Stereotactic Radiosurgery for Patients with Brain Metastases from Hepatopancreaticobiliary Cancers.

BACKGROUND: The role of stereotactic radiosurgery (SRS) for patients with brain metastases from hepatopancreaticobiliary (HPB) cancers has yet to be established. The authors present a single-institution experience of patients with HPB cancers who underwent SRS when their cancer spread to the brain. METHODS: We surveyed our Gamma Knife SRS data base of 18,000 patients for the years 1987-2022. In total, 19 metastatic HPB cancer patients (13 male) with 76 brain metastases were identified. The median age at SRS was 61 years (range: 48-83). The primary cancer sites were hepatocellular carcinoma (HCC, 11 patients), cholangiocarcinoma (CCC, 2 patients), and pancreatic carcinoma (PCC, 6 patients). The median Karnofsky Performance Score (KPS) was 80 (range: 50-90). Two patients underwent pre-SRS whole-brain fractionated radiation therapy (WBRT) and eight patients underwent pre-SRS surgical resection. All SRS was delivered in single session. The median margin dose was 18 Gy (range: 15-20). The median cumulative tumor volume was 8.1 cc (range: 1.0-44.2). RESULTS: The median patient overall survival (OS) after SRS was 7 months (range 1-79 months). Four patients had documented local tumor progression after SRS at a median time of 8.5 months (range: 2-15) between SRS and progression. Out of 76 treated tumors, 72 tumors exhibited local control. The local tumor control rate per patient was 78.9%. The local tumor control per tumor was 94.7%. Four patients developed new brain metastases at a median of 6.5 months (range: 2-17) after SRS. No patient experienced adverse radiation effects (AREs). At the last follow-up, 18 patients had died, all from systemic disease progression. CONCLUSIONS: Metastatic spread to the brain from HPB cancers occurs late in the course of the primary disease. In this study, all deceased patients ultimately died from primary disease progression. SRS is a non-invasive strategy that maximally preserves quality of life, and our results reported favorable outcomes compared to the existing literature. SRS should be considered as one of the primary management strategies for patients with brain metastatic spread from HPB cancer.

Stereotactic radiosurgery for brain metastasis from cholangiocarcinoma.

OBJECTIVE: Accounting for approximately 15% of primary liver cancers and 3% of gastrointestinal malignancies, cholangiocarcinoma (CCA) poses a serious health concern given its high mortality rate. Managing brain metastases (BMs) from CCA is challenging because of their rarity and poor prognosis, with little guidance on treatment from the literature. In this study, the authors aimed to evaluate the safety and efficacy of stereotactic radiosurgery (SRS) in managing BMs from CCA. METHODS: This multicenter retrospective study included 13 CCA patients with 41 BMs treated with SRS from October 2006 to April 2022 at eight institutions affiliated with the International Radiosurgery Research Foundation. Inclusion criteria were a CCA diagnosis, an age over 18 years, no other malignancies, single-fraction SRS treatment for BMs, and at least one follow-up image. Data on demographics, tumor characteristics, treatment details, and outcomes were collected. The primary endpoints were local control (LC), intracranial progression-free survival (PFS), and overall survival (OS). The secondary endpoint was the development of adverse radiation effects (AREs). RESULTS: The median radiological follow-up was 5 months (range 1-18 months). At the last follow-up, LC was achieved in 39 (95.1%) of 41 BMs. New distant metastases were observed in 3 patients (23.1%), and the mean intracranial PFS was 9.4 months (95% CI 6.5-12.3 months). Six-month and 1-year OS rates were 38.5% and 11.5%, respectively, and the median OS was 6 months (95% CI 4.9-7.2 months). Concurrent immunotherapy was associated with a high risk of local failure (HR 29.665, 95% CI 1.799-489.206, p = 0.018), and the absence of systemic chemotherapy before SRS was linked to reduced OS (HR 6.658, 95% CI 1.173-37.776, p = 0.032). Regarding AREs, only 1 patient (7.7%) experienced right hemiparesis and was treated with corticosteroid therapy. CONCLUSIONS: SRS is an effective option for managing BMs in CCA patients, showing promise in LC and a high safety profile.

Early recognition and treatment of OSA in hospitalized patients and its impact on health care utilization in rural population: a real-world study.

STUDY OBJECTIVES: Obstructive sleep apnea (OSA) is a highly prevalent, yet under-diagnosed condition. Due to its adverse impact on risk for cardiopulmonary disorders, there is interest in pro-active screening of OSA in hospitalized patients. We studied the long-term outcome of such screened patients who were initiated on positive airway pressure (PAP) therapy. METHODS: Hospitalized patients who screened positive for OSA and were confirmed with post-discharge polysomnography (PSG) were dichotomized by PAP adherence and followed for a period of 12 months to evaluate for the composite endpoint of hospital readmissions and emergency room (ED) visits for cardiopulmonary reasons. Cost analysis between the two groups was also conducted. RESULTS: 2042 hospitalized patients were assessed for OSA as part of a hospital sleep medicine program from August 2019 to June 2023. Of these, 293 patients were diagnosed with OSA and prescribed PAP therapy. Of these 293 patients, 108 were adherent to therapy and 185 were non-adherent. The overall characteristics of the groups included a mean (SD) age: 58 years (12.82), mean BMI (kg/m2): 39.72 (10.71), male sex: 57%, and apnea-hypopnea index (AHI): 25.49 (26). 78%, 41% and 43% had hypertension, congestive heart failure, and diabetes mellitus, respectively.The composite endpoint of hospital readmissions and ED visits for cardiovascular and pulmonary reasons was significantly higher in the non-adherent group as compared to the adherent group (HR: 1.24, 95% CI: 1-1.54) (p=0.03). The cost of care for both hospital billing (HB) as well as professional billing(PB) was higher for the non-adherent group ($1455.6 vs $1723.5, p = 0.004) in HB cost and $130.9 vs $144.7, p<0.001) in PB. Length of stay was higher for non-adherent patients (2.7 ± 5.1 days vs. 2.3 ± 5.9 days). CONCLUSIONS: Hospitalized patients diagnosed with OSA and adherent to therapy have reduced readmissions and ED visits for cardiopulmonary reasons 12 months after discharge. Adherent patients have reduced cost of health care and length of stay during hospitalizations.

Repeat stereotactic radiosurgery for persistent cerebral arteriovenous malformations in pediatric patients.

OBJECTIVE: The purpose of this study was to describe the long-term outcomes and associated risks related to repeat stereotactic radiosurgery (SRS) for persistent arteriovenous malformations (AVMs) in pediatric patients. METHODS: Under the auspices of the International Radiosurgery Research Foundation, this retrospective multicenter study analyzed pediatric patients who underwent repeat, single-session SRS between 1987 and 2022. The primary outcome variable was a favorable outcome, defined as nidus obliteration without hemorrhage or neurological deterioration. Secondary outcomes included rates and probabilities of hemorrhage, radiation-induced changes (RICs), and cyst or tumor formation. RESULTS: The cohort included 83 pediatric patients. The median patient age was 11 years at initial SRS and 15 years at repeat SRS. Fifty-seven children (68.7%) were managed exclusively using SRS, and 42 (50.6%) experienced hemorrhage prior to SRS. Median AVM diameter and volume were substantially different between the first (25 mm and 4.5 cm3, respectively) and second (16.5 mm and 1.6 cm3, respectively) SRS, while prescription dose and isodose line remained similar. At the 5-year follow-up evaluation from the second SRS, nidus obliteration was achieved in 42 patients (50.6%), with favorable outcome in 37 (44.6%). The median time to nidus obliteration and hemorrhage was 35.5 and 38.5 months, respectively. The yearly cumulative probability of favorable outcome increased from 2.5% (95% CI 0.5%-7.8%) at 1 year to 44% (95% CI 32%-55%) at 5 years. The probability of achieving obliteration followed a similar pattern and reached 51% (95% CI 38%-62%) at 5 years. The 5-year risk of hemorrhage during the latency period after the second SRS reached 8% (95% CI 3.2%-16%). Radiographically, 25 children (30.1%) had RICs, but only 5 (6%) were symptomatic. Delayed cyst formation occurred in 7.2% of patients, with a median onset of 47 months. No radiation-induced neoplasia was observed. CONCLUSIONS: The study results showed nidus obliteration in most pediatric patients who underwent repeat SRS for persistent AVMs. The risks of symptomatic RICs and latency period hemorrhage were quite low. These findings suggest that repeat radiosurgery should be considered when treating pediatric patients with residual AVM after prior SRS. Further study is needed to define the role of repeat SRS more fully in this population.

Third Stereotactic Radiosurgery for Residual Arteriovenous Malformations: A Retrospective Multicenter Study.

BACKGROUND AND OBJECTIVES: There are no studies evaluating the efficacy and safety of more than 2 stereotactic radiosurgery (SRS) procedures for cerebral arteriovenous malformations (AVM). The aim of this study was to provide evidence on the role of third single-session SRS for AVM residual. METHODS: This multicenter, retrospective study included patients managed with a third single-session SRS procedure for an AVM residual. The primary study outcome was defined as AVM nidus obliteration without AVM bleeding or symptomatic radiation-induced changes (RIC). Secondary outcomes evaluated were AVM obliteration, AVM hemorrhage, asymptomatic, and symptomatic RIC. RESULTS: Thirty-eight patients (20/38 [52.6%] females, median age at third SRS 34.5 [IQR 20] years) were included. The median clinical follow-up was 46 (IQR 14.8) months, and 17/38 (44.7%) patients achieved favorable outcome. The 3-year and 5-year cumulative probability rates of favorable outcome were 23% (95% CI = 10%-38%) and 53% (95% CI = 29%-73%), respectively. The cumulative probability of AVM obliteration at 3 and 5 years after the third SRS was 23% (95% CI = 10%-37%) and 54% (95% CI = 29%-74%), respectively. AVM bleeding occurred in 2 patients, and 1 of them underwent subsequent resection. The cumulative probability rate of post-SRS AVM hemorrhage remained constant at 5.3% (95% CI = 1%-16%) during the first 5 years of follow-up. Transient symptomatic RIC managed conservatively occurred in 5/38 patients (13.2%) at a median time of 12.5 (IQR 22.5) months from third SRS. Radiation-induced cyst formation was noted in 1 patient (4.2%) 19 months post-SRS. No mortality, radiation-associated malignancy, or permanent symptomatic RIC was noted during follow-up. CONCLUSION: A third single-session SRS to treat a residual intracranial AVM offers obliteration in most patients. The risk of RIC was low, and these effects were transient. While not often required, a third SRS can be performed in patients with persistent residual AVMs.

Effect of cerebral arteriovenous malformation location on outcomes of repeat, single-fraction stereotactic radiosurgery: a matched-cohort analysis.

OBJECTIVE: Patients with deep-seated arteriovenous malformations (AVMs) have a higher rate of unfavorable outcome and lower rate of nidus obliteration after primary stereotactic radiosurgery (SRS). The aim of this study was to evaluate and quantify the effect of AVM location on repeat SRS outcomes. METHODS: This retrospective, multicenter study involved 505 AVM patients managed with repeat, single-session SRS. The endpoints were nidus obliteration, hemorrhage in the latency period, radiation-induced changes (RICs), and favorable outcome. Patients were split on the basis of AVM location into the deep (brainstem, basal ganglia, thalamus, deep cerebellum, and corpus callosum) and superficial cohorts. The cohorts were matched 1:1 on the basis of the covariate balancing score for volume, eloquence of location, and prescription dose. RESULTS: After matching, 149 patients remained in each cohort. The 5-year cumulative probability rates for favorable outcome (probability difference -18%, 95% CI -30.9 to -5.8%, p = 0.004) and AVM obliteration (probability difference -18%, 95% CI -30.1% to -6.4%, p = 0.007) were significantly lower in the deep AVM cohort. No significant differences were observed in the 5-year cumulative probability rates for hemorrhage (probability difference 3%, 95% CI -2.4% to 8.5%, p = 0.28) or RICs (probability difference 1%, 95% CI -10.6% to 11.7%, p = 0.92). The median time to delayed cyst formation was longer with deep-seated AVMs (deep 62 months vs superficial 12 months, p = 0.047). CONCLUSIONS: AVMs located in deep regions had significantly lower favorable outcomes and obliteration rates compared with superficial lesions after repeat SRS. Although the rates of hemorrhage in the latency period and RICs in the two cohorts were comparable, delayed cyst formation occurred later in patients with deep-seated AVMs.

Mineralocorticoid receptor-independent activation of ENaC in bile duct ligated mice.

Sodium and fluid retention in liver disease is classically thought to result from reduced effective circulating volume and stimulation of the renin-angiotensin-aldosterone system (RAAS). Aldosterone dives Na+ retention by activating the mineralocorticoid receptor and promoting the maturation and apical surface expression of the epithelial Na+ channel (ENaC), found in the aldosterone-sensitive distal nephron. However, evidence of fluid retention without RAAS activation suggests the involvement of additional mechanisms. Liver disease can greatly increase plasma and urinary bile acid concentrations and have been shown to activate ENaC in vitro. We hypothesize that elevated bile acids in liver disease activate ENaC and drive fluid retention independent of RAAS. We therefore increased circulating bile acids in mice through bile duct ligation (BDL) and measured effects on urine and body composition, while using spironolactone to antagonize the mineralocorticoid receptor. We found BDL lowered blood [K+] and hematocrit, and increased benzamil-sensitive natriuresis compared to sham, consistent with ENaC activation. BDL mice also gained significantly more body water. Blocking ENaC reversed fluid gains in BDL mice but had no effect in shams. In isolated collecting ducts from rabbits, taurocholic acid stimulated net Na+ absorption but had no effect on K+ secretion or flow-dependent ion fluxes. Our results provide experimental evidence for a novel aldosterone-independent mechanism for sodium and fluid retention in liver disease which may provide additional therapeutic options for liver disease patients.

Outcome Evaluation of Repeat Stereotactic Radiosurgery for Cerebral Arteriovenous Malformations.

BACKGROUND: Repeat stereotactic radiosurgery (SRS) for persistent cerebral arteriovenous malformation (AVM) has generally favorable patient outcomes. However, reporting studies are limited by small patient numbers and single-institution biases. The purpose of this study was to provide the combined experience of multiple centers, in an effort to fully define the role of repeat SRS for patients with arteriovenous malformation. METHODS: This multicenter, retrospective cohort study included patients treated with repeat, single-fraction SRS between 1987 and 2022. Follow-up began at repeat SRS. The primary outcome was a favorable patient outcome, defined as a composite of nidus obliteration in the absence of hemorrhage or radiation-induced neurological deterioration. Secondary outcomes were obliteration, hemorrhage risk, and symptomatic radiation-induced changes. Competing risk analysis was performed to compute yearly rates and identify predictors for each outcome. RESULTS: The cohort comprised 505 patients (254 [50.3%] males; median [interquartile range] age, 34 [15] years) from 14 centers. The median clinical and magnetic resonance imaging follow-up was 52 (interquartile range, 61) and 47 (interquartile range, 52) months, respectively. At last follow-up, favorable outcome was achieved by 268 (53.1%) patients (5-year probability, 50% [95% CI, 45%-55%]) and obliteration by 300 (59.4%) patients (5-year probability, 56% [95% CI, 51%-61%]). Twenty-eight patients (5.6%) experienced post-SRS hemorrhage with an annual incidence rate of 1.38 per 100 patient-years. Symptomatic radiation-induced changes were evident in 28 (5.6%) patients, with most occurring in the first 3 years. Larger nidus volumes (between 2 and 4 cm3, subdistribution hazard, 0.61 [95% CI, 0.44-0.86]; P=0.005; >4 cm3, subdistribution hazard, 0.47 [95% CI, 0.32-0.7]; P<0.001) and brainstem/basal ganglia involvement (subdistribution hazard, 0.6 [95% CI, 0.45-0.81]; P<0.001) were associated with reduced probability of favorable outcome. CONCLUSIONS: Repeat SRS confers reasonable obliteration rates with a low complication risk. With most complications occurring in the first 3 years, extending the latency period to 5 years generally increases the rate of favorable patient outcomes and reduces the necessity of a third intervention.

Recent Advances in the Applications of Additive Manufacturing (3D Printing) in Drug Delivery: A Comprehensive Review.

There has been a tremendous increase in the investigations of three-dimensional (3D) printing for biomedical and pharmaceutical applications, and drug delivery in particular, ever since the US FDA approved the first 3D printed medicine, SPRITAM® (levetiracetam) in 2015. Three-dimensional printing, also known as additive manufacturing, involves various manufacturing techniques like fused-deposition modeling, 3D inkjet, stereolithography, direct powder extrusion, and selective laser sintering, among other 3D printing techniques, which are based on the digitally controlled layer-by-layer deposition of materials to form various geometries of printlets. In contrast to conventional manufacturing methods, 3D printing technologies provide the unique and important opportunity for the fabrication of personalized dosage forms, which is an important aspect in addressing diverse patient medical needs. There is however the need to speed up the use of 3D printing in the biopharmaceutical industry and clinical settings, and this can be made possible through the integration of modern technologies like artificial intelligence, machine learning, and Internet of Things, into additive manufacturing. This will lead to less human involvement and expertise, independent, streamlined, and intelligent production of personalized medicines. Four-dimensional (4D) printing is another important additive manufacturing technique similar to 3D printing, but adds a 4th dimension defined as time, to the printing. This paper aims to give a detailed review of the applications and principles of operation of various 3D printing technologies in drug delivery, and the materials used in 3D printing, and highlight the challenges and opportunities of additive manufacturing, while introducing the concept of 4D printing and its pharmaceutical applications.

Hot-Melt extrusion coupled with pressurized carbon dioxide for enhanced processability of pharmaceutical polymers and drug delivery applications - An integrated review.

Hot-melt extrusion (HME) technology is one of the primary approaches that has been implemented in recent years to overcome poor drug solubility/dissolution issues through the development of solid dispersion systems. Carbon dioxide (CO2) either in supercritical (SupC) or subcritical (SubC) forms has been introduced to HME as a temporary plasticizer, reducing the operating temperature and eventually processing heat-sensitive molecules more efficiently. In this paper, a comprehensive review of CO2-HME processes focused on pharmaceutical polymers and applications is presented. The steps and requirements for the setup of experimental devices are demonstrated, with a detailed influence of CO2 characteristics on HME processes. The most relevant physical and chemical properties of pharmaceutical grade polymers subjected to the CO2- HME process are described. The basic knowledge and main mechanisms of HME process parameters in conjunction with CO2 concentration with regard to process feasibility and final product formation are discussed. HME coupled with CO2 is extensively reviewed to provide a complete understanding of how to optimize the process parameters and conditions to reach optimized characteristics of final outcomes, as well as the sequential relationship between those outcomes (foaming → porosity → milling → tableting). Pharmaceutical applications of CO2-based HME are presented in detailed case studies, including extrusion feasibility, solubility, dissolution rate enhancement, and gastroretentive or floating drug delivery. Finally, the current status of general CO2-based techniques, as well as future perspectives and opportunities for promising applications through the integration of CO2 with HME is presented.

Pharmaceutical Co-Crystals, Salts, and Co-Amorphous Systems: A Novel Opportunity of Hot Melt Extrusion.

Enhancing the solubility of active drug ingredients is a major challenge faced by scientists and researchers. Different approaches have been explored for the enhancement of solubility and physicochemical properties of drugs, without affecting their stability or pharmacological activity. Among the various strategies available, pharmaceutical co-crystals, co-amorphous systems, and pharmaceutical salts as multicomponent systems (MCS) have gained interest to improve physicochemical properties of drugs. Development of MCS by conventional methods involves the utilization of excess amount of solvents, thus, making the product prone to instability, and may also cause harmful side effects in patients. Scale up is critical and involves the investment of huge capital and time. Lately, hot-melt extrusion has been utilized in the development of MCS to enhance solubility, bioavailability, stability, and physicochemical properties of the drugs. In this review, the authors discussed the development of different MCS produced via hot-melt extrusion technology. Specifically, approaches for screening of co-formers and co-crystals, selection of excipients for co-amorphous systems, pharmaceutical salts, and significance of MCS and process parameters affecting product quality are discussed.

Theophylline-nicotinamide pharmaceutical co-crystals generated using hot melt extrusion technology: Impact of polymeric carriers on processability.

The objective of the current study was to develop theophylline (TPH) nicotinamide (NAM) pharmaceutical co-crystals using the hot melt extrusion (HME) technology and evaluate the processability of the co-crystals using different polymeric carriers. A physical mixture of 1:1 M ratio of TPH and NAM was employed to prepare the co-crystals. Hydroxypropylmethylcellulose acetate succinate, polyethylene oxide, and Kollidon® VA-64 (5% w/w) were investigated as polymeric carriers for the HME process. Solid-state characterization using differential scanning calorimetry showed two endothermal peaks, one at 126.4 °C indicating eutectic formation and another at 174 °C indicating the melting point of the co-crystal for all formulations, except the Kollidon® VA-64 extrudates, which showed a single peak at 174 °C. Fourier-transform infrared spectroscopy and powder X-ray diffraction studies revealed the formation of co-crystals. The feasibility to formulate the extrudates into solid dosage forms was assessed by formulating a tablet blend. The three-month stability studies showed no degradation at the accelerated stability conditions of 40 (±2) ° C and 75 (±5) % RH. Finally, the results demonstrated that the presence of mixing zones in screw configuration and extrusion temperature are critical processing parameters that influence co-crystal formation.

Associations of Apolipoprotein E ε4 Genotype and Ball Heading With Verbal Memory in Amateur Soccer Players.

Importance: Emerging evidence suggests that long-term exposure to ball heading in soccer, the most popular sport in the world, confers risk for adverse cognitive outcomes. However, the extent to which the apolipoprotein E ε4 (APOE ε4) allele, a common risk factor for neurodegeneration, and ball heading are associated with cognition in soccer players remains unknown. Objective: To determine whether the APOE ε4 allele and 12-month ball heading exposure are associated with verbal memory in a cohort of adult amateur soccer players. Design, Settings, and Participants: A total of 379 amateur soccer players were enrolled in the longitudinal Einstein Soccer Study from November 11, 2013, through January 23, 2018. Selection criteria included participation in soccer for more than 5 years and for more than 6 months per year. Of the 379 individuals enrolled in the study, 355 were genotyped. Three players were excluded for reporting extreme levels of heading. Generalized estimating equation linear regression models were employed to combine data across visits for a cross-sectional analysis of the data. Exposures: At each study visit every 3 to 6 months, players completed the HeadCount 12-Month Questionnaire, a validated, computer-based questionnaire to estimate 12-month heading exposure that was categorized as low (quartiles 1 and 2), moderate (quartile 3), and high (quartile 4). Main Outcome and Measures: Verbal memory was assessed at each study visit using the International Shopping List Delayed Recall task from CogState. Results: A total of 352 soccer players (256 men and 96 women; median age, 23 years [interquartile range, 21-28 years]) across a total of 1204 visits were analyzed. High levels of heading were associated with worse verbal memory performance (ß = -0.59; 95% CI, -0.93 to -0.25; P = .001). There was no main association of APOE ε4 with verbal memory (ß = 0.09; 95% CI, -0.24 to 0.42; P = .58). However, there was a significant association of APOE ε4 and heading with performance on the ISRL task (χ2 = 7.22; P = .03 for overall interaction). In APOE ε4-positive players, poorer verbal memory associated with high vs low heading exposure was 4.1-fold greater (APOE ε4 negative, ß = -0.36; 95% CI, -0.75 to 0.03; APOE ε4 positive, ß = -1.49; 95% CI, -2.05 to -0.93), and poorer verbal memory associated with high vs moderate heading exposure was 8.5-fold greater (APOE ε4 negative, ß = -0.13; 95% CI, -0.54 to 0.29; APOE ε4 positive, ß = -1.11, 95% CI, -1.70 to -0.53) compared with that in APOE ε4-negative players. Conclusions and Relevance: This study suggests that the APOE ε4 allele is a risk factor for worse memory performance associated with higher heading exposure in the prior year, which highlights that assessing genetic risks may ultimately play a role in promoting safer soccer play.

Interactions Between Biological Products and Product Packaging and Potential Approaches to Overcome Them.

Biological products such as protein-based biopharmaceuticals are playing an important role in the healthcare and pharmaceutical industry. The interaction between biological products and packaging materials has become the focus of many studies since it can reduce the effectiveness of biological products. These interactions are heavily influenced by the surface properties and physicochemical nature of the therapeutic agents and the packaging materials. Therefore, it is critical to understand the interactions between packaging materials and biological products in order to design biocompatible packaging materials and develop approaches to minimize adverse interactions. We describe the interactions that occur when using several common packaging materials, including glass and polymer. We discuss the interaction between these materials and biological products such as blood, blood derivatives, recombinant proteins, monoclonal antibodies, and gene therapeutics. We also summarize approaches for overcoming these interactions. Understanding the interactions between biological materials and packaging materials is critical for the development of novel packaging materials that improve the safety of pharmaceutical products.

A natural small molecule inhibitor corilagin blocks HCV replication and modulates oxidative stress to reduce liver damage.

Hepatitis C virus (HCV) infection causes chronic liver disease, which often leads to hepatocellular carcinoma. Earlier, we have demonstrated anti-HCV property of the methanolic extract of Phyllanthus amarus, an age-old folk-medicine against viral hepatitis. Here, we report identification of a principal bioactive component 'corilagin', which showed significant inhibition of the HCV key enzymes, NS3 protease and NS5B RNA-dependent-RNA-polymerase. This pure compound could effectively inhibit viral replication in the infectious cell culture system, displayed strong antioxidant activity by blocking HCV induced generation of reactive oxygen species and suppressed up-regulation of NOX4 and TGF-ß mRNA levels. Oral administration of corilagin in BALB/c mice demonstrated its better tolerability and systemic bioavailability. More importantly, corilagin could restrict serum HCV RNA levels, decrease collagen deposition and hepatic cell denaturation in HCV infected chimeric mice harbouring human hepatocytes. Taken together, results provide a basis towards developing a pure natural drug as an alternate therapeutic strategy for restricting viral replication and prevent liver damage towards better management of HCV induced pathogenesis.

A modelling approach demonstrating micromechanical changes in the tibial cemented interface due to in vivo service.

Post-operative changes in trabecular bone morphology at the cement-bone interface can vary depending on time in service. This study aims to investigate how micromotion and bone strains change at the tibial bone-cement interface before and after cementation. This work discusses whether the morphology of the post-mortem interface can be explained by studying changes in these mechanical quantities. Three post-mortem cement-bone interface specimens showing varying levels of bone resorption (minimal, extensive and intermediate) were selected for this study Using image segmentation techniques, masks of the post-mortem bone were dilated to fill up the mould spaces in the cement to obtain the immediately post-operative situation. Finite element (FE) models of the post-mortem and post-operative situation were created from these segmentation masks. Subsequent removal of the cement layer resulted in the pre-operative situation. FE micromotion and bone strains were analyzed for the interdigitated trabecular bone. For all specimens micromotion increased from the post-operative to the post-mortem models (distally, in specimen 1: 0.1 to 0.5µm; specimen 2: 0.2 to 0.8µm; specimen 3: 0.27 to 1.62µm). Similarly bone strains were shown to increase from post-operative to post-mortem (distally, in specimen 1: -185 to -389µÎµ; specimen 2: -170 to -824µÎµ; specimen 3: -216 to -1024µÎµ). Post-mortem interdigitated bone was found to be strain shielded in comparison with supporting bone indicating that failure of bone would occur distal to the interface. These results indicate that stress shielding of interdigitated trabeculae is a plausible explanation for resorption patterns observed in post-mortem specimens.

Strain shielding in trabecular bone at the tibial cement-bone interface.

Aseptic loosening of the tibial component remains the leading cause for revision surgery in total knee arthroplasty (TKA). Understanding the mechanisms leading to loss of fixation can offer insight into preventative measures to ensure a longer survival rate. In cemented TKA, loosening occurs at the cement-trabecular interface probably due to a stress-shielding effect of the stiffer implant material in comparison with bone. Using finite element models of lab-prepared tibial cement-trabeculae interface specimens (n=4) based on micro-CT images, this study aims to investigate the micromechanics of the interlock between cement and trabecular bone. Finite element micromotion between cement and trabeculae and bone strain were compared in the interdigitated trabeculae as well as strain in the bone distal to the interface. Lab-prepared specimens and their FE models were assumed to represent the immediate post-operative situation. The cement layer was removed in the FE models while retaining the loading conditions, which resulted in FE models that represented the pre-operative situation. Results showed that micromotion and bone strain decrease when interdigitation depth increases. Bone-cement micromotion and bone strain at the distal interdigitated region showed a dependence on bone volume fraction. Comparing the immediate post-operative and pre-operative situations, trabeculae embedded deep within the cement generally showed the highest level of strain-shielding. Strain shielding of interdigitated bone, in terms of reduction in compressive strains, was found to be between 35 and 61 % for the four specimens. Strain adaptive remodeling could thus be a plausible mechanism responsible for loss of interdigitated bone.

Experimental and computational micromechanics at the tibial cement-trabeculae interface.

Aseptic loosening of the tibial component in cemented total knee arthroplasty remains a major concern. We hypothesize that micromotion between the cement and trabeculae leads to increased circulation of interstitial fluid which in turn causes fluid-induced resorption of the trabeculae. Another mechanism for implant loosening is trabecular strain shielding. Using a newly developed experimental setup and digital image correlation (DIC) methods we were able to measure micromotion and strains in lab-prepared cement-trabeculae interface specimens (n=4). Finite element (FE) models of these specimens were developed to determine whether differences in micromotion and strain in morphologically varying specimens could be simulated accurately. Results showed that the measured micromotion and strains correlated well with FE model predictions (r(2)=0.59-0.85; r(2)=0.66-0.90). Global specimen strains measured axially matched well with the FE model strains (r(2)=0.87). FE model cement strains showed an increasing trend with distance from the cement border. The influence of loss of trabecular connectivity at the specimen edges was studied using our FE model results. Micromotion values at the outer edge of the specimens were higher than the specimen interior when considering a very thin outer edge (0.1mm). When the outer edge thickness was increased to about one trabecular length (0.8mm), there was a drop in the median and peak values. Using the experimental and modelling approach outlined in this study, we can further study the mechanisms that lead to loss of interlock between cement and trabeculae at the tibial interface.

Effect of cementing technique and cement type on thermal necrosis in hip resurfacing arthroplasty--a numerical study.

Femoral fractures within resurfacing implants have been associated with bone necrosis, possibly resulting from heat generated by cement polymerization. The amount of heat generated depends on cement mantle volume and type of cement. Using finite element analysis, the effect of cement type and volume on thermal necrosis was analyzed. Based on CT-data of earlier implantations, two different models were created: a thick mantle model, representing a low-viscosity "cement filling" technique, and a thin mantle model, representing a high viscosity "cement packing" technique. Six cement types were analyzed. The polymerization heat generation and its effect on bone necrosis were predicted. In the thin cement mantle models, no thermal necrosis was predicted. Thick cement mantle models produced thermal necrosis at the cement-bone interface depending on cement type. In the worst case, 6% of the bone at the cement-bone interface became necrotic, covering almost the entire cross-sectional area. The current findings suggest a potential thermal drawback of thick cement mantles, although it is unclear whether thermal bone necrosis significantly affects implant fixation or increases the fracture risk. Furthermore, our study showed distinct differences between the heat generated and resulting thermal damage caused by the various cement types.