Factors influencing surgical outcomes of fixation with locking plate for three- and four-part proximal humerus fractures in patients aged 50 ​Years and older.

Background: Treating complex three- and four-part proximal humerus fractures, especially in the elderly, remains contentious, with internal fixation using locking plates and shoulder arthroplasty being primary options. Although proximal humerus locking plates are more commonly used than shoulder replacements, they have a high complication rate. Factors like low bone density, advanced age, multiple fragment fractures, and medial cortical support loss negatively impact treatment outcomes. This study evaluates the functional and radiographic outcomes of using locking plates for treating these fractures in patients aged 50 and older, and the factors influencing outcomes and complication rates at the Ho Chi Minh City Hospital for Trauma and Orthopedics. Method: A descriptive case series study was conducted on 58 patients aged 50 and older (15 males, 43 females) with three- and four-part proximal humerus fractures. These patients underwent open reduction and internal fixation with Locking - compression plate (LCP) periarticular proximal humerus plates at the Ho Chi Minh City Hospital for Traumatology and Orthopedics (HTO) from April 2020 to April 2022. The minimum postoperative follow-up period was 12 months. Results: The average age of the patients was 62.78 â€‹± â€‹7.73 years, with a mean follow-up of 26.24 â€‹± â€‹5.93 months. Among them, 41 had three-part fractures (70.68 â€‹%) and 17 had four-part fractures (29.32 â€‹%). At the final follow-up (≥12 months), the mean Constant-Murley score was 70.81 â€‹± â€‹9.15, and the mean QDASH score was 8.33 â€‹± â€‹2.77. Complications occurred in 6 cases (10.34 â€‹%). Complex fractures, such as four-part fractures with displacement greater than 2 â€‹mm, had lower Constant-Murley scores and higher QDASH scores (p â€‹< â€‹0.05). Age, gender, bone density by deltoid tuberosity index (DTI), bone grafting, and rotator cuff sutures showed similar trends, but the differences were not statistically significant. Conclusion: Open reduction and internal fixation (ORIF) provides good bone healing and functional outcomes for three- and four-part proximal humerus fractures. Factors such as age, gender, bone density, bone grafting, and rotator cuff sutures do not significantly affect outcomes. Therefore, osteoporosis should not be a contraindication for ORIF with locking plates in these cases. Complex fractures, however, often lead to poorer outcomes and higher complication rates post-surgery.

Echinococcus ortleppi infection in humans: An emerging zoonosis in Asia.

Echinococcus ortleppi is the genotype G5 of Echinococcus granulosus sensu lato and is a zoonotic canine tapeworm of which larvae causes cystic diseases in domestic animals and also humans. While this species is highly endemic and widely spread in domestic animals, human infection is extremely rare and only sporadic, and thus, entire picture of human cystic echinococcosis due to infection with E. ortleppi is unclear. We have made an extensive literature review on the cases of E. ortleppi infection in humans and found a total of 19 cases from various places in the world with recent emergence in Asian countries.

Chloroplast biogenesis involves spatial coordination of nuclear and organellar gene expression in Chlamydomonas.

The localization of translation can direct the polypeptide product to the proper intracellular compartment. Our results reveal translation by cytosolic ribosomes on a domain of the chloroplast envelope in the unicellular green alga Chlamydomonas (Chlamydomonas reinhardtii). We show that this envelope domain of isolated chloroplasts retains translationally active ribosomes and mRNAs encoding chloroplast proteins. This domain is aligned with localized translation by chloroplast ribosomes in the translation zone, a chloroplast compartment where photosystem subunits encoded by the plastid genome are synthesized and assembled. Roles of localized translation in directing newly synthesized subunits of photosynthesis complexes to discrete regions within the chloroplast for their assembly are suggested by differences in localization on the chloroplast of mRNAs encoding either subunit of the light-harvesting complex II or the small subunit of Rubisco. Transcription of the chloroplast genome is spatially coordinated with translation, as revealed by our demonstration of a subpopulation of transcriptionally active chloroplast nucleoids at the translation zone. We propose that the expression of chloroplast proteins by the nuclear-cytosolic and organellar genetic systems is organized in spatially aligned subcompartments of the cytoplasm and chloroplast to facilitate the biogenesis of the photosynthetic complexes.

Unusual conjunctival melanocytic proliferations. Report of five cases and review of the literature.

Indeterminate melanocytic proliferations of the conjunctiva have both benign and malignant features that previously made these lesions nearly impossible to categorize in existing classification schemes. With the evolution of immunohistochemistry and molecular genetics, however, subclassifications have emerged that allow for a more tailored diagnosis and management. These conjunctival melanocytic proliferations include deep penetrating nevus, granular cell nevus, and nevoid melanoma. There remains a small subset of conjunctival melanocytic proliferations that defy precise characterization as nevi, primary acquired melanosis, or melanomas despite currently available ancillary diagnostic modalities and remain indeterminate. We highlight these unusual types of nevi and melanomas, with an update on their morphologic, immunohistochemical, and molecular genetic characteristics.

Sympathetic Ophthalmia in Patients with Enucleation or Evisceration: Pathology Laboratory and IRIS® Registry Experience.

Introduction: Sympathetic ophthalmia (SO) is a rare bilateral granulomatous panuveitis that can follow surgical or nonsurgical ocular trauma in one eye. Because its diagnosis requires clinical-pathologic correlation, the true incidence of SO is unknown, and there is a need to understand the recent trends in risk factors and frequency of this condition. Methods: Pathology records of all enucleated or eviscerated (ENEV) eyes at three pathology laboratories were reviewed. Data collected included patient demographics, procedure indication, pathology diagnosis, and clinical history of trauma and uveitis. IRIS® Registry (Intelligent Research in Sight) was searched for all patients with SO, acquired absence of eye (AAE), and/or ENEV. Data obtained included patient demographics, ocular procedures, and preoperative diagnoses within 30 days of AAE/ENEV. Results: In the pathology laboratory setting, the incidence of SO over a 36-year period in patients who underwent ENEV was 0.2% (20/9,092); the 5-year incidence ranged from 0.0 to 0.3%. Among the 20 eyes with SO, the inciting event was surgical trauma in 50% (10/20), nonsurgical trauma in 45% (9/20), and missing/undetermined in 5% (1/20). SO was suspected preoperatively in 7/20 (35%) patients. Clinical concern for SO and ruptured globe were indications for ENEV in 50/9,092 (0.5%) and 872/9,092 (10%) patients, respectively. In the IRIS Registry, 0.7% (199/27,830) of patients with AAE/ENEV had diagnosis of SO. The frequency of SO between 2015 and 2020 was 0.01% (7,371/62,318,249); of these 7,371 cases, 199 (3%) had AAE/ENEV. In 25,975 patients with available data, injury and SO were listed as diagnoses less than 30 days prior to AAE/ENEV in 909 (4%) and 63 (0.2%) cases, respectively. Conclusion: The frequency of SO in recent decades has been low. Most cases of SO are not managed with eye removal. In histopathology-confirmed SO, surgical trauma is as frequent as nonsurgical trauma as an inciting etiology of disease.

Integrated modeling of the Nexin-dynein regulatory complex reveals its regulatory mechanism.

Cilia are hairlike protrusions that project from the surface of eukaryotic cells and play key roles in cell signaling and motility. Ciliary motility is regulated by the conserved nexin-dynein regulatory complex (N-DRC), which links adjacent doublet microtubules and regulates and coordinates the activity of outer doublet complexes. Despite its critical role in cilia motility, the assembly and molecular basis of the regulatory mechanism are poorly understood. Here, using cryo-electron microscopy in conjunction with biochemical cross-linking and integrative modeling, we localize 12 DRC subunits in the N-DRC structure of Tetrahymena thermophila. We also find that the CCDC96/113 complex is in close contact with the DRC9/10 in the linker region. In addition, we reveal that the N-DRC is associated with a network of coiled-coil proteins that most likely mediates N-DRC regulatory activity.

Regulatory mechanisms of the dynein-2 motility by post-translational modification revealed by MD simulation.

Intraflagellar transport for ciliary assembly and maintenance is driven by dynein and kinesins specific to the cilia. It has been shown that anterograde and retrograde transports run on different regions of the doublet microtubule, i.e., separate train tracks. However, little is known about the regulatory mechanism of this selective process. Since the doublet microtubule is known to display specific post-translational modifications of tubulins, i.e., "tubulin code", for molecular motor regulations, we investigated the motility of ciliary specific dynein-2 under different post-translational modification by coarse-grained molecular dynamics. Our setup allows us to simulate the landing behaviors of dynein-2 on un-modified, detyrosinated, poly-glutamylated and poly-glycylated microtubules in silico. Our study revealed that poly-glutamylation can play an inhibitory effect on dynein-2 motility. Our result indicates that poly-glutamylation of the B-tubule of the doublet microtubule can be used as an efficient means to target retrograde intraflagellar transport onto the A-tubule.

Ischemic Colitis Presented as Pseudomembranous Colitis: An Untypical Case from Vietnam.

Ischemic colitis (IC) is an underreported chronic disease characterized by the hypoperfusion of the bowel mucosa. The diagnosis and treatment may be challenging because its clinical course resembles other colitis or even colorectal malignancies. This paper reports an untypical case to underline the diversity of IC manifestation. A 68-year-old man with several comorbidities was admitted because of abdominal pain with a 6-month duration and a mass in the left lower quadrant. Colonoscopy revealed erosive pseudomembranous colitis narrowed colon segments with ulcerated mucosa mimicking colorectal cancer and inflammatory bowel disease. The stool cultures and Clostridium difficile toxin tests were negative. After the failure of conservative therapy, the Hartmann procedure with temporary ileostomy was performed uneventfully. The histological results of the surgical specimens revealed IC with focal pseudomembranous areas.

Remodeling and activation mechanisms of outer arm dyneins revealed by cryo-EM.

Cilia are thin microtubule-based protrusions of eukaryotic cells. The swimming of ciliated protists and sperm cells is propelled by the beating of cilia. Cilia propagate the flow of mucus in the trachea and protect the human body from viral infections. The main force generators of ciliary beating are the outer dynein arms (ODAs) which attach to the doublet microtubules. The bending of cilia is driven by the ODAs' conformational changes caused by ATP hydrolysis. Here, we report the native ODA complex structure attaching to the doublet microtubule by cryo-electron microscopy. The structure reveals how the ODA complex is attached to the doublet microtubule via the docking complex in its native state. Combined with coarse-grained molecular dynamic simulations, we present a model of how the attachment of the ODA to the doublet microtubule induces remodeling and activation of the ODA complex.

Induction of Antitumor Immunity by Exosomes Isolated from Cryopreserved Cord Blood Monocyte-Derived Dendritic Cells.

(1) Background: Dendritic cell (DC) vaccination has shown outstanding achievements in cancer treatment, although it still has some adverse side effects. Vaccination with DC-derived exosomes has been thought to overcome the side effects of the parental DCs. (2) Method: We performed the experiments to check the ability of cryopreserved umbilical cord blood mononuclear cell-derived DCs (cryo CBMDCs) and their exosomes to prime allogeneic T cell proliferation and allogeneic peripheral blood mononuclear cell (alloPBMCs) cytotoxicity against A549 lung cancer cells. (3) Results: We found that both lung tumor cell lysate-pulsed DCs and their exosomes could induce allogeneic T cell proliferation. Moreover, alloPBMCs primed with tumor cell lysate-pulsed DCs and their exosomes have a greater cytotoxic activity against A549 cells compared to unprimed cells and cells primed with unpulsed DCs and their exosomes. (4) Conclusion: Tumor cell lysate-pulsed DCs and their exosomes should be considered to develop into a novel immunotherapeutic strategy-e.g., vaccines-for patients with lung cancer. Our results also suggested that cryo umbilical cord blood mononuclear cells source, which is a readily and available source, is effective for generation of allogeneic DCs and their exosomes will be material for vaccinating against cancer.

Successive Kinesin-5 Microtubule Crosslinking and Sliding Promote Fast, Irreversible Formation of a Stereotyped Bipolar Spindle.

Separation of duplicated spindle poles is the first step in forming the mitotic spindle. Kinesin-5 crosslinks and slides anti-parallel microtubules (MTs), but it is unclear how these two activities contribute to the first steps in spindle formation. In this study, we report that in monopolar spindles, the duplicated spindle poles snap apart in a fast and irreversible step that produces a nascent bipolar spindle. Using mutations in Kinesin-5 that inhibit microtubule sliding, we show that the fast, irreversible pole separation is primarily driven by microtubule crosslinking. Electron tomography revealed microtubule pairs in monopolar spindles have short overlaps that intersect at high angles and are unsuited for ensemble Kinesin-5 sliding. However, maximal extension of a subset of anti-parallel microtubule pairs approaches the length of nascent bipolar spindles and is consistent with a Kinesin-5 crosslinking-driven transition. Nonetheless, microtubule sliding by Kinesin-5 contributes to stabilizing the nascent spindle and setting its stereotyped equilibrium length.

Efficacy and Safety Exposure-Response Analyses of Olaparib Capsule and Tablet Formulations in Oncology Patients.

Olaparib is a poly ADP-ribose polymerase inhibitor that induces synthetic lethality in tumors with deficient homologous recombination repair. Population exposure-response analyses were performed to evaluate the efficacy and safety of olaparib exposure in patients with cancer. Data from multiple phase I/II/III clinical studies from both capsule and tablet formulations were combined for efficacy (N = 410) and safety (N = 757) analyses. Exposure-progression-free survival (Cox proportional hazards model indicated that a 300 mg b.i.d. tablet was statistically superior to the 200 mg b.i.d. tablet dose (hazard ratio of 0.96), although the difference was small. Exposure-safety logistic regression models and hemoglobin models predicted similar probability of safety events or hemoglobin decrease with largely overlapping 95% confidence intervals at 300 mg b.i.d. tablet, 200 mg b.i.d. tablet, and 400 mg b.i.d. capsule. The analyses provided key assessments to support the approval of olaparib 300 mg tablet therapeutic dose in patients with ovarian and breast cancer, regardless of their breast cancer (BRCA) mutation status.

Bridging Olaparib Capsule and Tablet Formulations Using Population Pharmacokinetic Meta-analysis in Oncology Patients.

BACKGROUND: Olaparib is a first-in-class potent oral poly(ADP-ribose) polymerase inhibitor. OBJECTIVES: The aims of this analysis were to establish an integrated population pharmacokinetic (PK) model of olaparib in patients with solid tumors and to bridge the PK of olaparib between capsule and tablet formulations. METHODS: The population PK model was developed using plasma concentration data from 659 patients in 11 phase I, II, and III studies of olaparib tablets/capsules monotherapy. Relative bioavailability between the tablet and capsule formulations was estimated and the relative exposure between olaparib tablet and capsule therapeutic doses was further assessed. RESULTS: The concentration-time profile was described using a two-compartment model with sequential zero- and first-order absorption and first-order elimination for both capsules and tablets with different absorption parameters. Multiple-dose clearance compared with single-dose clearance was reduced by approximately 15% (auto-inhibition). Disease severity had an impact on olaparib clearance, and tablet strength had an impact on Ka. The olaparib geometric mean area under the curve (AUC) and maximal concentration (Cmax) following a single 300 mg tablet were 42.1 µg h/mL and 5.8 µg/mL, respectively, and the steady-state geometric mean AUC and Cmax following a 300 mg tablet twice daily were 49.0 µg h/mL and 7.7 µg/mL, respectively. The relative exposure (AUC) of the 300 mg tablet formulation is 13% higher than the 400 mg capsule formulation. CONCLUSION: This analysis bridged the olaparib capsule and tablet formulation PK and provided key assessment to support the approval of the olaparib tablet formulation in patients with ovarian cancer, regardless of their BRCA mutation status.

In Vitro Production of Cartilage Tissue from Rabbit Bone Marrow-Derived Mesenchymal Stem Cells and Polycaprolactone Scaffold.

In vitro production of tissues or tissue engineering is a promising approach to produce artificial tissues for regenerative medicine. There are at least three important components of tissue engineering, including stem cells, scaffolds and growth factors. This study aimed to produce cartilage tissues in vitro from culture and chondrogenic differentiation of rabbit bone marrow-derived mesenchymal stem cells (BMMSCs), induced by chondrogenesis medium, on biodegradable polycaprolactone (PCL) scaffolds. BMMSCs were isolated from rabbit bone marrow according to the standard protocol. The adherence, proliferation and differentiation of BMMSCs on scaffolds were investigated using two scaffold systems: PCL scaffolds and collagen-coated PCL (PCL/col) scaffolds. The results showed that BMMSCs could attach and grow on both PCL and PCL/col scaffolds. However, the adhesion efficacy of BMMSCs on the PCL/col scaffolds was significantly better than on PCL scaffolds. Under induced conditions, BMMSCs on PLC/col scaffolds showed increased aggrecan accumulation and upregulated expression of chondrogenesis-associated genes (e.g. collagen type II, collagen type I, aggrecan and collagen type X) after 3, 7, 21 and 28 days of induction. These in vitro cartilage tissues could form mature chondrocyte-like cells after they were grafted into rabbits. The results suggest that use of BMMSCs in combination with polycaprolactone scaffolds and chondrogenesis medium can be a way to form in vitro cartilage tissue.

Characterization of Senescence of Human Adipose-Derived Stem Cells After Long-Term Expansion.

INTRODUCTION: Since the 1980s, adipose-derived stem cells (ASCs) have become a powerful and potential source for stem cell-based therapy, regenerative medicine, and even drug delivery in cancer treatment. The development of off-the-shelf mesenchymal stem cells (MSCs), including ASCs, has rapidly advanced in recent years with several clinical trials and approved products. In this technology, ASCs should be expanded long term in order to harvest higher cell number. In this study, senescence of ASCs after long-term expansion was evaluated. METHODS: Human ASCs (hASCs) were isolated and cultured continuously at a density of 103 cells/cm2 up to passage 15. The cells were assessed for aging via changes in the following: characteristics of MSCs, mitochondrial activity, accumulation of beta-galactosidase, and expression of tumor suppressor genes. RESULTS: The results showed that following in vitro expansion to the 15th passage, ASCs did not show changes in immunophenotype, except for decreased expression of CD105. However, the cells increased in size and in shape and complexity (toward the "fried egg" morphology). They also almost ceased to proliferate in passage 15. Nonetheless, they maintained in vitro differentiation potential toward osteoblasts, chondrocytes, and adipocytes. Expression of tumor suppressor genes p53 and p16 did not significantly change, while p27 was significantly downregulated. Mitochondrial activities also decreased slightly in culture from passage 5 to passage 10 and remained stable to passage 15. ASCs also showed increased accumulation of beta-galactosidase in culture, but it was negligible. CONCLUSION: In conclusion, hASCs exhibited some particular characteristics of aged stem cells when the number of subculture cells increased. However, up to passage 10, ASCs also retained almost all of the characteristics of MSCs.

Effect of multiple-dose osimertinib on the pharmacokinetics of simvastatin and rosuvastatin.

AIM: We report on two Phase 1, open-label, single-arm studies assessing the effect of osimertinib on simvastatin (CYP3A substrate) and rosuvastatin (breast cancer resistance protein substrate [BCRP] substrate) exposure in patients with advanced epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer who have progressed after treatment with an EGFR tyrosine kinase inhibitor, to determine, upon coadministration, whether osimertinib could affect the exposure of these agents. METHODS: Fifty-two patients in the CYP3A study (pharmacokinetic [PK] analysis, n = 49), and 44 patients in the BCRP study were dosed (PK analysis, n = 44). In the CYP3A study, patients received single doses of simvastatin 40 mg on Days 1 and 31, and osimertinib 80 mg once daily on Days 3-32. In the BCRP study, single doses of rosuvastatin 20 mg were given on Days 1 and 32, and osimertinib 80 mg once daily on Days 4-34. RESULTS: Geometric least squares mean (GLSM) ratios (90% confidence intervals) of simvastatin plus osimertinib for area under the plasma concentration-time curves from zero to infinity (AUC) were 91% (77-108): entirely contained within the predefined no relevant effect limits, and Cmax of 77% (63, 94) which was not contained within the limits. GLSM ratios of rosuvastatin plus osimertinib for AUC were 135% (115-157) and Cmax were 172 (146, 203): outside the no relevant effect limits. CONCLUSIONS: Osimertinib is unlikely to have any clinically relevant interaction with CYP3A substrates and has a weak inhibitory effect on BCRP. No new safety concerns were identified in either study.

The effect of itraconazole and rifampicin on the pharmacokinetics of osimertinib.

AIMS: We investigated the effects of a strong CYP3A4 inhibitor (itraconazole) or inducer (rifampicin) on the pharmacokinetics of the epidermal growth factor receptor-tyrosine kinase inhibitor osimertinib, in patients with advanced non-small cell lung cancer in two Phase I, open-label, two-part clinical studies. Part one of both studies is reported. METHODS: In the itraconazole study (NCT02157883), patients received single-dose osimertinib 80 mg on Days 1 and 10 and itraconazole (200 mg twice daily) on Days 6-18 orally. In the rifampicin study (NCT02197247), patients received osimertinib 80 mg once daily on Days 1-77 and rifampicin 600 mg once daily on Days 29-49. RESULTS: In the itraconazole study (n = 36), the geometric least squares mean (GMLSM) ratios (osimertinib plus itraconazole/osimertinib alone) for Cmax and AUC were 80% (90% CI 73, 87) and 124% (90% CI 115, 135), respectively, below the predefined no-effect upper limit of 200%. In the rifampicin study (n = 40), the GMLSM ratios (osimertinib plus rifampicin/osimertinib alone) for Css,max and AUCτ were 27% (90% CI 24, 30) and 22% (90% CI 20, 24), respectively, below the predefined no-effect lower limit of 50%. The induction effect of rifampicin was apparent within 7 days of initiation; osimertinib Css,max and AUCτ values returned to pre-rifampicin levels within 3 weeks of rifampicin discontinuation. No new osimertinib safety findings were observed. CONCLUSIONS: Osimertinib can be co-administered with CYP3A4 inhibitors, but strong CYP3A inducers should be avoided if possible.

Predictive Performance of Physiologically Based Pharmacokinetic (PBPK) Modeling of Drugs Extensively Metabolized by Major Cytochrome P450s in Children.

The accuracy of physiologically based pharmacokinetic (PBPK) model prediction in children, especially those younger than 2 years old, has not been systematically evaluated. The aim of this study was to characterize the pediatric predictive performance of the PBPK approach for 10 drugs extensively metabolized by CYP1A2 (theophylline), CYP2C8 (desloratidine, montelukast), CYP2C9 (diclofenac), CYP2C19 (esomeprazole, lansoprazole), CYP2D6 (tramadol), and CYP3A4 (itraconazole, ondansetron, sufentanil). Model performance in children was evaluated by comparing simulated plasma concentration-time profiles with observed clinical results for each drug and age group. PBPK models reasonably predicted the pharmacokinetics of desloratadine, diclofenac, itraconazole, lansoprazole, montelukast, ondansetron, sufentanil, theophylline, and tramadol across all age groups. Collectively, 58 out of 67 predictions were within 2-fold and 43 out of 67 predictions within 1.5-fold of observed values. Developed PBPK models can reasonably predict exposure in children age 1 month and older for an array of predominantly CYP metabolized drugs.

Prevalence, genotyping and risk factors of Giardia duodenalis from dogs in Vietnam.

This study was carried out to determine the prevalence, genotypes/assemblages and possible risk factors associated with Giardia duodenalis infection in dogs in central Vietnam. A total of 209 dog fecal samples, randomly collected from private owned dogs (n=105) and dogs from stores (n=104), were examined for Giardia cysts by microscopy. Positive samples were genotyped by PCR-sequence analysis of ß-giardin and triosephosphate isomerase genes markers. Risk factors were studied using a structured questionnaire and collected data were analyzed by univariate and multivariate logistic regression analyses. Results indicated that the overall infection rate was 8.6% (18/209) with the detected parasites were belonging to the non-zoonotic assemblages C and D. Age, gender and origin of animals were the main risk factors associated with G. duodenalis infection in dogs under study. Occurrence of infection was more likely in young animals compared to old ones and in females compared to males. Dogs originated from stores were more prone to Giardia infection compared to private owned counterparts.