Intradermal Delivery of a Near-Infrared Photosensitizer Using Dissolving Microneedle Arrays

Nodular basal cell carcinoma is a deep skin lesion and one of the most common cancers. Conventional photodynamic therapy is limited to treatment of superficial skin lesions. The parenteral administration of near-IR preformed photosensitizers suffers from poor selectivity and may result in prolonged skin photosensitivity. Microneedles (MNs) can provide localized drug delivery to skin lesions. Intradermal delivery of the preformed near-IR photosensitizer; 5,10,15,20-tetrakis(2,6-difluoro-3-N-methylsulfamoylphenyl bacteriochlorin (Redaporfin?) using dissolving MN was successful in vitro and in vivo. MN demonstrated complete dissolution 30 min after skin application and showed sufficient mechanical strength to penetrate the skin to a depth of 450 μm. In vitro deposition studies illustrated that the drug was delivered and detected down to 5 mm in skin. In vivo biodistribution studies in athymic nude mice Crl:NU(NCr)-Foxn1^nu showed both fast initial release and localized drug delivery. The MN-treated mice showed a progressive decrease in the fluorescence intensity at the application site over the 7-day experiment period, with the highest and lowest fluorescence intensities measured being 9.2 × 10¹⁰ ± 2.5 × 10¹⁰ and 3.8 × 10⁹ ± 1.6 × 10⁹ p/s, respectively. By day 7, there was some migration of fluorescence away from the site of initial MN application. However, the majority of the body surfaces showed fluorescence levels that were comparable to those seen in the negative control group. This work suggests utility for polymeric MN arrays in minimally invasive intradermal delivery to enhance photodynamic therapy of deep skin lesions.     

N-acetyl cysteine in prevention of amphotericin- induced electrolytes imbalances: a randomized,double-blinded,placebo-controlled,clinical trial

Purpose

The aim of this study was to evaluate the effectiveness of oral n-acetyl cysteine, as a potential nephroprotective agent, in preventing and/or attenuating amphotericin B-induced electrolytes imbalances.

Methods

During a one year period, patients were to receive conventional amphotericin b for any indication for at least one week and were randomly allocated to receive either placebo or 600 mg oral n-acetyl cysteine twice daily during the treatment course of amphotericin b. Demographic and clinical data of the study population were gathered. Different aspects of amphotericin b nephrotoxicity including decrease of glomerular filtration rate, hypokalemia, hypomagnesemia, renal magnesium and potassium wasting were assessed. Each patient was monitored for any adverse reaction to n-acetyl cysteine. Sixteen and 14 patients in the n-acetyl cysteine and placebo groups completed the study, 3incidences of hypokalemia (75 % versus 70 %; P?=?0.724) and hypomagnesemia (30 % versus 20 %; P?=?0.468) did not differ significantly between placebo and NAC groups, respectively. Although the rate of AmB nephrotoxicity was higher in the placebo than in the NAC group (60 % versus 40 %), this difference was not statistically significant (P?=?0.209) even after adjusting for probable associated factors of amphotericin b nephrotoxicity (P?=?0.206). The incidence as well as time of onset of electrolyte abnormalities also did not differ significantly between placebo and n-acetyl cysteine groups. About 44 % of n-acetyl cysteine recipients experienced new onset nausea and a mild unpleasant taste during the study.

Conclusion

Oral n-acetyl cysteine during the amphotericin B treatment course was not significantly effective in preventing or mitigating different features of its nephrotoxicity including decrease of glomerular filtration rate, hypokalemia, hypomagnesemia, and renal potassium as well as magnesium wasting.     

Father involvement with three-to-four-year olds at home: giving fathers a chance

This study examined fathers' perceptions regarding their home-based activities (HBA) and the influence of fathers' demographic characteristics on their perceptions and practices at home. A total of 396 fathers completed a survey questionnaire describing their demographic information, perceptions and their practices regarding their involvement in HBA. Results indicated that fathers have moderate level of practice concerning their HBA, yet they have low perception of their actual practice at HBA. In addition, there was a statistical significance in HBA due to fathers' age, educational level and specialisation which had an influence on their perceptions as well. Recommendations and implications of future research were discussed.     

Photocatalysis of nanocomposite titania–natural silica as antibacterial against Staphylococcus aureus and Pseudomonas aeruginosa

The entries of pathogenic bacteria into the human body remain a severe problem to health that can be prevented using antibacterial agents. Meanwhile, the photocatalytic technique using semiconductor nanocomposite TiO₂–SiO₂ has great potential as an antibacterial method. In order to utilize natural resources, SiO₂ supporting materials are obtained from the extraction of beach sand due to the high silica content. Therefore, this study aims to synthesize a nanocomposite of TiO₂ with SiO₂ extracted from beach sand as an antibacterial agent against Staphylococcus aureus and Pseudomonas aeruginosa. The antibacterial activity test used the dilution and optical density method. Based on XRD analysis, the crystals of TiO₂ in the synthesized composites showed a more dominant anatase structure. Furthermore, Ti–O–Si bonds were identified from the IR spectrum, which showed the interaction between TiO₂ and SiO₂. In addition, SEM-EDX results showed agglomerated spherical particles with a TiO₂–SiO₂ nanocomposite particle size of 40–107 nm. The best antibacterial activity was demonstrated by the 1 : 0.5 TiO₂–SiO₂ nanocomposite, with inactivation percentages of S. aureus and P. aeruginosa of 98.69% and 97.44%, respectively.

TiO₂ material is composited with silica obtained from natural sand with indirect sonochemistry method. The addition of SiO₂ increase the photocatalyst activity of TiO₂ as an antibacterial against S. aureus and P. aeruginosa.     

Efficacy of late concurrent hypofractionated radiotherapy in advanced melanoma patients failing anti-PD-1 monotherapy

Advanced melanoma patients who failed anti-PD-1 therapy have limited options. We analyzed a cohort of 133 advanced melanoma patients receiving anti-PD-1 monotherapy in a referral center between April 2015 and December 2017, and included the 26 patients with confirmed progressive (PD) or stable disease who received additional radiotherapy with an unmodified anti-PD-1 mAb regimen. Tumor evaluations were done on radiated and nonradiated (RECIST 1.1) lesions, with abscopal effect defined as a partial (PR) or complete response (CR) outside radiated fields. Primary endpoint was the CR + PR rate in radiated + nonradiated lesions. Secondary endpoints were progression-free survival (PFS), melanoma-specific survival (MSS) and safety. First late radiotherapy, consisting of hypofractionated radiotherapy (3–5 sessions, 20–26 Gy), standard palliative radiotherapy or brain radiosurgery was begun after a median of 6.3 months of anti-PD-1 in 23, 2 and 1 patient(s), respectively. Best response was 8 (31%) CR, 2 (8%) profound PR allowing surgical resection of remaining metastases and 16 (62%) PD. Abscopal effect was seen in 35% of patients. Median PFS and MSS since anti-PD-1 initiation was 15.2 [95% CI: 8.0 not achieved (na)] and 35.3 [95% CI: 18.5 na] months, respectively. PFS curves seemed to achieve a plateau. We discontinued anti-PD-1 therapy in 9/10 of patients with no residual evaluable disease and observed one relapse after a median of 10 months off anti-PD1-therapy. No unusual adverse event was recorded. Limitations of the study include its retrospective nature and limited size. Hypofractionated radiotherapy may enhance anti-PD1 monotherapy efficacy in patients who previously failed anti-PD-1 therapy. Controlled studies are needed.     

Corrosion and Microstructural Investigation on Additively Manufactured 316L Stainless Steel: Experimental and Statistical Approach

The use of metal additive manufacturing (AM) has strongly increased in the industry during the last years. More specifically, selective laser melting (SLM) is one of the most used techniques due to its numerous advantages compared to conventional processing methods. The purpose of this study is to investigate the effects of process parameters on the microstructural and corrosion properties of the additively manufactured AISI 316L stainless steel. Porosity, surface roughness, hardness, and grain size were studied for specimens produced with energy densities ranging from 51.17 to 173.91 J/mm³ that resulted from different combinations of processing parameters. Using experimental results and applying the Taguchi model, 99.38 J/mm³ was determined as the optimal energy density needed to produce samples with almost no porosity. The following analysis of variance ANOVA confirmed the scanning speed as the most influential factor in reducing the porosity percentage, which had a 74.9% contribution, followed by the position along the building direction with 22.8%, and finally, the laser energy with 2.3%. The influence on corrosion resistance was obtained by performing cyclic potentiodynamic polarization tests (CPP) in a 3.5 wt % NaCl solution at room temperature for different energy densities and positions (Z axis). The corrosion properties of the AM samples were studied and compared to those obtained from the traditionally manufactured samples. The corrosion resistance of the samples worsened with the increase in the percentage of porosity. The process parameters have consequently been optimized and the database has been extended to improve the quality of the AM-produced parts in which microstructural heterogeneities were observed along the building direction.