Arterolane-piperaquine-mefloquine versus arterolane-piperaquine and artemether-lumefantrine in the treatment of uncomplicated Plasmodium falciparum malaria in Kenyan children: a single-centre, open-label, randomised, non-inferiority trial.

BACKGROUND: Triple antimalarial combination therapies combine potent and rapidly cleared artemisinins or related synthetic ozonides, such as arterolane, with two, more slowly eliminated partner drugs to reduce the risk of resistance. We aimed to assess the safety, tolerability, and efficacy of arterolane-piperaquine-mefloquine versus arterolane-piperaquine and artemether-lumefantrine for the treatment of uncomplicated falciparum malaria in Kenyan children. METHODS: In this single-centre, open-label, randomised, non-inferiority trial done in Kilifi County Hospital, Kilifi, coastal Kenya, children with uncomplicated Plasmodium falciparum malaria were recruited. Eligible patients were aged 2-12 years and had an asexual parasitaemia of 5000-250 000 parasites per µL. The exclusion criteria included the presence of an acute illness other than malaria, the inability to tolerate oral medications, treatment with an artemisinin derivative in the previous 7 days, a known hypersensitivity or contraindication to any of the study drugs, and a QT interval corrected for heart rate (QTc interval) longer than 450 ms. Patients were randomly assigned (1:1:1), by use of blocks of six, nine, and 12, and opaque, sealed, and sequentially numbered envelopes, to receive either arterolane-piperaquine, arterolane-piperaquine-mefloquine, or artemether-lumefantrine. Laboratory staff, but not the patients, the patients' parents or caregivers, clinical or medical officers, nurses, or trial statistician, were masked to the intervention groups. For 3 days, oral artemether-lumefantrine was administered twice daily (target dose 5-24 mg/kg of bodyweight of artemether and 29-144 mg/kg of bodyweight of lumefantrine), and oral arterolane-piperaquine (arterolane dose 4 mg/kg of bodyweight; piperaquine dose 20 mg/kg of bodyweight) and oral arterolane-piperaquine-mefloquine (mefloquine dose 8 mg/kg of bodyweight) were administered once daily. All patients received 0·25 mg/kg of bodyweight of oral primaquine at hour 24. All patients were admitted to Kilifi County Hospital for at least 3 consecutive days and followed up at day 7 and, thereafter, weekly for up to 42 days. The primary endpoint was 42-day PCR-corrected efficacy, defined as the absence of treatment failure in the first 42 days post-treatment, of arterolane-piperaquine-mefloquine versus artemether-lumefantrine, and, along with safety, was analysed in the intention-to-treat population, which comprised all patients who received at least one dose of a study drug. The 42-day PCR-corrected efficacy of arterolane-piperaquine-mefloquine versus arterolane-piperaquine was an important secondary endpoint and was also analysed in the intention-to-treat population. The non-inferiority margin for the risk difference between treatments was -7%. The study is registered in ClinicalTrials.gov, NCT03452475, and is completed. FINDINGS: Between March 7, 2018, and May 2, 2019, 533 children with P falciparum were screened, of whom 217 were randomly assigned to receive either arterolane-piperaquine (n=73), arterolane-piperaquine-mefloquine (n=72), or artemether-lumefantrine (n=72) and comprised the intention-to-treat population. The 42-day PCR-corrected efficacy after treatment with arterolane-piperaquine-mefloquine (100%, 95% CI 95-100; 72/72) was non-inferior to that after treatment with artemether-lumefantrine (96%, 95% CI 88-99; 69/72; risk difference 4%, 95% CI 0-9; p=0·25). The 42-day PCR-corrected efficacy of arterolane-piperaquine-mefloquine was non-inferior to that of arterolane-piperaquine (100%, 95% CI 95-100; 73/73; risk difference 0%). Vomiting rates in the first hour post-drug administration were significantly higher in patients treated with arterolane-piperaquine (5%, 95% CI 2-9; ten of 203 drug administrations; p=0·0013) or arterolane-piperaquine-mefloquine (5%, 3-9; 11 of 209 drug administrations; p=0·0006) than in patients treated with artemether-lumefantrine (1%, 0-2; three of 415 drug administrations). Upper respiratory tract complaints (n=26 for artemether-lumefantrine; n=19 for arterolane-piperaquine-mefloquine; n=23 for arterolane-piperaquine), headache (n=13; n=4; n=5), and abdominal pain (n=7; n=5; n=5) were the most frequently reported adverse events. There were no deaths. INTERPRETATION: This study shows that arterolane-piperaquine-mefloquine is an efficacious and safe treatment for uncomplicated falciparum malaria in children and could potentially be used to prevent or delay the emergence of antimalarial resistance. FUNDING: UK Department for International Development, The Wellcome Trust, The Bill & Melinda Gates Foundation, Sun Pharmaceutical Industries.

A randomized, double-blind, phase 2b study to investigate the efficacy, safety, tolerability and pharmacokinetics of a single-dose regimen of ferroquine with artefenomel in adults and children with uncomplicated Plasmodium falciparum malaria.

BACKGROUND: For uncomplicated Plasmodium falciparum malaria, highly efficacious single-dose treatments are expected to increase compliance and improve treatment outcomes, and thereby may slow the development of resistance. The efficacy and safety of a single-dose combination of artefenomel (800 mg) plus ferroquine (400/600/900/1200 mg doses) for the treatment of uncomplicated P. falciparum malaria were evaluated in Africa (focusing on children ≤ 5 years) and Asia. METHODS: The study was a randomized, double-blind, single-dose, multi-arm clinical trial in patients aged > 6 months to < 70 years, from six African countries and Vietnam. Patients were followed up for 63 days to assess treatment efficacy, safety and pharmacokinetics. The primary efficacy endpoint was the polymerase chain reaction (PCR)-adjusted adequate clinical and parasitological response (ACPR) at Day 28 in the Per-Protocol [PP] Set comprising only African patients ≤ 5 years. The exposure-response relationship for PCR-adjusted ACPR at Day 28 and prevalence of kelch-13 mutations were explored. RESULTS: A total of 373 patients were treated: 289 African patients ≤ 5 years (77.5%), 64 African patients > 5 years and 20 Asian patients. None of the treatment arms met the target efficacy criterion for PCR-adjusted ACPR at Day 28 (lower limit of 95% confidence interval [CI] > 90%). PCR-adjusted ACPR at Day 28 [95% CI] in the PP Set ranged from 78.4% [64.7; 88.7%] to 91.7% [81.6; 97.2%] for the 400 mg to 1200 mg ferroquine dose. Efficacy rates were low in Vietnamese patients, ranging from 20 to 40%. A clear relationship was found between drug exposure (artefenomel and ferroquine concentrations at Day 7) and efficacy (primary endpoint), with higher concentrations of both drugs resulting in higher efficacy. Six distinct kelch-13 mutations were detected in parasite isolates from 10/272 African patients (with 2 mutations known to be associated with artemisinin resistance) and 18/20 Asian patients (all C580Y mutation). Vomiting within 6 h of initial artefenomel administration was common (24.6%) and associated with lower drug exposures. CONCLUSION: The efficacy of artefenomel/ferroquine combination was suboptimal in African children aged ≤ 5 years, the population of interest, and vomiting most likely had a negative impact on efficacy. Trial registration ClinicalTrials.gov, NCT02497612. Registered 14 Jul 2015, https://clinicaltrials.gov/ct2/show/NCT02497612?term=NCT02497612&draw=2&rank=1.

The Formation, Persistence, and Resistance to Disinfectant of the Erysipelothrix piscisicarius Biofilm.

Erysipelothrix piscisicarius is an emergent pathogen in fish aquaculture, particularly in the ornamental fish trade. Very little is known on the biology of this pathogen; however, the recurrence of infection and disease outbreaks after removing the fish from a system and disinfecting the tank suggest its environmental persistence. Moreover, biofilm lifestyle in E. piscisicarius has been suspected but not previously shown. The purpose of this study was to investigate the formation of biofilms on an abiotic surface in Erysipelothrix spp. We used hydroxyapatite-coated plastic pegs to demonstrate the attachment, growth, and persistence of E. piscisicarius on abiotic surfaces in both fresh and marine environments and to investigate the susceptibility of this pathogen to different disinfectants that are used in the aquaculture industry. E. piscisicarius formed biofilms that persisted significantly longer than planktonic cells did in both freshwater and saltwater over a period of 120 h (P = 0.004). The biofilms were also more resistant to disinfectants than the planktonic cells were. Hydrogen peroxide was the most effective disinfectant against E. piscisicarius, and it eradicated the biofilms and planktonic cells at the recommended concentrations. In contrast, Virkon and bleach were able to eradicate only the planktonic cells. This information should be taken into consideration when developing biosecurity protocols in aquaculture systems, aquariums, and private collections.

Effect of oxygen-producing suture material on hypoxic colonic anastomoses in an experimental model.

Background: Anastomotic leak remains a significant cause of morbidity and mortality after colorectal surgery. Among multiple risk factors considered, hypoxia-ischaemia is considered to be a primary cause of intestinal anastomotic leakage. The aim of this experimental study was to assess safety, usability for surgical tasks, and efficacy of a newly developed oxygen-producing suture material in the healing of colonic anastomoses under critical conditions. Methods: An oxygen-producing suture material was produced that is capable of releasing oxygen directly into the surrounding tissue. Off-the-shelf sutures loaded with calcium peroxide nano-crystals and covered with poly(d,l-lactide-co-glycolide) were assessed in vitro and in a rat model of hypoxic colonic anastomosis. Results: In vitro assessment showed that these sutures can increase oxygen levels in a hypoxic environment. Potential oxygen byproducts did not seem to have a negative impact on the viability of intestinal cells. The use of oxygen-producing sutures in vivo resulted in increased tissue oxygen saturation, measured by visible light spectroscopy, and increased mechanical stability of the anastomosis. Conclusion: Oxygen-producing suture material increased tissue oxygen saturation and mechanical stability of colonic anastomosis in a rat model.

Antecedentes: Las fugas anastomóticas siguen siendo una causa importante de morbilidad y mortalidad después de la cirugía colorrectal. Entre los múltiples factores de riesgo, se considera que la hipoxia/isquemia es una de las causas principales de la fuga anastomótica intestinal. El objetivo de este estudio experimental fue evaluar, en condiciones críticas, la seguridad, la facilidad de uso en los procedimientos quirúrgicos y la eficacia en la cicatrización de la anastomosis de colon de un material de sutura productor de oxígeno recientemente desarrollado. Métodos: Hemos producido un material de sutura productor de oxígeno que es capaz de liberar oxígeno directamente en el tejido circundante. Las suturas disponibles en el mercado cargadas con nanocristales de peróxido de calcio (calcium peroxide, CPO) y cubiertas con ácido poliláctico coglicólico (PLGA) se evaluaron in vitro y en un modelo de rata de anastomosis hipóxica de colon. Resultados: La evaluación in vitro mostró que estas suturas pueden aumentar los niveles de oxígeno en un ambiente hipóxico, y que los posibles subproductos de oxígeno no parecen tener un impacto negativo en la viabilidad de las células intestinales. El uso de suturas productoras de oxígeno in vivo causó una elevada saturación de oxígeno en el tejido medida por espectroscopia de luz visible, así como un aumento en la estabilidad mecánica de las anastomosis. Conclusión: El material de sutura productor de oxígeno aumenta la saturación de oxígeno en los tejidos y la estabilidad mecánica de la anastomosis de colon en un modelo de rata.

A Single-Dose Combination Study with the Experimental Antimalarials Artefenomel and DSM265 To Determine Safety and Antimalarial Activity against Blood-Stage Plasmodium falciparum in Healthy Volunteers.

Artefenomel and DSM265 are two new compounds that have been shown to be well tolerated and effective when administered as monotherapy malaria treatment. This study aimed to determine the safety, pharmacokinetics, and pharmacodynamics of artefenomel and DSM265 administered in combination to healthy subjects in a volunteer infection study using the Plasmodium falciparum-induced blood-stage malaria model. Thirteen subjects were inoculated with parasite-infected erythrocytes on day 0 and received a single oral dose of artefenomel and DSM265 on day 7. Cohort 1 (n = 8) received 200 mg artefenomel plus 100 mg DSM265, and cohort 2 (n = 5) received 200 mg artefenomel plus 50 mg DSM265. Blood samples were collected to measure parasitemia, gametocytemia, and artefenomel-DSM265 plasma concentrations. There were no treatment-related adverse events. The pharmacokinetic profiles of artefenomel and DSM265 were similar to those of the compounds when administered as monotherapy, suggesting no pharmacokinetic interactions. A reduction in parasitemia occurred in all subjects following treatment (log10 parasite reduction ratios over 48 h [PRR48] of 2.80 for cohort 1 and 2.71 for cohort 2; parasite clearance half-lives of 5.17 h for cohort 1 and 5.33 h for cohort 2). Recrudescence occurred in 5/8 subjects in cohort 1 between days 19 and 28 and in 5/5 subjects in cohort 2 between days 15 and 22. Low-level gametocytemia (1 to 330 female gametocytes/ml) was detected in all subjects from day 14. The results of this single-dosing combination study support the further clinical development of the use of artefenomel and DSM265 in combination as a treatment for falciparum malaria. (This study has been registered at ClinicalTrials.gov under identifier NCT02389348.).

Enhancement of cisplatin efficacy by lipid-CaO2 nanocarrier-mediated comprehensive modulation of the tumor microenvironment.

Hypoxia, acidosis and high level of glutathione (GSH) are characteristic abnormalities of the tumor microenvironment (TME), which promote tumor progression, metastasis, and resistance to therapies. Previous attempts to improve therapeutic efficacy were limited to modifying individual TME elements. In this study, we proposed a comprehensive TME modulation strategy that modifies multiple elements of the TME in order to enhance cisplatin anticancer efficacy. To do so, we prepared biocompatible lipid-coated CaO2/cisplatin nanoparticles (LipoCaO2/DDP) by the reverse microemulsion method. We imbued CaO2 with the following reverse-TME properties: O2 generation, increased pH value in tumor cells, and oxidation of intracellular glutathione. In vitro experiments showed that LipoCaO2/DDP could deplete GSH for preventing the binding of GSH to cisplatin. Simultaneously, CaO2 could significantly downregulate multidrug resistance-associated protein 2 (MRP2) by O2-dependent hypoxia-inducible factor 1 (HIF-1) inactivation. Hence, the complete drug-efflux pathway was blocked, and the anticancer effect of cisplatin was enhanced both in vitro and in vivo. Herein, we not only demonstrated the GSH depletion capacity of CaO2 for the first time, but also provided a new comprehensive therapeutic strategy to overcome therapeutic resistance caused by multiple factors in the TME.

Understanding the skin sensitization capacity of ascaridole: a combined study of chemical reactivity and activation of the innate immune system (dendritic cells) in the epidermal environment.

To improve the prediction of the possible allergenicity of chemicals in contact with the skin, investigations of upstream events are required to better understand the molecular mechanisms involved in the initiation of allergic reactions. Ascaridole, one of the compounds responsible for skin sensitization to aged tea tree oil, degrades into intermediates that evolve via different mechanisms involving radical species. We aimed at broadening the knowledge about the contribution of radical intermediates derived from ascaridole to the skin sensitization process by assessing the reactivity profile towards amino acids, identifying whether free radicals are formed in a reconstructed human epidermis (RHE) model and their biological properties to activate the immune system, namely dendritic cells in their natural context of human HaCaT keratinocytes and RHE. Electron paramagnetic resonance combined to spin-trapping in EpiSkin™ RHE confirmed the formation of C-radicals in the epidermal tissue from 10 mM ascaridole concentration, while reactivity studies toward amino acids showed electrophilic intermediates issued from radical rearrangements of ascaridole as the main reactive species. Activation of THP-1 cells, as surrogate for dendritic cells, that were cocultured with HaCaT was significantly upregulated after treatment with low micromolar concentrations based on cell surface expression of the co-stimulatory molecule CD86 and the adhesion molecule CD54. Placing THP-1 cells underneath the RHE allowed us to monitor which of the concentrations that produce radical(s) and/or protein antigens in the epidermal skin environment promote the activation of dendritic cells. We detected no significant upregulation of CD86/CD54 after topical RHE application of concentrations up to 30 mM ascaridole (t = 24 h) but clear upregulation after 60 mM.

Impact of Ferroquine on the Solubilization of Artefenomel (OZ439) during in Vitro Lipolysis in Milk and Implications for Oral Combination Therapy for Malaria.

Milk is an attractive lipid-based formulation for the delivery of poorly water-soluble drugs to pediatric populations. We recently observed that solubilization of artefenomel (OZ439) during in vitro intestinal lipolysis was driven by digestion of triglycerides in full-cream bovine milk, reflecting the ability of milk to act as an enabling formulation in the clinic. However, when OZ439 was co-administered with a second antimalarial drug, ferroquine (FQ) the exposure of OZ439 was reduced. The current study therefore aimed to understand the impact of the presence of FQ on the solubilization of OZ439 in milk during in vitro intestinal digestion. Synchrotron small-angle X-ray scattering was used for in situ monitoring of drug solubilization (inferred via decreases in the intensity of drug diffraction peaks) and polymorphic transformations that occurred during the course of digestion. Quantification of the amount of each drug solubilized over time and analysis of their distributions across the separated phases of digested milk were determined using high-performance liquid chromatography. The results show that FQ reduced the solubilization of OZ439 during milk digestion, which may be due to competitive binding of FQ to the digested milk products. Interactions between the protonated FQ-H+ and ionized liberated free fatty acids resulted in the formation of amorphous salts, which removes the low-energy crystalline state as a barrier to dissolution of FQ, while inhibiting the solubilization of OZ439. We conclude that although milk could enhance the solubilization of poorly water-soluble OZ439 during in vitro digestion principally due to the formation of fatty acids, the solubilization efficiency was reduced by the presence of FQ by competition for the available fatty acids. Assessment of the solubilization of both drugs during digestion of fixed-dose combination lipid formulations (such as milk) is important and may rationalize changes in bioavailability when compared to that of the individual drugs in the same formulation.

Spray drying OZ439 nanoparticles to form stable, water-dispersible powders for oral malaria therapy.

BACKGROUND: OZ439 is a new chemical entity which is active against drug-resistant malaria and shows potential as a single-dose cure. However, development of an oral formulation with desired exposure has proved problematic, as OZ439 is poorly soluble (BCS Class II drug). In order to be feasible for low and middle income countries (LMICs), any process to create or formulate such a therapeutic must be inexpensive at scale, and the resulting formulation must survive without refrigeration even in hot, humid climates. We here demonstrate the scalability and stability of a nanoparticle (NP) formulation of OZ439. Previously, we applied a combination of hydrophobic ion pairing and Flash NanoPrecipitation (FNP) to formulate OZ439 NPs 150 nm in diameter using the inexpensive stabilizer hydroxypropyl methylcellulose acetate succinate (HPMCAS). Lyophilization was used to process the NPs into a dry form, and the powder's in vitro solubilization was over tenfold higher than unprocessed OZ439. METHODS: In this study, we optimize our previous formulation using a large-scale multi-inlet vortex mixer (MIVM). Spray drying is a more scalable and less expensive operation than lyophilization and is, therefore, optimized to produce dry powders. The spray dried powders are then subjected to a series of accelerated aging stability trials at high temperature and humidity conditions. RESULTS: The spray dried OZ439 powder's dissolution kinetics are superior to those of lyophilized NPs. The powder's OZ439 solubilization profile remains constant after 1 month in uncapped vials in an oven at 50 °C and 75% RH, and for 6 months in capped vials at 40 °C and 75% RH. In fasted-state intestinal fluid, spray dried NPs achieved 80-85% OZ439 dissolution, to a concentration of 430 µg/mL, within 3 h. In fed-state intestinal fluid, 95-100% OZ439 dissolution is achieved within 1 h, to a concentration of 535 µg/mL. X-ray powder diffraction and differential scanning calorimetry profiles similarly remain constant over these periods. CONCLUSIONS: The combined nanofabrication and drying process described herein, which utilizes two continuous unit operations that can be operated at scale, is an important step toward an industrially-relevant method of formulating the antimalarial OZ439 into a single-dose oral form with good stability against humidity and temperature.

The Evidence Behind Peroxide in Orthopedic Surgery.

Peroxide is a strong oxidizing agent and disinfectant frequently used in orthopedic surgery. The authors conducted a systematic literature review of peroxide in orthopedic surgery, evaluating use, complications, efficacy, and appropriate concentrations. One hundred seventy-five reports were identified, with 24 being eligible for analysis. Orthopedic surgeons used peroxide for irrigation and bacterial reduction in various procedures. Complications included cytotoxicity, allergic reactions, suture damage, and inflammation. Use of the standard concentration of 3% peroxide and standard time in situ are without evidence. Laboratory studies suggest that diluted concentrations retain the benefit of bacterial decolonization without increasing the risk for complications. [Orthopedics. 2018; 41(6):e756-e764.].

High-concentration carbamide peroxide can reduce the sensitivity caused by in-office tooth bleaching: a single-blinded randomized controlled trial.

Objectives A single-blinded, randomized, parallel clinical trial evaluated the use of 37% carbamide peroxide (CP) on bleaching effectiveness and tooth sensitivity reported by patients undergoing in-office tooth bleaching, in comparison with the results of using 35% hydrogen peroxide. Material and Methods Forty patients were allocated to receive two sessions of in-office tooth bleaching using either 35% hydrogen peroxide (HP) or 37% CP. Each patient's sensitivity level was evaluated during and up to 24 h after bleaching. The effectiveness of the bleaching procedures was evaluated with a spectrophotometer one week after each session and 30 days after the last session. The impact of tooth bleaching on the patients' perceptions regarding smile changes, in addition to the bleaching procedures and their results, were also recorded. Absolute and relative sensitivity risks were calculated. Data on sensitivity level were analyzed using the Mann-Whitney or T-test, and data from the color evaluation were subjected to 2-way repeated measures ANOVA. Results The use of CP reduced the risk and level of tooth sensitivity to values close to zero, whereas the difference between the bleaching agents disappeared after 24 h. An increased bleaching effect was observed for HP, mainly due to an improved reduction of redness and yellowness. Participants perceived improved tooth bleaching for HP and reduced sensitivity for CP, but no differences regarding the comfort of the techniques were noted. Conclusions In our study, 37% CP resulted in reduced tooth sensitivity but decreased the tooth bleaching effectiveness. However, both bleaching agents resulted in high levels of patient satisfaction.

Oxygen producing microscale spheres affect cell survival in conditions of oxygen-glucose deprivation in a cell specific manner: implications for cell transplantation.

This study outlines the synthesis of microscale oxygen producing spheres, which, when used in conjunction with catalase, can raise the dissolved oxygen content of cell culture media for 16-20 hours. In conditions of oxygen and glucose deprivation, designed to mimic the graft environment in vivo, the spheres rescue SH-SY5Y cells and meschymal stem cells, showing that oxygen producing biomaterials may hold potential to improve the survival of cells post-transplantation.

Encapsulation of OZ439 into Nanoparticles for Supersaturated Drug Release in Oral Malaria Therapy.

Malaria poses a major burden on human health and is becoming increasingly difficult to treat due to the development of antimalarial drug resistance. The resistance issue is further exacerbated by a lack of patient adherence to multi-day dosing regimens. This situation motivates the development of new antimalarial treatments that are less susceptible to the development of resistance. We have applied Flash NanoPrecipitation (FNP), a polymer-directed self-assembly process, to form stable, water-dispersible nanoparticles (NPs) of 50-400 nm in size containing OZ439, a poorly orally bioavailable but promising candidate for single-dose malaria treatment developed by Medicines for Malaria Venture (MMV). During the FNP process, a hydrophobic OZ439 oleate ion paired complex was formed and was encapsulated into NPs. Lyophilization conditions for the NP suspension were optimized to produce a dry powder. The in vitro release rates of OZ439 encapsulated in this powder were determined in biorelevant media and compared with the release rates of the unencapsulated drug. The OZ439 NPs exhibit a sustained release profile and several-fold higher release concentrations compared to that of the unencapsulated drug. In addition, XRD suggests the drug was stabilized into an amorphous form within the NPs, which may explain the improvement in dissolution kinetics. Formulating OZ439 into NPs in this way may be an important step toward developing a single-dose oral malaria therapeutic, and offers the possibility of reducing the amount of drug required per patient, lowering delivery costs, and improving dosing compliance.

Effectiveness and effect of non-vital bleaching on the quality of life of patients up to 6 months post-treatment: a randomized clinical trial.

OBJECTIVES: The aim of this study was to evaluate the esthetic perception of patients at 6 months after bleaching of non-vital teeth with 35% of hydrogen peroxide and 37% of carbamide peroxide using a walking bleach technique. We also assessed psychosocial impacts as well as the clinical effectiveness and stability of the color change. MATERIALS AND METHODS: The teeth bleaching treatment was randomly assigned to two groups according to the bleaching agent used: G1 HP = 35% of hydrogen peroxide (n = 25) and G2 CP = 37% of carbamide peroxide (n = 25). The non-vital bleaching was performed in four sessions using the walking bleach technique. The color was objectively (ΔE) and subjectively (ΔSGU) evaluated. The esthetic perception and psychosocial factors were evaluated before treatment as well as one and 6 months post-treatment using Oral Health Impact Profile (OHIP) esthetics and Psychosocial Impact of Dental Esthetics Questionnaire (PIDAQ). RESULTS: The color change (ΔE) at 6 months (G1 = 14.53 ± 5.07 and G2 = 14.09 ± 6.61) for both color groups remained stable until the 6-month post-treatment (p > 0.05). There was a decrease in the values of OHIP esthetics and PIDAQ after treatment compared to the baseline (p < 0.05), and this effect was maintained 6 months post-treatment. CONCLUSIONS: Both agents were highly effective and maintained the color stability at 6 months; this positively affected the esthetic perception and psychosocial impact of patients who also remained stable over time. CLINICAL RELEVANCE: Non-vital bleaching produces a positive and stable impact on the esthetic perception and psychosocial factors at medium-term follow-ups.

A controlled human malaria infection model enabling evaluation of transmission-blocking interventions.

BACKGROUND: Drugs and vaccines that can interrupt the transmission of Plasmodium falciparum will be important for malaria control and elimination. However, models for early clinical evaluation of candidate transmission-blocking interventions are currently unavailable. Here, we describe a new model for evaluating malaria transmission from humans to Anopheles mosquitoes using controlled human malaria infection (CHMI). METHODS: Seventeen healthy malaria-naive volunteers underwent CHMI by intravenous inoculation of P. falciparum-infected erythrocytes to initiate blood-stage infection. Seven to eight days after inoculation, participants received piperaquine (480 mg) to attenuate asexual parasite replication while allowing gametocytes to develop and mature. Primary end points were development of gametocytemia, the transmissibility of gametocytes from humans to mosquitoes, and the safety and tolerability of the CHMI transmission model. To investigate in vivo gametocytocidal drug activity in this model, participants were either given an experimental antimalarial, artefenomel (500 mg), or a known gametocytocidal drug, primaquine (15 mg), or remained untreated during the period of gametocyte carriage. RESULTS: Male and female gametocytes were detected in all participants, and transmission to mosquitoes was achieved from 8 of 11 (73%) participants evaluated. Compared with results in untreated controls (n = 7), primaquine (15 mg, n = 5) significantly reduced gametocyte burden (P = 0.01), while artefenomel (500 mg, n = 4) had no effect. Adverse events (AEs) were mostly mild or moderate. Three AEs were assessed as severe - fatigue, elevated alanine aminotransferase, and elevated aspartate aminotransferase - and were attributed to malaria infection. Transaminase elevations were transient, asymptomatic, and resolved without intervention. CONCLUSION: We report the safe and reproducible induction of P. falciparum gametocytes in healthy malaria-naive volunteers at densities infectious to mosquitoes, thereby demonstrating the potential for evaluating transmission-blocking interventions in this model. TRIAL REGISTRATION: ClinicalTrials.gov NCT02431637 and NCT02431650. FUNDING: Bill & Melinda Gates Foundation.

Effect of Vital Tooth Bleaching on Surface Roughness and Streptococcal Biofilm Formation on Direct Tooth-Colored Restorative Materials.

OBJECTIVE: To compare the effect of simulated bleaching with a 10% carbamide peroxide (CP) or a 40% hydrogen peroxide (HP) system on surface roughness of resin composite and resin-modified glass ionomer cement (RMGI) and streptococcal biofilm formation on these surfaces. METHODS AND MATERIALS: Specimens of nanofilled resin composite and RMGI (n=108 each) were randomly divided into three groups (n=36 each): no treatment control, 10% CP, and 40% HP. The surface roughness values (Ra) were measured before and after treatments. The specimens in each group were randomly divided into three subgroups (n=12) and incubated with Streptococcus mutans, Streptococcus sanguinis, and trypticase soy broth control for 24 hours. Biofilm formation was quantified by crystal violet staining, and the structure was visualized by scanning electron microscopy. The differences between the mean changes in Ra between the 10% CP and 40% HP groups of each material were evaluated with an independent t-test. The quantity of biofilm formation on each material was analyzed with one-way analysis of variance with the post hoc Tukey test ( α=0.05). RESULTS: Surface roughness significantly increased after bleaching in all groups. There was no significant difference between the 10% CP and 40% HP groups of each material. For S. mutans biofilm formation, bleaching with 10% CP and 40% HP increased biofilm on both materials compared to controls. However, S. sanguinis biofilm formation was significantly higher on bleached resin composite but not on RMGI specimens. CONCLUSIONS: Simulated bleaching with 10% CP or 40% HP increased both surface roughness and biofilm formation on resin composite and RMGI, except for S. sanguinis biofilm on RMGI.

Randomized clinical trial of 2 nonvital tooth bleaching techniques: A 1-year follow-up.

STATEMENT OF PROBLEM: Controlled clinical trials comparing the effectiveness of the walking bleaching (WB) technique and the inside-outside (I-O) technique used in a short daily regimen are lacking. PURPOSE: The purpose of this randomized clinical trial was to investigate the effectiveness of WB with that of the I-O technique conducted over 4 weeks and to compare color changes after 1 year. MATERIAL AND METHODS: Discolored and endodontically treated anterior teeth received a cervical seal and were randomly divided into groups according to the technique. In the WB group (n=9), a mixture of sodium perborate and 20% hydrogen peroxide was applied in the pulp chambers and replaced weekly up to 4 weeks. For the I-O group (n=8), participants applied 10% carbamide peroxide in the pulp chambers and wore custom-fitted trays for 1 hour per day over 4 weeks. CIELab parameters were obtained using a spectrophotometer at baseline, during bleaching (1, 2, 3, and 4 weeks) and after 1 year. Changes in color (ΔE), lightness (ΔL*), green-red axis (Δa*), blue-yellow axis (Δb*), and absolute color parameters (L*, b*, and a*) for each evaluation time were calculated and analyzed by repeated measures analysis of variance (ANOVA) and post hoc Bonferroni test (α=.05). RESULTS: No significant differences between WB and I-O techniques were observed for ΔE, ΔL*, Δa*, Δb*, L*, a*, or b* values (P>.05); however, significant differences were observed among the evaluation times (P<.05). Color changes observed after 2 weeks were stable after 1 year; ΔL* and Δa* values after 1 year were not significantly different from the 1-week evaluation, and significant changes in Δb* after 3 weeks were maintained at the 1-year follow-up. The same trend was observed for the absolute CIELab color parameters. CONCLUSIONS: Both WB and I-O regimens were similarly effective as shown by significant ΔE after 2 weeks and no color regression after 1 year.

High-concentration carbamide peroxide can reduce the sensitivity caused by in-office tooth bleaching: a single-blinded randomized controlled trial

Abstract Objectives A single-blinded, randomized, parallel clinical trial evaluated the use of 37% carbamide peroxide (CP) on bleaching effectiveness and tooth sensitivity reported by patients undergoing in-office tooth bleaching, in comparison with the results of using 35% hydrogen peroxide. Material and Methods Forty patients were allocated to receive two sessions of in-office tooth bleaching using either 35% hydrogen peroxide (HP) or 37% CP. Each patient's sensitivity level was evaluated during and up to 24 h after bleaching. The effectiveness of the bleaching procedures was evaluated with a spectrophotometer one week after each session and 30 days after the last session. The impact of tooth bleaching on the patients' perceptions regarding smile changes, in addition to the bleaching procedures and their results, were also recorded. Absolute and relative sensitivity risks were calculated. Data on sensitivity level were analyzed using the Mann-Whitney or T-test, and data from the color evaluation were subjected to 2-way repeated measures ANOVA. Results The use of CP reduced the risk and level of tooth sensitivity to values close to zero, whereas the difference between the bleaching agents disappeared after 24 h. An increased bleaching effect was observed for HP, mainly due to an improved reduction of redness and yellowness. Participants perceived improved tooth bleaching for HP and reduced sensitivity for CP, but no differences regarding the comfort of the techniques were noted. Conclusions In our study, 37% CP resulted in reduced tooth sensitivity but decreased the tooth bleaching effectiveness. However, both bleaching agents resulted in high levels of patient satisfaction.

Oxygen generating nanoparticles for improved photodynamic therapy of hypoxic tumours.

Photodynamic therapy (PDT) is a clinically approved anti-cancer treatment that involves the activation of an otherwise inactive sensitiser drug with light, which in the presence of molecular oxygen, generates cytotoxic reactive oxygen species (ROS). As oxygen is a key requirement for the generation of ROS in PDT and given the fact that hypoxia is a characteristic of most solid cancerous tumours, treating hypoxic tumours using PDT can be a challenge. In this manuscript, we have prepared a CaO2 nanoparticle (NP) formulation coated with a pH-sensitive polymer to enable the controlled generation of molecular oxygen as a function of pH. The polymer coat was designed to protect the particles from decomposition while in circulation but enable their activation at lower pH values in hypoxic regions of solid tumours. The oxygen generating capability of the polymer coated NPs was demonstrated in aqueous solution with minimal oxygen produced at pH7.4, whereas it increased significantly when the pH was reduced to 6.2. The polymer coated CaO2 NPs were also observed to significantly increase tumour pO2 levels (p<0.05) in mice bearing ectopic human xenograft MIA PaCa-2 pancreatic tumours with an average increase in tumour pO2 of 6.5mmHg in the period 10-30min following administration. A statistically significant improvement in PDT mediated efficacy (p<0.001) was also observed when the particles were administered to mice bearing the same tumours 20min prior to PDT treatment. These results suggest that the polymer coated CaO2 NP formulation offers significant potential as an in situ method for oxygen generation to enhance the efficacy of treatments that depend on the presence of oxygen to elicit a cytotoxic effect.

A randomized controlled trial of home bleaching of tetracycline-stained teeth.

OBJECTIVES: To investigate the effectiveness of two home bleaching modalities on whitening of tetracycline-stained teeth (TST). METHODS: A randomized controlled trial on the bleaching effect of 15% carbamide peroxide gel loaded in tray and 6.5% hydrogen peroxide strip in subjects with TST was performed. Eligible subjects were judged independently by two assessors, and randomly assigned into the tray or the strip group. Lightness (L*), redness (a*) and yellowness (b*) were measured with colorimeter at baseline, one, two and three months. Any adverse reaction associated with bleaching were also recorded. Overall colour changes (ΔE) were analysed by one-sample and independent t-test/Wilcoxon test at significance level α=0.05. RESULT: Twelve and fourteen participants were allocated to the tray and the strip group respectively. Both groups experienced noticeable and significant L*a*b* improvement at the end of the trial in comparison to the baseline (p<0.05). Significant improvement was observed in the first month for the tray group (p<0.05) and in the first two months for the strip group (p<0.05). While greater lightness improvement was observed in the tray group over the strip group in the first month (p=0.02), the reverse was noticed in the second month (p=0.01). There was no difference between two groups at the end of this trial (p<0.05) and no significant adverse reactions were observed. CONCLUSION: Over a three-month period, 6.0% hydrogen peroxide strip performed equally well as the 15% carbamide peroxide tray delivery system in TST. CLINICAL SIGNIFICANCE: Home bleaching systems produce noticeable tooth whitening effect in subjects with tetracycline-stained teeth.