Pressure-Gradient Counterwork of Dual-Fuel Driven Nanocarriers in Abnormal Interstitial Fluids for Enhancing Drug Delivery Efficiency.

The abnormal pressure in tumor tissue is a significant limitation on the drug delivery efficiency of tumor therapy. This work reports a gradient-driven nanomotor as drug nanocarrier with the pressure-counterworking function. The dual-fuel nanomotors are formed by co-electrospinning of the photosensitive polymers with calcium peroxide (CaO2 ) and catalase (CAT), followed by ultraviolet (UV) irradiation and bovine serum albumin (BSA) incubation. The UV-responsive cleavage nanomotors can effectively release O2 molecules at the fractures as a driving force to increase the delivery speed and escape the phagocytosis of macrophage system in normal tissues. Furthermore, CAT catalyzes H2 O2 produced by CaO2 and the tumor interstitial fluids to provide stronger power for the nanomotors. Additionally, according to the analysis of directional motions of the nanomotors, the functional relationship between the rotational diffusion coefficient (DR ) and the physiological viscosity is constructed. The dual-fuel nanocarriers enable up to 13.25% of the injected dose (ID)/per gram tissue and significantly improve the penetration in deep tumor. It is of vital importance to design and obtain the adaptive pressure-gradient counterworking nanomotors, which can effectively improve the drug delivery efficiency in vitro and in vivo.

Prolactin-Induced Protein is a novel biomarker for Keratoconus.

PURPOSE: The purpose of the study was to investigate the role of Prolactin-Induced Protein (PIP) as a predictive biomarker for Keratoconus (KC). PARTICIPANTS: This study included one hundred and forty-seven patients with KC (105 male, 42 female), and sixty healthy controls (27 male, 33 female). METHODS: Tears, plasma and saliva samples were collected from all participants. In both KC and healthy groups all collected samples were divided into four age subgroups (15-24y), (25-34y), (35-44y) and (45y and up). Samples were analyzed using western blot (WB) and enzyme-linked immunosorbent assay (ELISA). Areas under the receiver operating characteristic curves (AUROCs) were used to evaluate diagnostic accuracy for distinguishing between KC and healthy eyes. MAIN OUTCOME MEASURES: Difference in PIP protein levels between patients with KC and healthy controls. RESULTS: Results showed significant downregulation of PIP expression in all three biological fluids on KC patients when compared to healthy controls, independent of age, sex and severity. Since PIP is a hormonal-regulated protein, we also investigated the expression of major sex hormones. We detected significant upregulation in salivary and plasma Dehydroepiandrosterone sulfate (DHEA-S) levels and significant downregulation of estrone and estriol levels, in KC patients compared to healthy controls, independent of sex, age, and KC severity stage. ROC was used to determine the overall predictive accuracy of this protein in KC. Data showed an area under the curve (AUC) for PIP in tears of 0.937 (95%CI: 0.902-0.971), in plasma of 0.928 (95%CI: 0.890-0.968) and in saliva of 0.929 (95%CI: 0.890-0.968). CONCLUSIONS: Conclusively, our results show that PIP levels are reduced in all three human biological fluids tested, and may independently or in combination with current imaging techniques aid in screening and diagnosis of KC. Our data revealed that PIP levels can potentially differentiate between disease and healthy cases, and PIP levels are stable in relation to KC severity, sex and age. Moreover, alterations in sex hormone levels in correlation with reduced PIP levels in KC provide an intriguing insight in the underlying KC pathophysiology and highlights the role of PIP as a KC biomarker.

Folate Ligand Orientation Optimized during Cell Membrane Mimetic Micelle Formation for Enhanced Tumor Cell Targeting.

Nanocarriers with strong tumor cell targeting ability have been expected to overcome limitations of cancer chemotherapy. Herein, cell membrane mimetic micelles were prepared from a random copolymer (PMNCF) containing cell membrane phosphorylcholine zwitterion, cholesterol, and tumor cell targeting folic acid (FA) at the side chain ends. Surface orientation of the FA ligand was optimized during PMNCF micelle preparation by controlling solvent solubility for FA. The out-oriented ligands on the micelles were immobilized by the strongly associated hydration layer around the closely packed phosphorylcholine zwitterions. The doxorubicin (DOX) loaded PMNCF micelles were demonstrated to reduce normal cell toxicity to less than 20%. More significantly, HeLa and MCF-7 tumor cell killing efficacy of the optimized formulation was enhanced to 160% compared with that of free DOX. The excellent performances of the drug loaded PMNCF micelles on both tumor cell killing and normal cell toxicity reducing efficacies reveal great potential for developing advanced drug delivery system.

The effect of punctal plugs in reducing ocular surface irritation after povidone-iodine preparation of intravitreal injection-a randomized trial.

PURPOSE: To evaluate the utility of dissolvable collagen punctal plugs (CPP) in reducing ocular surface irritation after intravitreal injections (IVI). METHODS: Sixty-four subjects in the experimental group received CPP after intravitreal injections. Sixty-two controls did not receive CPP. Reductions in the Ocular Surface Disease Index© (OSDI) and Standardized Patient Evaluation of Eye Dryness II (SPEED II) scores were analysed. RESULTS: Dry eye symptoms, as measured by reductions from the pre- to post-injection OSDI (p = 0.137) and SPEED II (p = 0.381) scores, did not significantly differ between the two groups. In sub-group analysis, patients with objective findings of dry eyes had significant improvement in their symptoms (p = 0.046) with CPP. The effect of CPP is not significant in those without dry eyes (p = 0.27). CONCLUSION: CPPs were not effective in reducing post-injection ocular irritation in patients with no or only mild dry eye symptoms. CPPs improved patients' post-injection comfort levels in those who had moderate-to-severe symptoms and objective findings of dry eye. Though costly CPP could be considered in selective patients. A standardized eye rinse could be a simple, efficacious, and cost-effective way to reduce post-injection ocular irritation; however, more studies are needed.

Titanium alloy cannulated screws and biodegradable magnesium alloy bionic cannulated screws for treatment of femoral neck fractures: a finite element analysis.

BACKGROUND: Cannulated screws (CS) are one of the most widely used treatments for femoral neck fracture, however, associated with high rate of complications. In this study, we designed a new type of cannulated screws called degradable magnesium alloy bionic cannulated screws (DMBCS) and our aim was to compare the biomechanical properties of DMBCS, the traditionally used titanium alloy bionic cannulated screws (TBCS) and titanium alloy cannulated screws (TTCS). METHODS: A proximal femur model was established based on CT data of a lower extremity from a voluntary healthy man. Garden type III femoral neck fracture was constructed and fixed with DMBCS, TBCS, and TTCS, respectively. Biomechanical effect which three type of CS models have on femoral neck fracture was evaluated and compared using von Mises stress distribution and displacement. RESULTS: In the normal model, the maximum stress value of cortical bone and cancellous bone was 76.18 and 6.82 MPa, and the maximum displacement was 5.52 mm. Under 3 different fracture healing status, the stress peak value of the cortical bone and cancellous bone in the DMBCS fixation model was lower than that in the TTCS and TBCS fixation, while the maximum displacement of DMBCS fixation model was slightly higher than that of TTCS and TBCS fixation models. As the fracture heals, stress peak value of the screws and cortical bone of intact models are decreasing, while stress peak value of cancellous bone is increasing initially and then decreasing. CONCLUSIONS: The DMBCS exhibits the superior biomechanical performance than TTCS and TBCS, whose fixation model is closest to the normal model in stress distribution. DMBCS is expected to reduce the rates of post-operative complications with traditional internal fixation and provide practical guidance for the structural design of CS for clinical applications.

Titanium Alloy Gamma Nail versus Biodegradable Magnesium Alloy Bionic Gamma Nail for Treating Intertrochanteric Fractures: A Finite Element Analysis.

OBJECTIVE: To using finite element analysis to investigate the effects of the traditional titanium alloy Gamma nail and a biodegradable magnesium alloy bionic Gamma nail for treating intertrochanteric fractures. METHODS: Computed tomography images of an adult male volunteer of appropriate age and in good physical condition were used to establish a three-dimensional model of the proximal femur. Then, a model of a type 31A1 intertrochanteric fracture of the proximal femur was established, and the traditional titanium alloy Gamma nails and biodegradable magnesium alloy bionic Gamma nails were used for fixation, respectively. The von Mises stress, the maximum principal stress, and the minimum principal stress were calculated to evaluate the effect of bone ingrowth on stress distribution of the proximal femur after fixation. RESULTS: In the intact model, the maximum stress was 5.8 MPa, the minimum stress was -11.7 MPa, and the von Mises stress was 11.4 MPa. The maximum principal stress distribution of the cancellous bone in the intact model appears in a position consistent with the growth direction of the principal and secondary tensile zones. After traditional Gamma nail healing, the maximum stress was 32 MPa, the minimum stress was -23.5 MPa, and the von Mises stress was 31.3 MPa. The stress concentration was quite obvious compared with the intact model. It was assumed that the nail would biodegrade completely within 12 months postoperatively. The maximum stress was 18.7 MPa, the minimum stress was -12.6 MPa, and the von Mises stress was 14.0 MPa. For the minimum principal stress, the region of minimum stress value less than -10 MPa was significantly improved compared with the traditional titanium alloy Gamma nail models. Meanwhile, the stress distribution of the bionic Gamma nail model in the proximal femur was closer to that of the intact bone, which significantly reduced the stress concentration of the implant. CONCLUSION: The biodegradable magnesium alloy bionic Gamma nail implant can improve the stress distribution of fractured bone close to that of intact bone while reducing the risk of postoperative complications associated with traditional internal fixation techniques, and it has promising clinical value in the future.

Smart MSN-Drug-Delivery System for Tumor Cell Targeting and Tumor Microenvironment Release.

Tumor-targeted delivery and controlled release of antitumor drugs are promising strategies for increasing chemotherapeutic efficacy and reducing adverse effects. Although mesoporous silica nanoparticles (MSNs) have been known as a potential delivery system for doxorubicin (DOX), they have restricted applications due to their uncontrolled leakage and burst release from their large open pores. Herein, we engineered a smart drug-delivery system (smart MSN-drug) based on MSN-drug loading, cell membrane mimetic coating, on-demand pore blocking/opening, and tumor cell targeting strategies. The pore size of DOX-loaded MSNs was narrowed by polydopamine coating, and the pores/channels were blocked with tumor-targeting ligands anchored by tumor environment-rupturable -SS- chains. Furthermore, a cell membrane mimetic surface was constructed to enhance biocompatibility of the smart MSN-drug. Confocal microscopy results demonstrate highly selective uptake (12-fold in comparison with L929 cell) of the smart MSN-drug by HeLa cells and delivery into the HeLa cellular nuclei. Further in vitro IC50 studies showed that the toxicity of the smart MSN-drug to HeLa cells was 4000-fold higher than to the normal fibroblast cells. These exciting results demonstrate the utility of the smart MSN-drug capable of selectively killing tumor cells and saving the normal cells.

Dual Versus Never Use of E-Cigarettes Among American Indians Who Smoke.

INTRODUCTION: Many American Indian communities have a high prevalence of smoking and e-cigarette use, but factors associated with their dual use are rarely studied. METHODS: In 2016, a total of 375 American Indian adults who smoke completed paper surveys regarding cigarette and e-cigarette use and provided saliva for cotinine levels. In 2018, cross-sectional analyses were performed, comparing dual users (12%), defined as using e-cigarettes on some or every day for the past 30 days, with never users of e-cigarettes (37%). RESULTS: Compared with never users, dual users were younger, more often reported history of depression (56% and 29%, respectively; p<0.01) and family history of smoking-related disease (77% and 59%, respectively; p<0.05), had lower harm perceptions of e-cigarettes (27% and 47%, respectively; p<0.01) or vapor (14% and 35%, respectively; p<0.01), and more often perceived e-cigarettes as cessation aids (75% and 16%, respectively; p<0.01) and as less harmful than cigarettes (70% and 17%, respectively; p<0.01). Dual users were less often uncertain/unknowing about e-cigarette benefits or harms (p<0.01) and more often reported likelihood to quit smoking (49% and 24%, respectively; p<0.01) and prior attempt to quit smoking, ever (89% and 67%, respectively; p<0.01) or in the past year (55% and 32%, respectively; p=0.01). Cigarette consumption and cotinine levels did not differ between groups. Dual users more often tried other nicotine products (p<0.02) and more often lived with a vaping partner/spouse (45% and 6%, respectively; p<0.01). CONCLUSIONS: Dual users perceived e-cigarettes as less harmful than cigarettes and more as cessation aids than cigarette-only users did, but cigarette consumption did not differ between groups. Whether e-cigarettes will reduce smoking-related disparities among American Indian people remains undetermined.

Dose Prediction Model for Duodenum Sparing With a Biodegradable Hydrogel Spacer for Pancreatic Cancer Radiation Therapy.

PURPOSE: We previously have shown the feasibility of duodenum sparing using a biodegradable hydrogel spacer in pancreatic cancer radiation therapy. In this study, we propose an overlap volume histogram (OVH) prediction model to select patients who might benefit from hydrogel placement and to predict the hydrogel spacing required to achieve clinical constraints. METHODS AND MATERIALS: OVH metrics for the duodenum were collected from the stereotactic body radiation therapy plans of 232 patients with unresectable pancreatic cancer (33 Gy in 5 fractions). OVH metrics L9cc and L3cc were defined as the tumor volume expansion distance at which 9 cm3 and 3 cm3 volumes of the duodenum overlap with tumor. D9cc and D3cc of the duodenum were defined as the dose-volume histogram dose to 9 cm3 and 3 cm3, respectively, of the duodenum. Prediction models were established by linear regression between Lx and Dx, where x = 3 cm3 and 9 cm3. OVH thresholds were obtained for predicting the target spacer thickness. The accuracy of the prediction model was then evaluated using treatment plans on pre-and post-hydrogel injection computed tomography scans from 2 cadaver specimens and 6 patients with previously treated locally advanced pancreatic cancer with simulated spacer. RESULTS: Linear regression analysis showed a significant correlation between Lx and Dx (r2 = 0.51 and 0.51 for L3cc-D3cc and L9cc-D9cc, respectively; both P < .01). The OVH thresholds were Lˆ3cc = 7 mm and Lˆ9cc = 13 mm. The observed planning doses D3cc and D9cc of duodenum from pre-and post-hydrogel injection computed tomography scans of cadaver specimens and clinical patients with simulated spacer using predicted target spacer thickness were within the OVH model prediction range. CONCLUSION: Our model may predict which patients require placement of a hydrogel spacer before stereotactic body radiation therapy to meet predefined dose constraints. Furthermore, by predicting the required target hydrogel thickness, the spacer injection can be better guided to improve efficacy.

E-cigarettes and Tobacco Exposure Biomarkers among American Indian Smokers.

Objective We assessed associations between electronic cigarette (e-cigarette) use and smoking-related measures among American Indians (AIs) who smoke. MethodsWe collected baseline survey and smoking biomarker data in a cohort of 375 adult AI smokers at a Cherokee Nation healthcare facility in Oklahoma. We used multivariate logistic and linear regression analyses to determine associations between e-cigarette use and smoking-related characteristics, including biomarkers. ResultsCurrent e-cigarette users were more likely than never users to report a quit attempt in the past 12 months (current vs never adjusted odds ratio (AOR) = 2.24 [95% CI 1.20-4.16]). Current and past e-cigarette users were more likely than never users to report a likelihood to quit smoking (current vs never AOR = 2.97 [95% CI 1.34-6.56]; past vs never AOR = 1.77 [95% CI 1.08-2.91]). E-cigarette use was not significantly associated with confidence to quit smoking, cigarette packs smoked per day, or cotinine levels. ConclusionsE-cigarette use was associated with previous and future quit attempts, but not with reductions in cigarette smoking or confidence in quitting. This suggests that many dual users might benefit from the addition of evidence-based smoking cessation treatments.

Quantitative fabrication, performance optimization and comparison of PEG and zwitterionic polymer antifouling coatings.

A versatile fabrication and performance optimization strategy of PEG and zwitterionic polymer coatings is developed on the sensor chip of surface plasma resonance (SPR) instrument. A random copolymer bearing phosphorylcholine zwitterion and active ester side chains (PMEN) and carboxylic PEG coatings with comparable thicknesses were deposited on SPR sensor chips via amidation coupling on the precoated polydopamine (PDA) intermediate layer. The PMEN coating showed much stronger resistance to bovine serum albumin (BSA) adsorption than PEG coating at very thin thickness (∼1nm). However, the BSA resistant efficacy of PEG coating could exceed that of PMEN due to stronger steric repelling effect when the thickness increased to 1.5∼3.3nm. Interestingly, both the PEG and PMEN thick coatings (≈3.6nm) showed ultralow fouling by BSA and bovine plasma fibrinogen (Fg). Moreover, changes in the PEG end group from -OH to -COOH, protein adsorption amount could increase by 10-fold. Importantly, the optimized PMEN and PEG-OH coatings were easily duplicated on other substrates due to universal adhesion of the PDA layer, showed excellent resistance to platelet, bacteria and proteins, and no significant difference in the antifouling performances was observed. These detailed results can explain the reported discrepancy in performances between PEG and zwitterionic polymer coatings by thickness. This facile and substrate-independent coating strategy may benefit the design and manufacture of advanced antifouling biomedical devices and long circulating nanocarriers. STATEMENT OF SIGNIFICANCE: Prevention of biofouling is one of the biggest challenges for all biomedical applications. However, it is very difficult to fabricate a highly hydrophilic antifouling coating on inert materials or large devices. In this study, PEG and zwitterion polymers, the most widely investigated polymers with best antifouling performance, are conveniently immobilized on different kinds of substrates from their aqueous solutions by precoating a polydopamine intermediate layer as the universal adhesive and readily re-modifiable surface. Importantly, the coating fabrication and antifouling performance can be monitored and optimized quantitatively by a surface plasma resonance (SPR) system. More significantly, the SPR on-line optimized coatings were successfully duplicated off-line on other substrates, and supported by their excellent antifouling properties.

A Novel Absorbable Radiopaque Hydrogel Spacer to Separate the Head of the Pancreas and Duodenum in Radiation Therapy for Pancreatic Cancer.

PURPOSE: We assessed the feasibility and theoretical dosimetric advantages of an injectable hydrogel to increase the space between the head of the pancreas (HOP) and duodenum in a human cadaveric model. METHODS AND MATERIALS: Using 3 human cadaveric specimens, an absorbable radiopaque hydrogel was injected between the HOP and duodenum by way of open laparotomy in 1 case and endoscopic ultrasound (EUS) guidance in 2 cases. The cadavers were subsequently imaged using computed tomography and dissected for histologic confirmation of hydrogel placement. The duodenal dose reduction and planning target volume (PTV) coverage were characterized using pre- and postspacer injection stereotactic body radiation therapy (SBRT) plans for the 2 cadavers with EUS-guided placement, the delivery method that appeared the most clinically desirable. Modeling studies were performed using 60 SBRT plans consisting of 10 previously treated patients with unresectable pancreatic cancer, each with 6 different HOP-duodenum separation distances. The duodenal volume receiving 15 Gy (V15), 20 Gy (V20), and 33 Gy (V33) was assessed for each iteration. RESULTS: In the 3 cadaveric studies, an average of 0.9 cm, 1.1 cm, and 0.9 cm HOP-duodenum separation was achieved. In the 2 EUS cases, the V20 decreased from 3.86 cm3 to 0.36 cm3 and 3.75 cm3 to 1.08 cm3 (treatment constraint <3 cm3), and the V15 decreased from 7.07 cm3 to 2.02 cm3 and 9.12 cm3 to 3.91 cm3 (treatment constraint <9 cm3). The PTV coverage improved or was comparable between the pre- and postinjection studies. Modeling studies demonstrated that a separation of 8 mm was sufficient to consistently reduce the V15, V20, and V33 to acceptable clinical constraints. CONCLUSIONS: Currently, dose escalation has been limited owing to radiosensitive structures adjacent to the pancreas. We demonstrated the feasibility of hydrogel separation of the HOP and duodenum. Future studies will evaluate the safety and efficacy of this technique with the potential for more effective dose escalation using SBRT or intensity-modulated radiation therapy to improve the outcomes in patients with unresectable pancreatic cancer.

Bacteria inactivation at a sub-stoichiometric titanium dioxide reactive electrochemical membrane.

This study investigated the use of a sub-stoichiometric TiO2 reactive electrochemical membrane (REM) for the inactivation of a model Escherichia coli (E. coli) pathogen in chloride-free solutions. The filtration system was operated in dead-end, outside-in filtration model, using the REM as anode and a stainless steel mesh as cathode. A 1-log removal of E. coli was achieved when the electrochemical cell was operated at the open circuit potential, due to a simple bacteria-sieving mechanism. At applied cell potentials of 1.3 and 3.5V neither live nor dead E. coli cells were detected in the permeate stream (detection limit of 1.0 cell mL(-1)), which was attributed to enhanced electrostatic bacteria adsorption at the REM anode. Bacteria inactivation in the retentate solution increased as a function of the applied cell potential, which was attributed to transport of E. coli to the REM and stainless steel cathode surfaces, and direct contact with the local acidic and alkaline environment produced by water oxidation at the anode and cathode, respectively. Clear evidence for an E. coli inactivation mechanism mediated by either direct or indirect oxidation was not found. The low energy requirement of the process (2.0-88Whm(-3)) makes the REM an attractive method for potable water disinfection.

Total syntheses of (Sp)-(+)- and (Rp)-(-)-spiniferin-1, a pair of unusual natural products with planar chirality.

(S(p))-(+)-Spiniferin-1 and (R(p))-(-)-spiniferin-1, a pair of unusual marine natural products with planar chirality, were firstly synthesized via a polyfluoroalkanosulfonyl fluoride induced homoallylic carbocation rearrangement reaction. The chiral resolution and palladium-catalyzed ß-H elimination of allylic alcohol derivatives were considered as the key steps of these divergent syntheses.

[Timing of treatment with bite-jumping appliance in orthodontics].

Bite-jumping appliance is a rational appliance for patients with severe overjet and retrusive mandible. In the pubertal growth spurt of patient, the appliance has good effect on skeletal or dental Angle class II malocclusions. After functional treatment, the probability of orthodontic treatment and orthopedic surgery in adult can be reduced. However, the most suitable time to use the bite-jumping appliance has been discussed continuously in various studies. According to many studies related, this paper summarized the treatment time of the fixed and the removable bite-jumping appliances, and compared the advantages and disadvantages between them.

[A clinical study of twin-wires on anchorage reinforcement].

OBJECTIVE: This clinical trial was designed to impose a simultaneous placement of large-size stainless steel round wire and small-size NiTi, and to assess its effect on anchorage reinforcement. METHODS: Twin-arch wires were in place for relief of severe crowding. Distalization of canines were well conducted with support of rigid wire, together with a simultaneous repositioning of upper lateral incisors facilitated by resilient wire. The linear distance between APo and the first molar, together with other parameters, was measured for the evaluation of anchorage consolidation. RESULTS: Anchorage molars and anteriors, as well as the integrity of dental arches remained unchanged upon fulfillment of crowding relief, which was justified by statistical analysis. CONCLUSION: Application of Twin-wires leads to a concurrence of efficient crowding relief and sufficient anchorage consolidation.