infection in humans., (Copyright © 2018 American Society for Microbiology.)

Essentials The pathogenesis of immune thrombocytopenia (ITP) has not been fully clarified. We analyzed the role of anti-αvβ3 autoantibody in the pathogenesis of ITP in patients. Anti-αvβ3 autoantibody impeded megakaryocyte migration and adhesion to the vascular niche. Anti-α v β 3 autoantibody potentially contributes to the pathogenesis of refractory ITP., Summary: Background The pathogenesis of immune thrombocytopenia (ITP) has not been fully clarified. Anti-αvβ3 integrin autoantibody is detected in chronic ITP patients, but its contribution to ITP is still unclear. Objectives To clarify the potential role of anti-αvβ3 integrin autoantibody in chronic ITP and the related mechanism. Methods Relationship between levels of anti-αvβ3 autoantibody and platelets in chronic ITP patients was evaluated. The influence of anti-αvβ3 antibody on megakaryocyte (MK) survival, differentiation, migration and adhesion was assessed, and the associated signal pathways were investigated. Platelet recovery and MKs' distribution were observed in an ITP mouse model pretreated with different antibodies. Result In this study, we showed that the anti-αvβ3 autoantibody usually coexists with anti-αIIbβ3 autoantibody in chronic ITP patients, and patients with both autoantibodies have lower platelets. In in vitro studies, we showed that the anti-αvβ3 antibody had no significant effect on the survival and proliferation of MKs, whereas it decreased formations of proplatelet significantly. Anti-αvβ3 antibody impeded stromal cell derived facor-1 alpha (SDF-1α)- mediated migration and inhibited the phosphorylation of protein kinase B. Anti-αvβ3 antibody significantly inhibited MKs' adhesion to endothelial cells and Fibrogen. The phosphorylation of focal adhesion kinase and proto-oncogene tyrosine-protein kinase Src induced by adhesion was inhibited when MKs were pretreated with anti-αvβ3 antibody. In in vivo studies, we showed that injection with anti-α v antibody delayed platelet recovery in a mouse model of ITP. Conclusions These findings demonstrate that the autoantibody against integrin α v β 3 may aggravate thrombocytopenia in ITP patients by impeding MK migration and adhesion to the vascular niche, which provides new insights into the pathogenesis of ITP., (© 2018 International Society on Thrombosis and Haemostasis.)