Evaluation of safety and efficacy as an adjuvant for the chitosan-based vaccine delivery vehicle ViscoGel in a single-blind randomised Phase I/IIa clinical trial

ViscoGel, a chitosan-based hydrogel, has earlier been shown to improve humoral and cell-mediated immune responses in mice. In this study, a Phase I/IIa clinical trial was conducted to primarily evaluate safety and secondarily to study the effects of ViscoGel in combination with a model vaccine, Act-HIB to Haemophilus influenzae type b, administered as a single intramuscular injection. Healthy volunteers of both sexes, ages 22–50 and not previously vaccinated to HIB, were recruited. The trial had two phases. In Phase A, three ascending dose levels of ViscoGel (25, 50 and 75 mg) were evaluated for safety in 3 × 10 subjects. Phase B had a single-blind, randomised, parallel-group design evaluating safety and efficacy in five groups, 20 subjects/group, comparing vaccination with 0.2 μg or 2 μg Act-HIB alone or combined with ViscoGel (50 mg) and one group receiving the standard Act-HIB dose (10 μg). No safety or tolerability concerns were identified. Local, transient reactions at the injection site were the most common adverse events. These were more frequent in groups receiving Act-HIB + ViscoGel, while other AEs were recorded at similar frequency in Act-HIB and Act-HIB + ViscoGel groups. Efficacy was evaluated by measuring serum anti-HIB antibodies and cellular responses in peripheral blood mononuclear cells (PBMC). There was a large variation in baseline anti-HIB antibody titres and no adjuvant effect was observed on the anti-HIB antibody production in groups vaccinated with Act-HIB + ViscoGel. ELISpot analyses revealed increased interferon-γ (IFN-γ) responses to Act-HIB in PBMCs from subjects vaccinated with Act-HIB in combination with ViscoGel, compared to groups receiving Act-HIB alone. Moreover, ViscoGel counteracted an inhibitory effect of Act-HIB vaccination on the IFN-γ response to both the vaccine itself and an irrelevant influenza antigen. In summary, ViscoGel was found to be safe and well-tolerated, supporting further examination of ViscoGel as a new innovative vehicle for vaccine development.     

Clinical and Radiographic Outcomes of Traumatized Immature Permanent Necrotic Teeth after Revascularization/Revitalization Therapy

Introduction

Revascularization treatment is rapidly becoming an accepted treatment alternative for the management of endodontic pathology in immature permanent teeth with necrotic dental pulps. However, the success and timing of clinical resolution of symptoms, and radiographic outcomes of interest, such as continued hard tissue deposition within the root, are largely unknown.

Methods

In this prospective cohort study, 20 teeth were treated with a standardized revascularization treatment protocol and monitored for clinical and radiographic changes for 1 year. Standardized radiographs were collected at regular intervals, and radiographic changes were quantified.

Results

All 20 treated teeth survived during the 12-month follow-up period, and all 20 also met the clinical criteria for success at 12 months. As a group, the treated teeth showed a statistically significant increase in radiographic root width and length and a decrease in apical diameter, although the changes in many cases were quite small (such that the clinical significance is unclear). The within-case percent change in apical diameter after 3 months was 16% and had increased to 79% by 12 months, with 55% (11/20) showing complete apical closure. The within-case percent change in root length averaged less than 1% at 3 months and increased to 5% at 12 months. The within-case percent change in root thickness averaged 3% at 3 months and 21% at 12 months.

Conclusions

Although clinical success was highly predictable with this procedure, clinically meaningful radiographic root thickening and lengthening are less predictable after 1-year of follow-up. Apical closure is the most consistent radiographic finding.     

Arginine deprivation alters microglial polarity and synergizes with radiation to eradicate non-arginine-auxotrophic glioblastoma tumors

New approaches for the management of glioblastoma (GBM) are an urgent and unmet clinical need. Here, we illustrate that the efficacy of radiotherapy for GBM is strikingly potentiated by concomitant therapy with the arginine-depleting agent ADI-PEG20 in a non-arginine-auxotrophic cellular background (argininosuccinate synthetase 1 positive). Moreover, this combination led to durable and complete radiological and pathological response, with extended disease-free survival in an orthotopic immune-competent model of GBM, with no significant toxicity. ADI-PEG20 not only enhanced the cellular sensitivity of argininosuccinate synthetase 1–positive GBM to ionizing radiation by elevated production of nitric oxide (˙NO) and hence generation of cytotoxic peroxynitrites, but also promoted glioma-associated macrophage/microglial infiltration into tumors and turned their classical antiinflammatory (protumor) phenotype into a proinflammatory (antitumor) phenotype. Our results provide an effective, well-tolerated, and simple strategy to improve GBM treatment that merits consideration for early evaluation in clinical trials.     

Spontaneous splenic rupture during infection of cytomegalovirus. A case report

Splenic rupture is most commonly encountered after blunt abdominal trauma. Spontaneous atraumatic splenic rupture is a rare but dramatic occurrence that is most commonly attributed to infection or neoplasia. We report the case of a 27-year-old female patient without pathological history. Admitted to the emergency department for the sudden onset of left hypochondrial pain associated with vomiting, rapidly progressing to hypovolemic shock. She had reported an influenza-like illness a week earlier for which her COVID-19 PCR was negative. Emergency abdominal ultrasound and CT-scan revealed a ruptured spleen and widespread hemorrhagic fluid in the abdomen. Exploration revealed multiple ruptures in the spleen capsule. The patient underwent splenectomy with good clinical evolution. Despite the rarity of this condition, physicians should consider the diagnosis of spontaneous non traumatic splenic rupture when encountering healthy patients presenting with nonspecific left hypochondrial abdominal pain and hypovolemia. Mortality is essentially related to the delay in diagnosis and treatment and to the severity of the underlying pathology. Treatment often consists of splenectomy.     

UV-selective organic absorbers for the cosensitization of greenhouse-integrated dye-sensitized solar cells: synthesis and computational study

Molecular cosensitization is favorable for manipulating solar radiation through the judicious choice of cosensitizers having complementary absorption spectra. For greenhouse-integrated dye-sensitized solar cells (DSCs), the manipulation of solar radiation is crucial in order to maximize the flow of photosynthetically active radiation (PAR) for the effectual photosynthetic activity of plants; meanwhile, non-PAR is utilized in agrivoltaics for generating electricity. In this study, we report the synthesis of novel four UV-selective absorbers, based on the diimide scaffold, functionalized with carboxylate and pyridyl anchoring groups, for adequate adsorption onto the TiO₂ electrode in DSC. The UV/Vis absorption spectra of the DMF solution-based free dyes were measured experimentally. Basic photophysical and energetics requirements for operating greenhouse-integrated DSCs were examined at the molecular level via (time-dependent) density functional theory-based calculations. The computational results revealed the outperformance of the biphenyldiimide-structured DI-CA1 dye, especially for maximum charge transferred to its anchor, lower thermodynamic barrier for dissociating the photogenerated exciton, largest Stokes'' shift, strong electronic coupling with TiO₂ nanoparticles, and higher degree of charge separation at the DI-CA1/TiO₂ interface. PDOS showed deeper existence for the LUMO level in the CB of TiO₂, which expedites the electron injection process. The chemical and optical compatibility of DI-CA1 were then investigated as a potential cosensitizer of a reference BTD–DTP1, a green light-absorbing dye. Considerable overlap between the fluorescence spectrum of DI-CA1 and absorption spectrum of the reference BTD–DTP1 advocated the opportunity of excitation energy transfer via the radiative trivial reabsorption mechanism, which confirms the cosensitization functionality. Energy decomposition analysis and reduced density gradient maps estimated the chemical compatibility owing to weak dispersion interactions as the dominant stabilizing attractive force. This noncovalent functionalization retains the chemical compatibility without distorting the π–π conjugation and the associated physicochemical properties of the individual dye molecules. Along with the expanded consumption of non-photosynthetically active solar radiation, an improved power conversion efficiency of greenhouse-integrated DSC is accordingly expected.

Molecular cosensitization is favorable for manipulating solar radiation through the judicious choice of cosensitizers having complementary absorption spectra.