A Randomized Phase 2/3 Study of Ensitrelvir, a Novel Oral SARS-CoV-2 3C-Like Protease Inhibitor, in Japanese Patients with Mild-to-Moderate COVID-19 or Asymptomatic SARS-CoV-2 Infection: Results of the Phase 2a Part.

This multicenter, double-blind, phase 2a part of a phase 2/3 study assessed the efficacy and safety of ensitrelvir, a novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) 3C-like protease inhibitor, in Japanese patients with mild-to-moderate coronavirus disease 2019 (COVID-19) or asymptomatic SARS-CoV-2 infection. Sixty-nine patients were randomized (1:1:1) to orally receive 5-day ensitrelvir fumaric acid (375 mg on day 1 followed by 125 mg daily, or 750 mg on day 1 followed by 250 mg daily) or placebo and followed up until day 28. The primary outcome was the change from baseline in the SARS-CoV-2 viral titer. A total of 16, 14, and 17 patients in the ensitrelvir 125 mg, ensitrelvir 250 mg, and placebo groups, respectively, were included in the intention-to-treat population (mean age: 38.0 to 40.4 years). On day 4, the change from baseline in SARS-CoV-2 viral titer (log10 50% tissue culture infectious dose/mL) in patients with positive viral titer and viral RNA at baseline was greater with ensitrelvir 125 mg (mean [standard deviation], -2.42 [1.42]; P = 0.0712) and 250 mg (-2.81 [1.21]; P = 0.0083) versus placebo (-1.54 [0.74]); ensitrelvir treatment reduced SARS-CoV-2 RNA by -1.4 to -1.5 log10 copies/mL versus placebo. The viral titer and viral RNA were similar across groups on and after day 6. The median time to infectious viral clearance decreased by approximately 50 h with ensitrelvir treatment. All adverse events were mild to moderate. Ensitrelvir treatment demonstrated rapid SARS-CoV-2 clearance and was well tolerated (Japan Registry of Clinical Trials identifier: jRCT2031210350).

Molar loss and powder diet leads to memory deficit and modifies the mRNA expression of brain-derived neurotrophic factor in the hippocampus of adult mice.

BACKGROUND: It is known that tooth loss is known to be a risk factor for Alzheimer's disease and soft diet feeding induces memory impairment. Recent studies have shown that brain-derived neurotrophic factor (BDNF) is associated with tooth loss or soft diet in young animal model, and that BDNF expression is decreased in patients with Alzheimer's disease. However, single or combined effect of tooth loss and/or soft diet on brain function has not fully understood. Here we examined the effect of molar loss and powder diet on memory ability and the expression of BDNF mRNA in the hippocampus of adult C57BL/6J mice. Twenty eight-weeks-old C57BL/6J mice were divided into intact molar group and extracted molar group. They were randomly divided into the I/S group (Intact upper molar teeth/Solid diet feeding), the E/S group (Extracted upper molar teeth/Solid diet feeding), the I/P group (Intact upper molar teeth/Powder diet feeding), and the E/P group (Extracted upper molar teeth/Powder diet feeding). The observation periods were 4 and 16-week. To analyze the memory ability, the step-through passive avoidance test was conducted. BDNF-related mRNA in the hippocampus was analyzed by real-time polymerase chain reaction (RT-PCR). RESULTS: At 4 weeks later, we performed memory test and isolated brains to analyze. There were no differences in memory function and BDNF mRNA level between these four groups. However, at 16 weeks later, E/S and E/P group showed memory impairment, and decreased level of BDNF mRNA. Whereas, the powder diet had no effect on memory function and BDNF mRNA level even at 16 weeks later. CONCLUSIONS: These results suggest that the effect of molar loss and powder diet on memory function and BDNF mRNA levels were different, molar loss may have a greater long-term effect on memory ability than powder diet does.

Camouflage Correction of Skeletal Class III Severe Open Bite with Tooth Ankylosis Treated by Temporary Anchorage Devices: A Case Report.

Tooth ankylosis is a disorder characterized by the fusion of tooth and alveolar bone. This case report describes the treatment of a severe open bite due to tooth ankylosis. A 14-year-old female patient with a chief complaint of masticatory dysfunction was diagnosed with skeletal Class III severe anterior open bite and tooth ankylosis. She visited our university hospital with a chief complaint of an anterior open bite. After the surgical luxation of the ankylosed maxillary right central incisor, the tooth was orthodontically retracted using a nickel-titanium wire. The right mandibular lateral incisor and canine were luxated and retracted using intermaxillary elastics from a temporary anchorage device (TAD), which was inserted in the opposite jaw. During the treatment, skeletal Class III malocclusion deteriorated due to anterior growth of the mandible. Therefore, TADs were inserted into the retromolar pad on both sides of the mandible and retracted into the mandibular dental arch. Although the mandibular right canine was luxated several times, it could not be brought to the occlusal line, and was thus extracted; the extraction space was replaced with a prosthesis. Consequently, a normal overjet and overbite with a straight profile were achieved. Extrusion of ankylosed teeth by intermaxillary elastics from a TAD is a valid treatment option for patients with severe open bites.

Preoperative evaluation of bone quality for dental implantation using an ultrasound axial transmission device in an ex vivo model.

This study investigated the clinical utility of an ultrasound axial transmission device in preoperative evaluation of bone quality for dental implantation, by clarifying the relationship between cortical bone speed of sound (cSOS), insertion torque values (ITV), and implant stability quotient (ISQ) in porcine femur bone. Eleven fresh porcine femurs, without soft tissue, were prepared. The cSOS of these bones were measured using the axial transmission device. Bone mineral density (BMD) and porosity (Po) were measured in cortical bone samples obtained from the region of ultrasound measurements by X-ray microcomputed tomography. Thirty-three implants were inserted into these samples (three implants per bone sample), and ITV and ISQ were measured for all implants. Then, cortical bone thickness (CbTh) of the area for implantation was measured for all implants using a micrometer. The mean cSOS was 3962 m/s; mean BMD and Po were 0.822 g/cm2 and 0.185%, respectively. cSOS and BMD values were positively correlated, and cSOS values and Po values were negatively correlated. Mean ITV, ISQ, and CbTh were 37.95 Ncm, 71.172, and 2.869 mm, respectively. There was a positive correlation between cSOS values and ISQ values. The cSOS of each bone did not correlate with ITV for all of the bone samples. However, when the CbTh ranges from 3.0 to 3.5 mm, ITV are correlated with cSOS. These findings suggest that cSOS, which reflects the cortical bone quality, may be clinical utility as a preoperative diagnosis of the implant.

The Effect of Superstructures Connected to Implants with Different Surface Properties on the Surrounding Bone.

The objective of this study was to investigate how the connection of superstructures to implants with different surface properties affects the surrounding bone. The right and left mandibular premolars and molars of 5 dogs were extracted. After 12 weeks, a machined implant was placed mesially and an anodized implant was placed distally on one side of the edentulous jaw, with the positions reversed on the opposite side. Twelve weeks after implantation, splinted superstructures were set to the implants. At 24 weeks after implantation, the implant stability quotient (ISQ) was measured, radiographs were obtained. Removal torque values were measured and histologic observation was performed. The ISQ values at 24 weeks after implantation were not significantly different between the groups. The removal torque values were significantly different between the distal anodized and distal machined implants (p < 0.05). From 12 to 24 weeks, marginal bone losses were not significantly different between the groups. Fluorescent observation of tissue samples revealed bone-remodeling activity around all of the implants. The results of this study suggest that when implants with different surface properties are connected, machined implants at the most distal sites might be a potential risk factor for implant-bone binding.

The effect of glycosylation on plasma N-terminal proBNP-76 levels in patients with heart or renal failure.

OBJECTIVE: Pro-brain natriuretic peptide (proBNP)-108 and N-terminal proBNP-76 (NT-BNP) contain seven sites for O-linked oligosaccharide attachment. Currently, levels of glycosylated NT-BNP are probably underestimated because it is not recognised by one antibody in the sandwich assay system. The pathophysiological significance of cardiac and plasma levels of non-glycosylated (nonglyNT-BNP) and glycosylated NT-BNP (glyNT-BNP) in heart failure (HF) and chronic renal failure (CRF) was investigated. METHODS: Plasma samples from 186 patients with HF and 76 patients with CRF on haemodialysis were studied, together with 11 atrial tissue samples. To measure nonglyNT-BNP and glyNT-BNP, samples were incubated with or without deglycosylating enzymes and NT-BNP was measured using Roche Elecsys proBNP I. The percentage glyNT-BNP was calculated as glyNT-BNP/(glyNT-BNP + nonglyNT-BNP). RESULTS: In HF, plasma BNP, nonglyNT-BNP and glyNT-BNP levels all increased with increasing disease severity (New York Heart Association class; p<0.0001), though the molar ratio remained constant (molar ratio, BNP:nonglyNT-BNP:glyNT-BNP = 1:2.4:9.6). Before haemodialysis for CRF, plasma BNP and nonglyNT-BNP were somewhat elevated, and glyNT-BNP was markedly increased (molar ratio, BNP:nonglyNT-BNP:glyNT-BNP = 1:8.5:82). After haemodialysis, plasma BNP, nonglyNT-BNP, atrial natriuretic protein and cGMP all declined (p<0.0001), but glyNT-BNP was unchanged. Notably, the percentage of glyNT-BNP was elevated before haemodialysis, and was further increased after haemodialysis (p<0.0001). Atrial tissue levels of BNP, nonglyNT-BNP and glyNT-BNP were similar. CONCLUSION: THE findings suggest that most endogenous plasma NT-BNP is glycosylated and therefore undetectable with the current assay system, and that the relative glycosylation level is increased by haemodialysis.

Beneficial effects of a combination of Rho-kinase inhibitor and ACE inhibitor on tubulointerstitial fibrosis induced by unilateral ureteral obstruction.

We and others recently reported that long-term Rho-kinase inhibition has renoprotective effects. This study was designed to compare the effects of an angiotensin-converting enzyme (ACE) inhibitor (imidapril), a Rho-kinase inhibitor (fasudil) and a combination of them both on renal interstitial fibrosis induced by unilateral ureteral obstruction (UUO). We also attempted to elucidate the mechanism involved. Imidapril (50 mg l(-1)), fasudil (1 g l(-1)) or a combination of them both was given in drinking water to mice, and their effects were compared on renal interstitial fibrosis induced by UUO. We assessed histological findings, monocyte/macrophage infiltration, myofibroblast differentiation, oxidative stress and the expression of various mRNA in the kidney by UUO. Eleven days after UUO, wild-type kidney was characterized by increased fibrotic area, dihydroethidium (DHE)-positive area, alpha-smooth muscle actin (SMA)-positive area, F4/80-positive area and the increased expression of various mRNA. Fasudil and imidapril similarly improved fibrotic area (-23%, -15%), DHE-positive area (-13%, -11%), alpha-SMA-positive area (-22%, -15%), F4/80-positive area (-42%, -34%) and the expression of various mRNA, most of which were significant (P<0.05). The combination of imidapril and fasudil further improved fibrotic area (-52%), DHE-positive area (-26%), alpha-SMA-positive area (-33%), F4/80-positive area (-62%) and the expression of various mRNA (all P<0.05 vs. monotherapy). Compared with either agent alone, the combination of an ACE inhibitor and a Rho-kinase inhibitor was more effective for the prevention of renal interstitial fibrosis because of the inhibition of transforming growth factor-beta/collagen, monocyte/macrophage infiltration, myofibroblast differentiation, inflammation and the oxidative stress pathway.