Comparison of double chevron-cut and biplanar distal femoral osteotomy techniques: A biomechanical study.

OBJECTIVE: This study aimed to compare the stability and mechanical properties of the double chevron-cut (DCC) and biplanar (BP) distal femoral osteotomy (DFO) techniques, along with analyzing their respective contact surface areas. METHODS: Biomechanical testing was performed using sawbone and 3D modeling techniques to assess axial and torsional stability, torsional stiffness, and maximum torque of both osteotomy configurations. Additionally, 3D models of the sawbone femur were created to calculate and compare the contact surface area of the DCC, BP, and conventional single-plane DFO techniques. RESULTS: Axial stiffness and maximum strength did not significantly differ between the two osteotomy techniques. However, in terms of torsional properties, the DCC technique exhibited superior torsional stiffness compared to the BP group (27 ± 7.7 Nm/° vs. 4.5 ± 1.5 Nm/°, p = 0.008). Although the difference in maximum torque did not reach statistical significance (63 ± 10.6 vs. 56 ± 12.1, p = 0.87), it is noteworthy that the DCC group sawbone model exhibited fracture in the shaft region instead of at the osteotomy site. Therefore, the actual maximum torque of the DCC construct may not be accurately reflected by the numerical values obtained in this study. The contact surface area analysis revealed that the BP configuration had the largest contact surface area, 111% larger than that of the single-plane configuration. but 60% of it relied on the less reliable axial cut. Conversely, the DCC osteotomy offered a 31% larger contact surface area than the single-plane configuration, with both surfaces being weight-bearing. CONCLUSION: The DCC osteotomy exhibited superior mechanical stability, showing improved rotational stiffness and maximum torque when compared to the BP osteotomy. Although the BP osteotomy resulted in a larger contact surface area than the DCC osteotomy, both were larger than the conventional single-plane configuration. In clinical practice, both the DCC and BP techniques should be evaluated based on patient-specific characteristics and surgical goals.

Building a Predictive PBPK Model for Human OATP Substrates: a Strategic Framework for Early Evaluation of Clinical Pharmacokinetic Variations Using Pitavastatin as an Example.

To select a drug candidate for clinical development, accurately and promptly predicting human pharmacokinetic (PK) profiles, assessing drug-drug interactions (DDIs), and anticipating potential PK variations in disease populations are crucial steps in drug discovery. The complexity of predicting human PK significantly increases when hepatic transporters are involved in drug clearance (CL) and volume of distribution (Vss). A strategic framework is developed here, utilizing pitavastatin as an example. The framework includes the construction of a monkey physiologically-based PK (PBPK) model, model calibration to obtain scaling factors (SF) of in vitro-in vivo extrapolation (IVIVE) for various clearance parameters, human model development and validation, and assessment of DDIs and PK variations in disease populations. Through incorporating in vitro human parameters and calibrated SFs from the monkey model of 3.45, 0.14, and 1.17 for CLint,active, CLint,passive, and CLint,bile, respectively, and together with the relative fraction transported by individual transporters obtained from in vitro studies and the optimized Ki values for OATP inhibition, the model reasonably captured observed pitavastatin PK profiles, DDIs and PK variations in human subjects carrying genetic polymorphisms, i.e., AUC within 20%. Lastly, when applying the functional reduction based on measured OATP1B biomarkers, the model adequately predicted PK changes in the hepatic impairment population. The present study presents a strategic framework for early-stage drug development, enabling the prediction of PK profiles and assessment of PK variations in scenarios like DDIs, genetic polymorphism, and hepatic impairment-related disease states, specifically focusing on OATP substrates.

The benefits of a percutaneous supplemental screw to reinforce the hinge of a medial open wedge tibial osteotomy.

INTRODUCTION: Our earlier studies reported that an additional lag screw placed from the opposite side increases the stability of the fixation construct in medial open wedge high tibia osteotomy (MOWHTO). The aim of the study was to evaluate the clinical relevance of the use of a supplemental screw with immediate post-operative full weight-bearing and its benefits in terms of functional outcome, radiographic outcome and complications. MATERIALS AND METHODS: A retrospective study was performed comparing the historical cohort (MOWHTO without opposite screw) (group A) with the current cohort (MOWHTO with opposite screw) (group B). The patients underwent clinical and radiological assessments. We evaluated the WOMAC (The Western Ontario and McMaster Universities) score, IKDC (International Knee Documentation Committee) scores, and Lysholm knee score. Patients' return to sports and work were also recorded. RESULTS: We included 123 knees receiving MOWHTO alone (group A) with 114 knees (group B) receiving MOWHTO with an opposite screw. A shorter bone union time (18.3 ± 2.1 weeks v.s. 11.5 ± 2.6 weeks, p < 0.001), earlier return to sports (6.1 months vs. 4.6 months, p < 0.001) and return to works (3.2 months vs. 2.3 months, p < 0.001) and better 6-month functional outcomes were found in group B (p < 0.001). The complications were similar in both groups. One patient experienced irritation at the site of the screw entrance and the screw was removed after union. CONCLUSION: The current study evaluated the clinical efficacy of a supplemental lag screw placed from the opposite side in MOWHTO. Comparing to the plate alone, the additional opposite screw improved the implant and fixation stability under immediate weight-bearing without causing complications. A shorter time for returning to sports and work was noted, and a better functional outcome at 6-month follow-up was registered.

Inhaled remdesivir reduces viral burden in a nonhuman primate model of SARS-CoV-2 infection.

Remdesivir (RDV) is a nucleotide analog prodrug with demonstrated clinical benefit in patients with coronavirus disease 2019 (COVID-19). In October 2020, the US FDA approved intravenous (IV) RDV as the first treatment for hospitalized COVID-19 patients. Furthermore, RDV has been approved or authorized for emergency use in more than 50 countries. To make RDV more convenient for non-hospitalized patients earlier in disease, alternative routes of administration are being evaluated. Here, we investigated the pharmacokinetics and efficacy of RDV administered by head dome inhalation in African green monkeys (AGM). Relative to an IV administration of RDV at 10 mg/kg, an approximately 20-fold lower dose administered by inhalation produced comparable concentrations of the pharmacologically active triphosphate in lower respiratory tract tissues. Distribution of the active triphosphate into the upper respiratory tract was also observed following inhaled RDV exposure. Inhalation RDV dosing resulted in lower systemic exposures to RDV and its metabolites as compared with IV RDV dosing. An efficacy study with repeated dosing of inhaled RDV in an AGM model of SARS-CoV-2 infection demonstrated reductions in viral replication in bronchoalveolar lavage fluid and respiratory tract tissues compared with placebo. Efficacy was observed with inhaled RDV administered once daily at a pulmonary deposited dose of 0.35 mg/kg beginning approximately 8 hours post-infection. Moreover, the efficacy of inhaled RDV was similar to that of IV RDV administered once at 10 mg/kg followed by 5 mg/kg daily in the same study. Together, these findings support further clinical development of inhalation RDV.

Boosted Tree Ensembles for Artificial Intelligence Based Automated Valuation Models (AI-AVM).

This paper develops an artificial intelligence based automated valuation model (AI-AVM) using the boosting tree ensemble technique to predict housing prices in Singapore. We use more than 300,000 private and public housing transactions in Singapore for the period from 1995 to 2017 in the training of the AI-AVM models. The boosting model is the best predictive model that produce the most robust and accurate predictions for housing prices compared to the decision tree and multiple regression analysis (MRA) models. The boosting AI-AVM models explain 91.33% and 94.28% of the price variances, and keep the mean absolute percentage errors at 8.55% and 5.34% for the public housing market and the private housing market, respectively. When subject the AI-AVM to the out-of-sample forecasting using the 2018 housing sale samples, the prediction errors remain within a narrow range of between 5% and 9%.

A Trigger and Response System for Preventing Cardiac Arrest in the ICU.

Although patients in the ICU are closely monitored, some ICU cardiac arrest events may be preventable. In this study, we sought to reduce the rate of cardiac arrests occurring in the ICU through a quality improvement initiative. DESIGN: Prospective, observational study. SETTING: ICUs of a single tertiary care center. PATIENTS: Patients hospitalized in the ICUs between August 2017 and November 2019. INTERVENTIONS: A comprehensive trigger and response tool. MEASUREMENT AND MAIN RESULTS: Forty-three patients experienced an ICU cardiac arrest in the preintervention epoch (6.79 arrests per 1,000 discharges), and 59 patients experienced an ICU cardiac arrest in the intervention epoch (7.91 arrests per 1,000 discharges). In the intervention epoch, the clinical trigger and response tool was activated 106 times over a 1-year period, most commonly due to unexpected new/worsening hypotension. There was no step change in arrest rate (2.24 arrests/1,000 patients; 95% CI, -1.82 to 6.28; p = 0.28) or slope change (-0.02 slope of arrest rate; 95% CI, -0.14 to 0.11; p = 0.79) comparing the preintervention and intervention time epochs. Cardiac arrests in the preintervention epoch were more likely to be "potentially preventable" than that in the intervention epoch (25.6% vs 12.3%, respectively; odds ratio, 0.58; 95% CI, 0.20-0.88; p < 0.01). CONCLUSIONS: A novel trigger-and-response tool did not reduce the frequency of ICU cardiac arrest. Additional investigation is needed into the optimal approach for ICU cardiac arrest prevention.

Patient-Specific Instrument Guided Double Chevron-Cut Distal Femur Osteotomy.

The risk of non-union and prolonged periods of protected weight-bearing still remain unsolved issues after distal femur osteotomy (DFO). To improve the stability, we developed the double chevron-cut technique, which is a modified medial closing-wedge DFO guided by a patient-specific instrument. The purpose of this study was to investigate the feasibility and outcome of this operative approach. Twenty-five knees in twenty-three consecutive patients with genu valgum and lateral compartment osteoarthritis that received double chevron-cut DFO were included. The target of correction was 50% on the weight-bearing line (WBL) ratio. Patient-reported outcomes included the Oxford Knee Score (OKS) and the 2011 Knee Society Score (KSS). The mean of the WBL ratio was corrected from 78.7% ± 12.0% to 48.7% ± 2.9% postoperatively. The mean time to full weight bearing was 3.7 ± 1.4 weeks. Union of the osteotomy was achieved at 11.3 ± 2.8 weeks. At a mean follow-up of 17 months, the OKS improved from a mean of 27.6 ± 11.7 to 39.1 ± 7.5 (p = 0.03), and the KSS from a mean of 92.1 ± 13.0 to 143.9 ± 10.2 (p < 0.001). Three patients developed complications, including one case of peri-implant fracture, one of loss of fixation, and one of non-union. The double chevron-cut DFO followed by immediate weight-bearing as tolerated is effective in treating genu valgum deformity and associated lateral compartment osteoarthritis.

Identification of a Proteomic Signature of Senescence in Primary Human Mammary Epithelial Cells.

Senescence is a permanent cell cycle arrest that occurs in response to cellular stress and promotes age-related disease. Because senescence differs greatly depending on cell type and senescence inducer, continued progress in the characterization of senescent cells is needed. Here, we analyzed primary human mammary epithelial cells (HMECs), a model system for aging and cancer, using mass spectrometry-based proteomics. By integrating data from replicative senescence, immortalization by telomerase reactivation, and quiescence, we identified a robust proteomic signature of HMEC senescence consisting of 34 upregulated and 10 downregulated proteins. This approach identified known senescence biomarkers including ß-galactosidase (GLB1) as well as novel senescence biomarkers including catechol O-methyltransferase (COMT), synaptic vesicle membrane protein VAT-1 homolog (VAT1), and plastin-1/3 (PLS1/PLS3). Gene ontology enrichment analysis demonstrated that senescent HMECs upregulated lysosomal proteins and downregulated RNA metabolic processes. In addition, a classification model based on our proteomic signature successfully discriminated proliferating and senescent HMECs at the transcriptional level. Finally, we found that the HMEC senescence signature was positively and negatively correlated with proteomic alterations in HMEC aging and breast cancer, respectively. Taken together, our results demonstrate the power of proteomics to identify cell type-specific signatures of senescence and advance the understanding of senescence in HMECs.

Significantly reducing blood loss via a peri-articular injection of tranexamic acid during total knee arthroplasty: a retrospective study.

BACKGROUND: The administration of an intra-articular injection (IAI) of tranexamic acid (TXA) has been demonstrated to be effective in reducing both blood loss and transfusion rate during total knee arthroplasty (TKA); however, few studies have reported the efficiency of a peri-articular injection (PAI) of TXA. We studied the efficiency of a PAI of TXA in reducing blood loss during TKA. METHODS: Fifty patients undergoing primary simultaneous bilateral TKA were enrolled in this retrospective study. The right knee received a PAI of 1 g of TXA (Group I), and the left knee received an IAI of 1 g of TXA (Group II). The clinical outcome measures were a change in blood loss from Hemovac drains and surgical time. RESULTS: The decrease in blood loss from the Hemovac was significantly lower in Group I (460.1 ± 36.79 vs. 576.0 ± 34.01, P < 0.001) than in Group II, and no significant difference in surgical times was observed. The blood transfusion rate in the present study was 16 %. CONCLUSIONS: A PAI of TXA may reduce blood loss more efficiently than an IAI of TXA during TKA without increased complications such as surgical site infection, poor wound healing, skin necrosis, pulmonary embolism, and deep vein thrombosis.

Biomechanical evaluation of high tibial osteotomy plate with internal support block using finite element analysis.

BACKGROUND/OBJECTIVE: High tibial osteotomy (HTO) is a common treatment for medial knee arthrosis. However, a high rate of complications associated with a plate and a significant loss of correction have been reported. Therefore, an internal support block (ISB) is designed to enhance the initial stability of the fixation device that is important for successful bone healing and maintenance of the correction angle of the osteotomy site. The purpose of this study was performed to examine if an internal support block combined with a plate reduces the stress on the plate and screw area. METHODS: Finite element models were reconstructed following three different implant combinations. Two loading conditions were applied to simulate standing and initial sit-to-stand postures. Data analysis was conducted to evaluate the axial displacement of the posteromedial tibial plateau, which represents the loss of the posteromedial tibial plateau in clinical observation. Moreover, the stresses on the bone plate and locking screws were evaluated. RESULTS: Compared to the TomoFix plate, the ISB reduced the axial displacement by 73% and 76% in standing and initial sit-to-stand loading conditions, respectively. The plate with an ISB reduced stress by 90% on the bone plate and by 73% on the locking screw during standing compared to the standalone TomoFix plate. During the initial sit-to-stand loading condition, the ISB reduced the stress by 93% and 77% on the bone plate and the locking screw, respectively. CONCLUSION: The addition of the PEEK block showed a benefit for structural stability in the osteotomy site. However, further clinical trials are necessary to evaluate the clinical benefit of reduced implant stress and the internal support block on the healing of the medial bone tissue.

Defining Best Practices for Interhospital Transfers.

INTRODUCTION: Interhospital transfers (IHT) are important yet high-risk transitions in care. Variable IHT processes and a lack of clarity around best practice may contribute to risk. To define the best practice principles for IHTs and identify improvement opportunities in the transfer process to our hospital's Cardiology services. METHODS: Through literature review, interviews with experts and key stakeholders, a survey of health care professionals at our institution, and a failure modes effect analysis, we identified themes in IHT best practices and improvement opportunities. RESULTS: We identified six critical elements of IHT: (1) initiation of transfer request; (2) the management of transfer request and information exchange; (3) updates between transfer acceptance and patient transport; (4) transport; (5) patient admission and information availability; and (6) measurement, evaluation, and feedback. Improvement opportunities were found in all elements. CONCLUSIONS: The standardization of these six critical elements may improve the safety of IHTs.

A supplemental screw enhances the biomechanical stability in medial open-wedge high tibial osteotomy.

BACKGROUND: The supplemental screw technique was introduced for salvage of lateral hinge fracture in medial open-wedge high tibial osteotomy (owHTO). The efficacy of its use in protection of lateral hinge fracture and corresponding biomechanical behaviors remained unclear. The current study was aimed to clarify if a supplemental screw can provide better protection to lateral hinge in biomechanical perspective. MATERIALS: An in vitro biomechanical test was conducted. Tibial sawbones, commercial owHTO plates and a cannulated screw were utilized for preparing the intact, owHTO, and owHTO with cannulated screw insertion specimens. A "staircase" dynamic load protocol was adopted for axial compressive test with increasing load levels to determine structural strength and durability by using a material testing system, while a motion capture system was applied for determining the dynamic changes in varus angle and posterior slope of the tibia plateau with various specimen preparation conditions. RESULTS: Type II lateral hinge fracture were the major failure pattern in all specimens prepared with owHTO. The insertion of a supplemental cannulated screw in medial owHTO specimens reinforced structural stability and durability in dynamic cyclic loading tests: the compressive stiffness increased to 58.9-62.2% of an intact specimen, whereas the owHTO specimens provided only 23.7-29.2% of stiffness of an intact specimen. In view of tibial plateau alignment, the insertion of a supplemental screw improved the structural deficiency caused by owHTO, and reduced the posterior slope increase and excessive varus deformity by 81.8% and 83.2%, respectively. CONCLUSION: The current study revealed that supplemental screw insertion is a simple and effective technique to improve the structural stability and durability in medial owHTO.

Benefits of opposite screw insertion technique in medial open-wedge high tibial osteotomy: A virtual biomechanical study.

BACKGROUND: Alignment correction of the lower limb by medial open-wedge high tibial osteotomy (HTO) is an efficient technique, but loss of correction and hardware failure can occur owing to inadequate fixation. A surgical technique using opposite screw insertion was previously applied for salvage of the lateral hinge fracture, but evidence for its utility as a protective strategy was unclear. METHODS: Finite element models were reconstructed using artificial bone models, commercial bone plate, and locking screws in the HTO model. The 6.5-mm cancellous or 6.5/8.0-mm pretensioned lag screw was virtually inserted from the opposite cortex to the medial tibial plateau. Testing loads were applied for simulating standing and initial sit-to-stand postures. The axial displacement of the posteromedial tibial plateau, which represents the loss of the posteromedial tibial plateau in clinical observation, and stresses on the bone plate, locking screws, and opposite screws were evaluated. RESULTS: Pretensioned lag screw insertion effectively reduced the loss of posteromedial reduction compared with the HTO model without opposite screw insertion [6.5-mm lag screw, by 50.8% (standing)/56.3% (sit-to-stand); 8.0-mm lag screws, by 51.9% (standing)/57.5% (sit-to-stand); normalised by the performance in the intact model]. The noncompressed opposite cancellous screw slightly reduced the stresses on the bone plate and screws, but did not contribute to the control of reduction loss at the posteromedial tibial plateau. Stresses on screws were lower than those on the corresponding bone plates, so the risk of screw breakage may be low. CONCLUSION: The present study revealed that pretensioned opposite lag screw insertion is a simple and effective technique to improve the structural stability in medial open-wedge HTO. Further biomechanical and clinical verification will be required to enhance user confidence in this technique. THE TRANSLATIONAL POTENTIAL OF THIS ARTICLE: The efficacy and advantages of additional opposite lag screw insertion in medial wedge high tibial osteotomy surgery have been described in this current study by a virtual biomechanical evaluation. Basing on this observation, it would worth further clinical trials for clarification and verification in reality.

Association between procedure appropriateness and patient-reported outcomes after percutaneous coronary intervention.

OBJECTIVE: The Appropriate Use Criteria (AUC) has been used to identify individuals who are likely to benefit from percutaneous coronary intervention (PCI) for stable ischaemic heart disease. However, whether physicians reliably grade PCI appropriateness and whether AUC categories stratify symptomatic improvement in real-world practice are unclear. METHODS: Patient-reported outcomes measures (PROMs) for angina (Seattle Angina Questionnaire (SAQ-7)), dyspnoea (Rose Dyspnea Scale (RDS)) and depression (Patient Health Questionnaire-2 (PHQ-2)) were collected on patients undergoing elective coronary angiography at an academic medical centre. Retrospectively, two physicians independently determined PCI appropriateness by the AUC criteria. RESULTS: Inter-rater agreement on appropriateness was moderate (κ=0.48, 95% CI 0.32 to 0.63). Of PCI procedures evaluated, 57 (47.1%) were appropriate (A-PCI), 62 (51.2%) were maybe appropriate (MA-PCI) and 2 (1.6%) were rarely appropriate. At baseline, A-PCI compared with MA-PCI patients had worse RDS scores (2.0 vs 1.2, p=0.01). At 30 days, the change in SAQ-7 summary score was similar between groups (A-PCI vs MA-PCI, +27.1 vs +20.7, p=0.11). The mean change in RDS score was greater in A-PCI than MA-PCI (-1.0 vs -0.5, p for group by time interaction=0.03). PHQ-2 scores were similar and did not improve at 30 days. CONCLUSION: In patients undergoing PCI with PROMs collected before and 30 days after PCI, similar improvements in angina were observed regardless of appropriateness. Inter-rater agreement on PCI appropriateness was only moderate. Use of PROMs may improve reliability of physician assessments of PCI appropriateness.

Cardiac arrest in the intensive care unit: An assessment of preventability.

AIM: Cardiac arrest in the intensive care unit (ICU-CA) is a common and highly morbid event. We investigated the preventability of ICU-CAs and identified targets for future intervention. METHODS: This was a prospective, observational study of ICU-CAs at a tertiary care center in the United States. For each arrest, the clinical team was surveyed regarding arrest preventability. An expert, multi-disciplinary team of physicians and nurses also reviewed each arrest. Arrests were scored 0 (not at all preventable) to 5 (completely preventable). Arrests were considered 'unlikely but potentially preventable' or 'potentially preventable' if at least 50% of reviewers assigned a score of ≥1 or ≥3 respectively. Themes of preventability were assessed for each arrest. RESULTS: 43 patients experienced an ICU-CA and were included. A total of 14 (32.6%) and 13 (30.2%) arrests were identified as unlikely but potentially preventable by the expert panel and survey respondents respectively, and an additional 11 (25.6%) and 10 (23.3%) arrests were identified as potentially preventable. Timing of response to clinical deterioration, missed/incorrect diagnosis, timing of acidemia correction, timing of escalation to a more senior clinician, and timing of intubation were the most commonly cited contributors to potential preventability. Additional themes identified included the administration of anxiolytics/narcotics for agitation later identified to be due to clinical deterioration and misalignment between team and patient/family perceptions of prognosis and goals-of-care. CONCLUSIONS: ICU-CAs may have preventable elements. Themes of preventability were identified and addressing these themes through data-driven quality improvement initiatives could potentially reduce CA incidence in critically-ill patients.

On-call transthoracic echocardiographic interpretation by first year cardiology fellows: comparison with attending cardiologists.

BACKGROUND: Transthoracic echocardiograms (TTE) performed and interpreted by cardiology fellows during off-duty hours are critical to patient care, however limited data exist on their interpretive accuracy. Our aims were to determine the discordance rate between TTEs performed and interpreted by cardiology fellows and National Board of Echocardiography certified attending cardiologists and to identify factors associated with discordance. METHODS: Consecutive on-call TTEs acquired and interpreted by 1st year cardiology fellows over 4.6 years at an academic center were prospectively evaluated by attending cardiologists. Fellow interpretations were classified as concordant or discordant with the attending interpretation. We assessed the association of patient, imaging and fellow characteristics with discordance. RESULTS: A total of 777 TTE interpretations (730 patients) were performed/interpreted by 40 first year fellows and overread by 13 attendings. The most common indications were assessment of left ventricular function (40.9%) and pericardial effusion (37.3%). There was a major or minor discordance in 4.1 and 17.4% of studies, respectively with 42.1% of disagreements occurring in assessment of left ventricular size and function. The indication to assess left ventricular function [OR 2.19, 95% CI (1.32, 3.62), P = 0.002 vs. pericardial effusion] and greater duration of echocardiographic image acquisition (OR 1.02, 95% CI 1.01, 1.03, P = 0.004) were independently associated with overall discordance. CONCLUSIONS: In this large prospective study we found that attending cardiologists disagreed with 1 in 5 fellow TTE interpretations. Standardized tools for evaluation of echocardiograms performed by fellows are needed to ensure quality of training and patient safety.

Inhibition of nucleotide synthesis promotes replicative senescence of human mammary epithelial cells.

Cellular senescence is a mechanism by which cells permanently withdraw from the cell cycle in response to stresses including telomere shortening, DNA damage, or oncogenic signaling. Senescent cells contribute to both age-related degeneration and hyperplastic pathologies, including cancer. In culture, normal human epithelial cells enter senescence after a limited number of cell divisions, known as replicative senescence. Here, to investigate how metabolic pathways regulate replicative senescence, we used LC-MS-based metabolomics to analyze senescent primary human mammary epithelial cells (HMECs). We did not observe significant changes in glucose uptake or lactate secretion in senescent HMECs. However, analysis of intracellular metabolite pool sizes indicated that senescent cells exhibit depletion of metabolites from nucleotide synthesis pathways. Furthermore, stable isotope tracing with 13C-labeled glucose or glutamine revealed a dramatic blockage of flux of these two metabolites into nucleotide synthesis pathways in senescent HMECs. To test whether cellular immortalization would reverse these observations, we expressed telomerase in HMECs. In addition to preventing senescence, telomerase expression maintained metabolic flux from glucose into nucleotide synthesis pathways. Finally, we investigated whether inhibition of nucleotide synthesis in proliferating HMECs is sufficient to induce senescence. In proliferating HMECs, both pharmacological and genetic inhibition of ribonucleotide reductase regulatory subunit M2 (RRM2), a rate-limiting enzyme in dNTP synthesis, induced premature senescence with concomitantly decreased metabolic flux from glucose into nucleotide synthesis. Taken together, our results suggest that nucleotide synthesis inhibition plays a causative role in the establishment of replicative senescence in HMECs.

Pancreatic Cancer Gene Therapy Delivered by Nanoparticles.

Pancreatic cancer is one of the most lethal forms of cancer and has proven to be difficult to treat through conventional methods, including surgery and chemotherapy. Gene therapy serves as a potential novel treatment to interfere with genes that make this cancer so aggressive, but free nucleic acids have low cell uptake due to their negative charge and are unstable in circulation. Nanoparticles can serve as an effective carrier for a wide variety of gene therapies for pancreatic cancer as they can improve the circulation time, decrease the recognition by the immune system, and be functionalized to target specific surface proteins. In this review, we focus on therapeutic strategies using nanoparticles as carriers of small interfering RNA (siRNA), microRNA (miRNA), and gene augmentation (DNA) therapies in the context of pancreatic cancer. Lastly, we discuss the future outlook of nanoparticle-based therapies, including challenges in the clinical setting.

Clinical Experience Using a 3D-Printed Patient-Specific Instrument for Medial Opening Wedge High Tibial Osteotomy.

PURPOSE: High tibial osteotomy (HTO) has been adopted as an effective surgery for medial degeneration of the osteoarthritis (OA) knee. However, satisfactory outcomes necessitate the precise creation and distraction of osteotomized wedges and the use of intraoperative X-ray images to continually monitor the wedge-related manipulation. Thus HTO is highly technique-demanding and has a high radiation exposure. We report a patient-specific instrument (PSI) guide for the precise creation and distraction of HTO wedge. METHODS: This study first parameterized five HTO procedures to serve as a design rationale for an innovative PSI guide. Preoperative X-ray and computed tomography- (CT-) scanning images were used to design and fabricate PSI guides for clinical use. The weight-bearing line (WBL) of the ten patients was shifted to the Fujisawa's point and instrumented using the TomoFix system. The radiological results of the PSI-guided HTO surgery were evaluated by the WBL percentage and tibial slope. RESULTS: All patients consistently showed an increased range of motion and a decrease in pain and discomfort at about three-month follow-up. This study demonstrates the satisfactory accuracy of the WBL adjustment and tibial slope maintenance after HTO with PSI guide. For all patients, the average pre- and postoperative WBL are, respectively, 14.2% and 60.2%, while the tibial slopes are 9.9 and 10.1 degrees. The standard deviations are 2.78 and 0.36, respectively, in postoperative WBL and tibial slope. The relative errors of the pre- and postoperative WBL percentage and tibial slope averaged 4.9% and 4.1%, respectively. CONCLUSION: Instead of using navigator systems, this study integrated 2D and 3D preoperative planning to create a PSI guide that could most likely render the outcomes close to the planning. The PSI guide is a precise procedure that is time-saving, radiation-reducing, and relatively easy to use. Precise osteotomy and good short-term results were achieved with the PSI guide.