Landscape of Phase II Trials in Alzheimer's Disease.

BACKGROUND: Drug development in Alzheimer's disease (AD) over the past two decades has had high rates of failure. Novel trial designs, such as adaptive designs, have the potential to improve the efficiency of drug development in AD. OBJECTIVE: To evaluate the design characteristics, temporal trends, and differences in design between sponsor types in phase II trials of investigational agents in AD. METHODS: Phase I/II, II, and II/III trials for AD with drug or other biological interventions registered from December 1996 to December 2021 in ClinicalTrials.gov were included. Descriptive statistics were used to summarize trial characteristics. Linear, logistic, and multinomial regression models assessed temporal trends and differences between sponsor types in design characteristics. RESULTS: Of N = 474 trials identified, randomized parallel group design was the most common design (72%). Only 12 trials (2.5%) used an adaptive design; adaptive features included early stopping rules, model-based dose-finding, adaptive treatment arm selection, and response adaptive randomization. The use of non-randomized parallel-group and open-label single arm designs increased over time. No temporal trend in the use of adaptive design was identified. Trials sponsored by industry only were more likely to use a randomized parallel-group design and have a larger estimated sample size than trials with other sponsor types. CONCLUSION: Our systematic review showed that very few phase II trials in AD used an adaptive trial design. Innovation and implementation of novel trial designs in AD trials can accelerate the drug development process.

Associations over the COVID-19 pandemic period and the mental health and substance use of youth not in employment, education or training in Ontario, Canada: a longitudinal, cohort study.

BACKGROUND: The economic shutdown and school closures associated with the COVID-19 pandemic have negatively influenced many young people's educational and training opportunities, leading to an increase in youth not in education, employment, or training (NEET) globally and in Canada. NEET youth have a greater vulnerability to mental health and substance use problems, compared to their counterparts who are in school and/or employed. There is limited evidence on the association between COVID-19 and NEET youth. The objectives of this exploratory study included investigating: longitudinal associations between the COVID-19 pandemic and the mental health and substance use (MHSU) of NEET youth; and MHSU among subgroups of NEET and non-NEET youth. METHODS: 618 youth (14-28 years old) participated in this longitudinal, cohort study. Youth were recruited from four pre-existing studies at the Centre for Addiction and Mental Health. Data on MHSU were collected across 11 time points during the COVID-19 pandemic (April 2020-August 2022). MHSU were measured using the CoRonavIruS Health Impact Survey Youth Self-Report, the Global Appraisal of Individual Needs Short Screener, and the PTSD Checklist for DSM-5. Linear Mixed Models and Generalized Estimating Equations were used to analyze associations of NEET status and time on mental health and substance use. Exploratory analyses were conducted to investigate interactions between sociodemographic characteristics and NEET status and time. RESULTS: At baseline, NEET youth were significantly more likely to screen positive for an internalizing disorder compared to non-NEET youth (OR = 1.92; 95%CI=[1.26-2.91] p = 0.002). No significant differences were found between youth with, and without, NEET in MHSU symptoms across the study time frame. Youth who had significantly higher odds of screening positive for an internalizing disorder included younger youth (OR = 1.06, 95%CI=[1.00-1.11]); youth who identify as Trans, non-binary or gender diverse (OR = 8.33, 95%CI=[4.17-16.17]); and those living in urban areas (OR = 1.35, 95%CI=[1.03-1.76]), compared to their counterparts. Youth who identify as White had significantly higher odds of screening positive for substance use problems (OR = 2.38, 95%CI=[1.72-3.23]) compared to racialized youth. CONCLUSIONS: Our findings indicate that sociodemographic factors such as age, gender identity, ethnicity and area of residence impacted youth MHSU symptoms over the course of the study and during the pandemic. Overall, NEET status was not consistently associated with MHSU symptoms over and above these factors. The study contributes to evidence on MHSU symptoms of NEET youth.

The predictability of orthodontic tooth movements through clear aligner among first-premolar extraction patients: a multivariate analysis.

BACKGROUND: The purpose was to determine the predictability of tooth movements through clear aligner among premolar extraction patients and to explore the effects of various factors on tooth movements. METHODS: A total of 31 extraction patients (10 males and 20 females; age 14-44) receiving clear aligner treatment (Invisalign) were enrolled in this study. The actual post-treatment models and pre-treatment models were superimposed using the palatal area as a reference and registered with virtual post-treatment models. A paired t test was used to compare the differences between actual and designed tooth movements of maxillary first molars, canines, and central incisors. A multivariate linear mixed model was performed to examine the influence of variables on actual tooth movements. RESULTS: Compared to the designed tooth movements, the following undesirable tooth movements occurred: mesial movement (2.2 mm), mesial tipping (5.4°), and intrusion (0.45 mm) of first molars; distal tipping (11.0°), lingual tipping (4.4°), and distal rotation of canines (4.9°); lingual tipping (10.6°) and extrusion (1.5 mm) of incisors. Age, crowding, mini-implant, overbite, and attachments have differential effects on actual tooth movements. Moreover, vertical rectangular attachments on canines are beneficial in achieving more predictable canine and incisor tooth movements over optimized attachments. Lingual tipping and extrusion of incisors were significantly influenced by the interaction effects between incisor power ridge and different canine attachments (p < 0.05). CONCLUSIONS: Incisors, canines, and first molars are subject to unwanted tooth movements with clear aligners among premolar extraction patients. Age, crowding, mini-implant, overbite, and attachments influence actual tooth movements. Moreover, vertical rectangular attachments on canines are beneficial in achieving more predictable incisor tooth movements over optimized canine attachments.

A comparison of resin infiltration and microabrasion for postorthodontic white spot lesion.

INTRODUCTION: The objective of this research was to evaluate and compare the effectiveness of microabrasion and resin infiltration for white spot lesions (WSLs). METHODS: Patients with postorthodontic WSLs were enrolled and randomly assigned to the control, microabrasion, and resin-infiltration groups. Intraoral photographs were taken before and after (6 months later) treatment. WSL sizes were determined through ImageJ (Wayne Rasband, Kensington, Md). Integrated optical density (IOD) was determined for a WSL and its surrounding normal enamel through Image-Pro Plus (version 6.0; Media Cybernetics, Rockville, Md), and their differences of IOD were considered as the IOD surrogate for that WSL. The color change of WSL were measured through ΔE. RESULTS: A total of 27 eligible patients were enrolled; 9 subjects were assigned to each group, resulting in 56 teeth in the control group, 72 in the microabrasion group, and 58 in the resin-infiltration group. The ratios of WSL size (after/before) were similar between the microabrasion and resin-infiltration group (43.94 ± 0.03% vs 45.02 ± 0.03%; P = 0.96 > 0.05), but those of the 2 groups were significantly lower than those of the control group (92.15 ± 0.02%) (P <0.001). Moreover, the ratios of IOD (after/before) were significantly lower in the resin-infiltration group (22.94 ± 0.02%) than in the microabrasion (78.11 ± 0.03%) and control (83.79 ± 0.02%) (P <0.001) groups. The highest ΔE improvement was obtained by infiltration, but there was no significant difference between microabrasion and control group. CONCLUSIONS: Resin infiltration and microabrasion are comparably effective in reducing the sizes of WSL, but resin infiltration enjoys an esthetic advantage over microabrasion.

Placebo modulation in orthodontic pain: a single-blind functional magnetic resonance study.

OBJECTIVES: The mechanism of orthodontic pain modulation with a placebo remains largely unknown. This study aimed to investigate the placebo modulation of brain activity associated with orthodontic pain using functional magnetic resonance imaging (fMRI). METHODS: This longitudinal fMRI experiment recruited 23 volunteers and a self-contrast method was used. At first time, the participants were scanned without placebo (first period), followed by a 30-day washout, the participants were scanned again with placebo administration (second period). Orthodontic pain was caused by orthodontic separators placement between the lower right molars for both two periods. 24 h after placement, the MRI scans were taken, including a bite/non-bite task fMRI and a resting-state fMRI. A generalized linear model was used to identify pain-regulating network from task fMRI. Functional connectivity analysis of pain-related brain regions was performed to study the placebo effect on connectivity of pain-regulating networks using resting-state fMRI. RESULTS: The results of brain activation patterns were largely similar under placebo and non-placebo conditions. Under the non-placebo condition, the activities in multiple brain regions, including the pre-central gyrus, superior frontal gyrus, superior parietal lobule, and supramarginal gyrus, were significantly higher than that of the placebo condition. However, the anterior cingulate cortex (ACC) was activated under the non-placebo condition but not in the placebo one. The functional connectivities between ACC and orbitofrontal cortex, and the dorsolateral prefrontal cortex and orbitofrontal cortex were reduced under placebo condition. CONCLUSION: Participants demonstrated similar brain activation patterns for orthodontic pain with or without placebos. With placebo, reduced activation in primary sensory cortex and decreased activation in ACC indicated that ACC could be fundamental in analgesia.

The Role of Acid-sensing Ion Channel 3 in the Modulation of Tooth Mechanical Hyperalgesia Induced by Orthodontic Tooth Movement.

This study aimed to explore the role of acid-sensing ion channel 3 (ASIC3) in the modulation of tooth mechanical hyperalgesia induced by orthodontic tooth movement. In male Sprague-Dawley rats, closed coil springs were ligated between mandibular incisors and molars to mimic orthodontic tooth movement. Bite force was assessed to evaluate tooth mechanical hyperalgesia. The alveolar bone, trigeminal ganglia, and trigeminal nucleus caudalis underwent immunohistochemical staining and immunoblotting for ASIC3. The inferior alveolar nerves were transected to explore the interaction between the periodontal sensory endings and trigeminal ganglia. The role of ASIC3 in trigeminal ganglia was further explored with lentivirus-mediated ASIC3 ribonucleic acid interference. Results showed that ASIC3 was expressed in the periodontal Ruffini endings and expression of ASIC3 protein was elevated in periodontal tissues, trigeminal ganglia, and trigeminal nucleus caudalis, following orthodontic tooth movement. ASIC3 agonists and antagonists significantly aggravated and mitigated tooth mechanical hyperalgesia, respectively. ASIC3 expression decreased after inferior alveolar nerve transection in periodontal tissues. Both in vitro and vivo, the lentivirus vector carrying ASIC3 shRNA inhibited ASIC3 expression and relieved tooth mechanical hyperalgesia. To conclude, ASIC3 is important in the modulation of tooth mechanical hyperalgesia induced by orthodontic tooth movement. Further, the role of ASIC3 in the modulation of pain in periodontal tissues is regulated by trigeminal ganglia. An adjuvant analgesic therapy targeting ASIC3 could alleviate orthodontic movement-associated mechanical hyperalgesia in rats.

Transient receptor potential Vanilloid 1-based gene therapy alleviates orthodontic pain in rats.

Orthodontic pain that is induced by tooth movement is an important sequela of orthodontic treatment and has a significant effect on patient quality of life. Studies have shown that the high expression of transient receptor potential vanilloid 1 (TRPV1) in trigeminal ganglions plays a vital role in the transmission and modulation of orofacial pain. However, little is known about the role of TRPV1 in orthodontic pain. In this study, male Sprague-Dawley rats were randomly assigned to six groups to study the role of TRPV1 in the modulation of tooth-movement pain. The expression levels of TRPV1 mRNA and protein were determined by real-time PCR and western blot, respectively. Moreover, pain levels were assessed using the rat grimace scale (RGS). The role of TRPV1 in modulating tooth-movement pain was examined by injecting a TRPV1 antagonist into the trigeminal ganglia of rats. A lentivirus containing a TRPV1 shRNA sequence was constructed and transduced into the rats' trigeminal ganglia. The results showed that the expression levels of TRPV1 protein and mRNA were elevated following tooth-movement pain. Pain levels increased rapidly on the 1st day, peaked on the 3rd day and returned to baseline on the 14th day. The TRPV1 antagonist significantly reduced tooth-movement pain. The lentivirus containing a TRPV1 shRNA sequence was able to inhibit the expression of TRPV1 and relieved tooth-movement pain. In conclusion, TRPV1-based gene therapy may be a treatment strategy for the relief of orthodontic pain.

Bite force measurements for objective evaluations of orthodontic tooth movement-induced pain in rats.

OBJECTIVE: To examine the reliability of bite force for evaluating orthodontic tooth movement-induced pain in rats. DESIGN: Orthodontic tooth movement-induced pain was induced by mounting springs (40 g) between incisors and ipsilateral molars in male Sprague-Dawley rats. Five group sets of animals were used: for the first group set, 20 rats were randomly divided into a force group (n = 10) and a sham group (n = 10); for the second group set, 20 rats were divided into a 20-g group and a 80-g group; for the third group set, 20 rats were randomly divided into either a CFA group (complete freund's adjuvant) (n = 10) receiving periodontal injections of CFA at baseline or a control group (n = 10) receiving periodontal injections of saline at baseline; for the forth group set, 24 rats were randomly divided into the following four groups: force + saline, control + saline, force + antiNGF and control + NGF (NGF: nerve growth factor). Rats in the fifth group set were used for immunostaining against CGRP. Bite force and bite frequency were measured at baseline (day 0) and following interventions (day 1, day 3, day 5, day 7 and day 14). Two-way ANOVA with repeated measures was used for statistical analysis and a p value less than 0.05 was considered statistical significance. RESULTS: Our results revealed that bite force was significantly smaller in the force group than in the sham group at all time points (p < .001). As compared to the control group, periodontal injections of CFA significantly decreased bite force on the 3rd day (p < .01). Moreover, bite force was significantly higher in the force + antiNGF group than in the force + saline group (p = .01 < .05) while significantly smaller in the control + NGF group than in the control + saline group (p < .05). Bite force was similar between the force + antiNGF group and the control + saline group (p = .71 > .05) and between the control + NGF group and the force + saline group (p = .58 > .05). Similar results were found for bite frequency.

A novel technique of delivering viral vectors to trigeminal ganglia in rats.

The objective of this study was to develop a viable and reliable technique of delivering viral vectors to rat trigeminal ganglia. Adult Sprague-Dawley rats (200-300 g) were used, and lentiviral vectors containing enhanced green fluorescence protein and calcitonin gene-related peptide short hairpin RNA (shRNA) were generated. Following general anesthesia, viral vectors were delivered to rat trigeminal ganglia using the technique described in this study. Both X-ray and micro-computed tomography (micro-CT) were employed to verify the position of the needles when injecting the vectors. In vivo fluorescence imaging and immunostaining against enhanced green fluorescence protein were performed to determine the success of viral transduction.The levels of calcitonin gene-related peptide in trigeminal ganglia were determined using real-time PCR, and pain levels following injections were evaluated using the Rat Grimace Scale. Our results show that injection needles can be advanced precisely at the trigeminal fossa and that viral vectors can successfully transduce trigeminal ganglia. Moreover, the levels of calcitonin gene-related peptide at trigeminal ganglia were down-regulated on day 7 after viral transduction. Pain levels returned to baseline by day 7 following injection. Therefore, we suggest that our trigeminal ganglion-targeting technique could be used for delivering genes or drugs to rat trigeminal ganglia.

The role of periodontal ASIC3 in orofacial pain induced by experimental tooth movement in rats.

OBJECTIVES: This study aimed to clarify the roles of Acid-sensing ion channel 3 (ASIC3) in orofacial pain following experimental tooth movement. MATERIALS AND METHODS: Sixty male Sprague-Dawley rats were divided into the experimental group (40g, n = 30) and the sham group (0g, n = 30). Closed coil springs were ligated between maxillary incisor and molars to achieve experimental tooth movement. Rat grimace scale (RGS) scores were assessed at 0, 1, 3, 5, 7, and 14 days after the placement of the springs. ASIC3 immunostaining was performed and the expression levels of ASIC3 were measured through integrated optical density/area in Image-Pro Plus 6.0. Moreover, 18 rats were divided into APETx2 group (n = 6), amiloride group (n = 6), and vehicle group (n = 6), and RGS scores were obtained compared among them to verify the roles of ASIC3 in orofacial pain following tooth movement. RESULTS: ASIC3 expression levels became significantly higher in the experimental group than in sham group on 1, 3, and 5 days and became similar on 7 and 14 days. Pain levels (RGS scores) increased in both groups and were significantly higher in the experimental group on 1, 3, 5, and 7 days and were similar on 14 days. Periodontal ASIC3 expression levels were correlated with orofacial pain levels following experimental tooth movement. Periodontal administrations of ASIC3 antagonists (APETx2 and amiloride) could alleviate pain. LIMITATION: This study needs to be better evidenced by RNA interference of ASIC3 in periodontal tissues in rats following experimental tooth movement. Moreover, we hope further studies would concentrate on the pain perception of ASIC3 knockout (ASIC3-/-) mice. CONCLUSIONS: Our results suggest that periodontal ASIC3 plays an important role in orofacial pain induced by experimental tooth movement.

The effects of blocking N/OFQ receptors on orofacial pain following experimental tooth movement in rats.

OBJECTIVE: The aim of this study was to determine the effects of nociceptin/orphanin FQ peptide receptor (N/OFQ receptor) antagonist on orofacial pain induced by experimental tooth movement in rats. METHODS: A total of 36 male Sprague-Dawley rats weighing 200-300 g were divided into six groups: a control group, force group, force+saline intraperitoneal group, force+saline periodontal group, force+UFP-101 ([Nphe¹,Arg¹4,Lys¹5]N/OFQ-NH 2 antagonist for N/OFQ receptor) intraperitoneal group, and force+UFP-1 01 periodontal group. Closed coil springs were ligated between the upper incisors and first molar to exert an orthodontic force (40 g) between the teeth. Injectable administration dosages were 30 µl saline or 30 µl saline containing 0.03 mg/kg UFP-1 01. Following the injections, orofacial pain levels were assessed through directed face grooming (mouth wiping). Statistical analyses were performed in SPSS 17.0 (Statistical Package for the Social Sciences) and p values less than 0.05 were considered as statistically significant. RESULTS: Orofacial pain levels were significantly higher in the force group than in the control group. Orofacial pain levels differed significantly between the force)group, force+saline periodontal group and force+UFP-101 periodontal group, but were similar between the control group, force+UFP-101 intraperitoneal group and force+saline intraperitoneal group. Moreover, orofacial pain levels did not differ between the force group, force+saline intraperitoneal group and force+UFP-1 01 intraperitoneal group. CONCLUSIONS: Periodontal, but not intraperitoneal, administration of UFP-101 could alleviate orofacial pain induced by experimental tooth movement in rats, suggesting that periodontal N/OFQ receptors participate in orofacial pain induced by experimental tooth movement.

DNA degradation within mouse brain and dental pulp cells 72 hours postmortem.

In this study, we sought to elucidate the process of DNA degradation in brain and dental pulp cells of mice, within postmortem 0-72 hours, by using the single cell gel electrophoresis assay and professional comet image analysis and processing techniques. The frequency of comet-like cells, the percentage of tail DNA, tail length, tail moment, Olive moment and tail area increased in tandem with increasing postmortem interval. In contrast, the head radius, the percentage of head DNA and head area showed a decreasing trend. Linear regression analysis revealed a high correlation between these parameters and the postmortem interval. The findings suggest that the single cell gel electrophoresis assay is a quick and sensitive method to detect DNA degradation in brain and dental pulp cells, providing an objective and accurate new way to estimate postmortem interval.

[Comprehensive traditional Chinese medicine intervention for perimenopausal syndrome in women: a community study].

BACKGROUND: As perimenopausal syndrome is a particularly disturbing condition to the patient, it is practical and necessary to establish a program of comprehensive traditional Chinese medicine therapy for women with perimenopausal syndrome. OBJECTIVE: To observe the therapeutic effects of a comprehensive traditional Chinese medicine therapy for women with perimenopausal syndrome in the community. DESIGN, SETTING, PARTICIPANTS AND INTERVENTIONS: Women with perimenopausal syndrome who met the inclusion criteria in 3 communities of Shanghai were selected for this study. Comprehensive traditional Chinese medicine therapy, including administration of Chinese herbs, auricular point therapy, psychological counseling and the practice of Tai Chi, was applied for these women. MAIN OUTCOME MEASURES: The modified Kupperman index was measured once every 4 weeks for 12 weeks; the indexes of menopause-specific quality of life (MENQOL) questionnaire were measured before and after the treatment. RESULTS: There was no significant difference in 4 groups of negative conversion ratio of the modified Kupperman index at the 4th, 8th and 12th week, respectively. The indexes of the MENQOL questionnaire showed significant differences in 4 groups before and after the treatment. The overall efficacy rate of the comprehensive traditional Chinese medicine therapy in women with perimenopausal syndrome achieved 97.84% at the 8th and the 12th week. CONCLUSION: The comprehensive traditional Chinese medicine therapy can achieve significant improvements in women with perimenopausal syndrome who exhibit both physical and psychological symptoms. With such significant clinical effects, the comprehensive traditional Chinese medicine therapy should be promoted in the community.