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Objectives A multicentric randomized, 3-year prospective study was conducted to determine for how long Biodentine, a new biocompatible dentine substitute, can remain as a posterior restoration. Materials and methods First, Biodentine was compared to the composite Z100®, to evaluate whether and for how long it could be used as a posterior restoration according to selected United States Public Health Service (USPHS)’ criteria (mean ± SD). Second, when abrasion occurred, Biodentine was evaluated as a dentine substitute combined with Z100®. Results A total of 397 cases were included. This interim analysis was conducted on 212 cases that were seen for the 1-year recall. On the day of restoration placement, both materials obtained good scores for material handling, anatomic form (0.12 ± 0.33), marginal adaptation (0.01 ± 0.10) and interproximal contact (0.11 ± 0.39). During the follow-up, both materials scored well in surface roughness (≤1) without secondary decay and post-operative pain. Biodentine kept acceptable surface properties regarding anatomic form score (≤1), marginal adaptation score (≤2) and interproximal contact score (≤1) for up to 6 months after placement. Resistance to marginal discoloration was superior with Biodentine compared to Z100®. When Biodentine was retained as a dentine substitute after pulp vitality control, it was covered systematically with the composite Z100®. This procedure yielded restorations that were clinically sound and symptom free. Conclusions Biodentine is able to restore posterior teeth for up to 6 months. When subsequently covered with Z100®, it is a convenient, efficient and well tolerated dentine substitute. Clinical relevance Biodentine as a dentine substitute can be used under a composite for posterior restorations.

Insecticides used for agricultural pest control, as cypermethrin-based insecticide (CBI) and fipronil-based insecticide (FBI), are constant threats to non-target aquatic organisms. This study aimed to investigate the effect of different concentrations of cypermethrin and fipronil on neurotoxicity and oxidative stress in Physalaemus gracilis . Physalaemus gracilis tadpoles were exposed to five insecticide concentrations and a control treatment, with six replicates. During the experimental period, the tadpole mortality rate was evaluated and after 168 h, the neurotoxic enzyme activity and metabolite quantification related to the antioxidant system were measured. Tadpoles reduced acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) activities when exposed to 20 μg L −1 CBI and at all FBI concentrations, respectively. Glutathione S-transferase (GST) and superoxide dismutase (SOD) activities showed an increase from concentrations of 6 μg L −1 and 20 μg L −1 of CBI, respectively. After exposure of P. gracilis tadpoles to FBI, inhibitions of AChE and BChE were observed at the highest concentrations evaluated (500 and 1500 μg L −1 ). SOD activity decreased from 50 μg L −1 of FBI; however, catalase (CAT) and GST activities and carbonyl protein levels increased, regardless of the evaluated dose. We observed that both insecticides promoted oxidative stress and neurotoxic effects in P. gracilis tadpoles. These results suggest that biochemical biomarkers can be used for monitoring toxicity insecticides for the purpose of preservation of P. gracilis .

The growing pressure on food production has led to the widespread use of pesticides to ensure high crop yields. Herbicides are extensively applied in Brazil, with diquat-based herbicides (DBH) being one of the most commercialized. DBH has gained prominence as a substitute for paraquat and as a solution for glyphosate-resistant weeds. However, strict regulations govern the permissible levels of these substances in drinking water. In this context, we evaluated environmentally relevant concentrations of DBH in zebrafish ( Danio rerio ), a model organism in ecotoxicological studies. To evaluate the impact on behavior and early development, embryos were exposed to DBH at concentrations of 20, 50, or 250 µg L −1 during organogenesis (3–120 hpf). Developmental impacts were assessed through survival rates, spontaneous movement, and heart rate, while behavioral effects were analyzed using open-field and aversive stimulus tests. DBH exposure reduced survival, increased spontaneous movements and heart rate, and impaired larval behavior. Notably, all tested concentrations induced adverse effects in at least one endpoint, clearly demonstrating the detrimental impact of DBH on zebrafish embryos and larvae at environmentally relevant concentrations.

The impact of environmental pollutants has been a focus of investigation in recent years. Studies assessing the effects of these pollutants are essential for understanding the challenges faced by non-target species. Among the many substances used for agricultural purposes, the herbicide glyphosate is one of the most widely marketed in recent years. This broad-spectrum herbicide is commonly used to protect a variety of crops. In this study, we evaluated the effects of chronic glyphosate exposure on a native amphibian species, Physalaemus gracilis . Amphibians, which develop in aquatic environments, are highly sensitive to pesticides. Because of this, we investigated morphological, physiological, behavioral, and biochemical parameters in the early stages of development. The animals were exposed to environmentally relevant concentrations of a glyphosate-based herbicide (0, 100, 350, and 700 µg L⁻¹) during their first seven days of life. As a result, we observed impairments in anti-predatory behavior, reduced body mass index, and scaled mass index, malformations of the mouth and intestine, increased acetylcholinesterase activity, cardiotoxicity, and oxidative stress. These findings underscore the importance of studying native non-target species and highlight the need to evaluate the effects of environmentally relevant concentrations, as well as to review legislation regarding permissible levels of glyphosate in surface water and public water supplies.

Anorexia and fasting are host adaptations to acute infection, and induce a metabolic switch towards ketogenesis and the production of ketone bodies, including β-hydroxybutyrate (BHB) 1 – 6 . However, whether ketogenesis metabolically influences the immune response in pulmonary infections remains unclear. Here we show that the production of BHB is impaired in individuals with SARS-CoV-2-induced acute respiratory distress syndrome (ARDS) but not in those with  influenza-induced ARDS. We found that BHB promotes both the survival of and the production of interferon-γ by CD4 + T cells. Applying a metabolic-tracing analysis, we established that BHB provides an alternative carbon source to fuel oxidative phosphorylation (OXPHOS) and the production of bioenergetic amino acids and glutathione, which is important for maintaining the redox balance. T cells from patients with SARS-CoV-2-induced ARDS were exhausted and skewed towards glycolysis, but could be metabolically reprogrammed by BHB to perform OXPHOS, thereby increasing their functionality. Finally, we show in mice that a ketogenic diet and the delivery of BHB as a ketone ester drink restores CD4 + T cell metabolism and function in severe respiratory infections, ultimately reducing the mortality of mice infected with SARS-CoV-2. Altogether, our data reveal that BHB is an alternative source of carbon that promotes T cell responses in pulmonary viral infections, and highlight impaired ketogenesis as a potential confounding factor in severe COVID-19. The ketone body β-hydroxybutyrate can be used as an alternative carbon source by T cells to maintain their function during severe respiratory viral infections, including infection with SARS-CoV-2.

Nutrition is an important modifiable risk factor in Alzheimer's disease. Previous trials of the multinutrient Fortasyn Connect showed benefits in mild Alzheimer's disease dementia. LipiDiDiet investigated the effects of Fortasyn Connect on cognition and related measures in prodromal Alzheimer's disease. Here, we report the 24-month results of the trial. LipiDiDiet was a 24-month randomised, controlled, double-blind, parallel-group, multicentre trial (11 sites in Finland, Germany, the Netherlands, and Sweden), with optional 12-month double-blind extensions. The trial enrolled individuals with prodromal Alzheimer's disease, defined according to the International Working Group (IWG)-1 criteria. Participants were randomly assigned (1:1) to active product (125 mL once-a-day drink containing Fortasyn Connect) or control product. Randomisation was computer-generated centrally in blocks of four, stratified by site. All study personnel and participants were masked to treatment assignment. The primary endpoint was change in a neuropsychological test battery (NTB) score. Analysis was by modified intention to treat. Safety analyses included all participants who consumed at least one study product dose. This trial is registered with the Dutch Trial Register, number NTR1705. Between April 20, 2009, and July 3, 2013, 311 of 382 participants screened were randomly assigned to the active group (n=153) or control group (n=158). Mean change in NTB primary endpoint was −0·028 (SD 0·453) in the active group and −0·108 (0·528) in the control group; estimated mean treatment difference was 0·098 (95% CI −0·041 to 0·237; p=0·166). The decline in the control group was less than the prestudy estimate of −0·4 during 24 months. 66 (21%) participants dropped out of the study. Serious adverse events occurred in 34 (22%) participants in the active group and 30 (19%) in control group (p=0·487), none of which were regarded as related to the study intervention. The intervention had no significant effect on the NTB primary endpoint over 2 years in prodromal Alzheimer's disease. However, cognitive decline in this population was much lower than expected, rendering the primary endpoint inadequately powered. Group differences on secondary endpoints of disease progression measuring cognition and function and hippocampal atrophy were observed. Further study of nutritional approaches with larger sample sizes, longer duration, or a primary endpoint more sensitive in this pre-dementia population, is needed. European Commission 7th Framework Programme.

Feline infectious peritonitis (FIP) is a fatal but now treatable disease in cats caused by feline coronavirus (FCoV). This study prospectively investigated viral coinfections in 100 cats diagnosed with FIP and subsequently treated with oral GS-441524 (Bova UK) and their influence on outcome, focusing on viruses potentially associated with feline chronic gingivostomatitis (FCGS). Cats were tested for feline leukemia virus (FeLV), feline immunodeficiency virus (FIV), feline calicivirus (FCV), feline herpesvirus (FHV), feline foamy virus (FFV), and feline gammaherpesvirus (FcaGHV1). Coinfections were identified at the following frequencies: FCV (27), FFV (22), FHV (6), FIV (4), FcaGHV1 (2), and FeLV (2, both progressive infections). FFV infection was significantly associated with FIV (pF = 0.0021) and FHV (pF = 0.0226) infection. FCGS was present in 25/97 cats with FCV infection being associated with FCGS (pF = 0.0032); no significant associa-tions were found for the other viruses and FCGS. The 42-day oral GS-441524 treatment’s success rate was 94% (five cats died, one relapsed). Coinfections did not significantly influence disease severity or treatment outcome, although the low number of cases for some pathogens warrants further investigation. However, advanced age was associated with treatment failure, potentially due to delayed diagnosis as FIP is considered to be less common in older individuals, or to age-related changes in immune function. In summary, viral coinfections, particularly with FCV, were common and should be considered in the clinical and hygienic management of cats with FIP.

ObjectivesCD19-targeting chimeric antigen receptor (CAR) T-cell therapy can induce long-term drug-free remission in patients with autoimmune diseases (AIDs). The efficacy of CD19-CAR T-cell therapy is presumably based on deep tissue depletion of B cells; however, such effect has not been proven in humans in vivo.MethodsSequential ultrasound-guided inguinal lymph node biopsies were performed at baseline and after CD19-CAR T-cell therapy in patients with AIDs. Results were compared with lymph node biopsies from rituximab (RTX)-treated AID patients with absence of peripheral B cells. Conventional and immunohistochemistry staining were performed on lymph node tissue to assess architecture as well the number of B cells, follicular dendritic cells (FDCs), plasma cells, T cells and macrophages.ResultsSequential lymph node biopsies were analysed from five patients with AID before and after CD19-CAR T-cell therapy and from five patients with AID after RTX treatment. In addition, non-lymphoid organ biopsies (colon, kidney and gallbladder) from three additional patients with AID after CD19-CAR T-cell therapy were analysed. CD19+ and CD20+ B cells were completely depleted in the lymph nodes after CD19-CAR T-cell therapy, but not after RTX treatment. Plasma cells, T cells and macrophages in the lymph nodes remained unchanged. Follicular structures were disrupted and FDCs were depleted in the lymph nodes after CD19-CAR T-cell therapy, but not after RTX. Non-lymphoid organs were completely depleted of B cells.DiscussionThis study demonstrates complete B-cell depletion in secondary lymphoid tissues of patients with AIDs following CD19-CAR T-cell therapy combined with standard lymphodepleting therapy.

Atrazine and glyphosate are considered some of the main pollutants for aquatic ecosystems, directly and indirectly affecting non-target organisms, such as amphibians. This study aimed to evaluate the sublethal effects of different concentrations of atrazine-based herbicide (ABH) and glyphosate-based herbicide (GBH) commercial formulations, both individually and in a mixture, through toxicity tests on the larval stage of Boana faber . Tadpoles were exposed to concentrations of ABH (2, 9.33, 10.40, 47.21, and 240 μg L −1 ) and GBH (65, 144, 280, 500, and 1000 μg L −1 ), as well as a mixture ABH + GBH, for 7 days. Although survival and swimming activity were not significantly affected by herbicide exposure, tadpoles in all treatments showed damage to the mouth and intestine, changes in size and mass, and an increase in the frequency of micronuclei and other nuclear abnormalities. Despite differences in some variables analyzed, it is not possible to definitively state that there is a difference in the toxicity of these two herbicides, as both caused morphological damage and were cyto-genotoxic. Our findings suggest that exposure to commercial formulations of these herbicides, whether alone or in mixture, can directly impact the quality of life of B. faber tadpoles.

Traumatic brain injury (TBI) is considered a public health problem and is often related to motor and cognitive disabilities, besides behavioral and emotional changes that may remain for the rest of the subject’s life. Resident astrocytes and microglia are the first cell types to start the inflammatory cascades following TBI. It is widely known that continuous or excessive neuroinflammation may trigger many neuropathologies. Despite the large numbers of TBI cases, there is no effective pharmacological treatment available. This study aimed to investigate the effects of the new hybrid molecule 3-ethoxycarbonyl-2-methyl-4-(2-nitrophenyl)-4,11-dihydro1H-pyrido[2,3-b][1,5]benzodiazepine (JM-20) on TBI outcomes. Male Wistar rats were submitted to a weight drop model of mild TBI and treated with a single dose of JM-20 (8 mg/kg). Twenty-four hours after TBI, JM-20–treated animals showed improvements on locomotor and exploratory activities, and short-term memory deficits induced by TBI improved as well. Brain edema was present in TBI animals and the JM-20 treatment was able to prevent this change. JM-20 was also able to attenuate neuroinflammation cascades by preventing glial cells—microglia and astrocytes—from exacerbated activation, consequently reducing pro-inflammatory cytokine levels (TNF-α and IL-1β). BDNF mRNA level was decreased 24 h after TBI because of neuroinflammation cascades; however, JM-20 restored the levels. JM-20 also increased GDNF and NGF levels. These results support the JM-20 neuroprotective role to treat mild TBI by reducing the initial damage and limiting long-term secondary degeneration after TBI.