Efficacy of a Novel Pleiotropic MMP-Inhibitor, CMC2.24, in a Long-Term Diabetes Rat Model with Severe Hyperglycemia-Induced Oral Bone Loss.

Purpose: CMC2.24, a novel 4-(phenylaminocarbonyl)-chemically-modified-curcumin, is a pleiotropic MMP-Inhibitor of various inflammatory/collagenolytic diseases including periodontitis. This compound has demonstrated efficacy in host modulation therapy along with improved resolution of inflammation in various study models. The objective of current study is to determine the efficacy of CMC2.24 in reducing the severity of diabetes, and its long-term role as an MMP-inhibitor, in a rat model. Methods: Twenty-one adult male Sprague-Dawley rats were randomly distributed into three groups: Normal (N), Diabetic (D) and Diabetic+CMC2.24 (D+2.24). All three groups were orally administered vehicle: carboxymethylcellulose alone (N, D), or CMC2.24 (D+2.24; 30mg/kg/day). Blood was collected at 2-months and 4-months' time-point. At completion, gingival tissue and peritoneal washes were collected/analyzed, and jaws examined for alveolar bone loss by micro-CT. Additionally, sodium hypochlorite(NaClO)-activation of human-recombinant (rh) MMP-9 and its inhibition by treatment with 10µM CMC2.24, Doxycycline, and Curcumin were evaluated. Results: CMC2.24 significantly reduced the levels of lower-molecular-weight active-MMP-9 in plasma. Similar trend of reduced active-MMP-9 was also observed in cell-free peritoneal and pooled gingival extracts. Thus, treatment substantially decreased conversion of pro- to actively destructive proteinase. Normalization of the pro-inflammatory cytokine (IL-1ß, resolvin-RvD1), and diabetes-induced osteoporosis was observed in presence of CMCM2.24. CMC2.24 also exhibited significant anti-oxidant activity by inhibiting the activation of MMP-9 to a lower-molecular-weight (82kDa) pathologically active form. All these systemic and local effects were observed in the absence of reduction in severity of hyperglycemia. Conclusion: CMC2.24 reduced activation of pathologic active-MMP-9, normalized diabetic osteoporosis, and promoted resolution of inflammation but had no effect on the hyperglycemia in diabetic rats. This study also highlights the role of MMP-9 as an early/sensitive biomarker in the absence of change in any other biochemical parameter. CMC2.24 also inhibited significant activation of pro-MMP-9 by NaOCl (oxidant) adding to known mechanisms by which this compound treats collagenolytic/inflammatory diseases including periodontitis.

Thermal Effects of Diode Laser-Irradiation on Titanium Implants in Different Room Temperatures In Vitro.

Objective: The aim of this study was to determine the thermal effects of diode laser irradiation on titanium implants. Methods: An implant (3.5 × 11 mm) was placed into a bovine bone block. A three-wall intrabony defect was created to simulate peri-implant defect. Two thermocouples were secured to the apical and coronal surfaces to measure temperature changes (ΔT) during irradiation. The block was placed in a 37°C water bath and at room temperature (21°C). The defect was irradiated with different diode lasers (fiber 300 µm), while the coronal part of the implant was slightly emerging from the water. While the laser tip was positioned parallel to the implant, the defect was irradiated for 30 sec at 2 W in continuous and pulsed mode. Twenty laser irradiations were performed for each laser wavelength for assessment of ΔT. The linear mixed model was used for comparative statistics. Results: The 980 nm pulsed laser resulted in the highest ΔT (°C) at the coronal (22.45 ± 2.1/14.15 ± 0.13) and apical level (5.4 ± 0.56/3.56 ± 0.35) when this laser was used in both room temperature and water bath conditions, respectively. Similarly, highest ΔT (p < 0.0001) for the 810 nm was 14.3 ± 1.6/12.51 ± 0.63 and apical 3.42 ± 0.52/2.58 ± 0.25, for the 970 nm was 13 ± 1.4/9.93 ± 0.47 and apical 2.89 ± 0.19/2.01 ± 0.19 compared to the 940 nm laser coronally 10.1 ± 0.6/9.19 ± 0.35 and apically 1.67 ± 0.34/1.80 ± 0.17. The coronal part of the implant surpassed the critical threshold of 10°C when irradiated with each of the lasers in the room temperature conditions. Conclusions: Within the limitations of the study, the 940 nm laser seems to control better the risks of overheating during implant irradiation.

Clinical and Radiographic Evaluation of a Novel Triangular Implant Neck Design: A Case Series.

The objective of this study was to evaluate the clinical and radiographic behavior of a novel triangular neck implant configuration in partially edentulous patients. Sixteen patients with a mean age of 58.3 years, were rehabilitated with 25 implants inserted in the healed sites of the maxilla and mandible; implant diameter was Ø3.3 and 3.9 mm. Clinical and radiographic measurements were first performed at prosthesis delivery that served as baseline; they were further evaluated after a mean period of 15.6 months. The interproximal peri-implant bone levels were the primary outcome; the mesial and distal data were recorded and a mean value was calculated. Secondary outcomes included peri-implant probing depth (PPD) and bleeding on probing (BoP). The paired t-test was used to compare the radiographic and clinical outcomes between baseline and follow-up. The mean bone levels at the mesial and distal aspects at baseline were 0.45 (0.47) and 0.57 (0.69), respectively; at follow-up they were 0.59 (0.42) and 0.78 (0.59), respectively. The differences were not statistically significant. Similarly, no significant differences were found for the clinical parameters. Within the limitations of the present study, it could be concluded that this new triangular neck bone level implant macro-design was used successfully to treat partially edentulous patients. Larger controlled clinical studies are warranted to confirm the present radiographic and clinical findings.

A prospective study of peer victimization and depressive symptoms among left-behind children in rural China: the mediating effect of stressful life events.

BACKGROUND: The Ministry of Civil Affairs of the People's Republic of China reported that in 2018, 6.97 million left-behind children (LBC), children who live in rural areas away from their parents, were being cared for by grandparents, relatives, elder siblings, or often living alone. Their parents have migrated to cities for better income opportunities. While a number of studies have detailed elevated depressive symptoms among LBC, relatively little is known about the causes of poorer mental health in LBC. METHODS: This study used longitudinal data to examine associations between peer victimization, stressful life events, and depressive symptom severity in LBC from four randomly-selected middle schools in Guizhou Province, China. A total of 862 children aged 11-18 years, with 472 LBC (54.76%) and 390 non-left-behind children (NLBC) (45.24%), were included in the analysis. T-test was used to compare the depressive symptoms, peer victimization, and stressful life events between LBC and NLBC at baseline and follow-up (6 months later). Multivariable linear regression models were used to examine the mediation effect of follow-up stressful life events on the relationship between baseline peer victimization and follow-up depressive symptoms among LBC. RESULTS: Results suggested that LBC had higher peer victimization and stressful life events than NLBC (ß = 1.28, p = 0.04), and peer victimization and stressful life events at baseline were associated with increased follow-up depressive symptoms among LBC (Peer victimization: ß = 0.25, p < 0.0001; Stressful life events: ß = 0.15, p < 0.001). Peer victimization affected depressive symptoms partially through stressful life events for female LBC and completely through stressful life events for male LBC, controlling for age, perceived socioeconomic status, and school. CONCLUSIONS: This study highlights the vulnerability of LBC exhibiting negative mental health outcomes as they were found to experience more peer victimization and feel more stressed when stressful life events happened, compared with NLBC. Results of this study suggested that protecting LBC from peer victimization experiences can potentially prevent LBC from experiencing an increased impact of other stressful life events, thus decreasing the likelihood of their depressive symptoms. Intervention design should consider the different mediating effects of stressful life events on the relationship between peer victimization and depressive symptoms among female and male LBC.

Efficacy of Nd:YAG laser-assisted periodontal therapy for the management of periodontitis: A double-blind split-mouth randomized controlled clinical trial.

BACKGROUND: This study aimed to explore the efficacy of Nd:YAG laser-assisted periodontal therapy for management of patients with stage II-IV periodontitis. METHODS: Patients who presented with residual periodontal pockets were enrolled. After non-surgical periodontal therapy (NSPT), test sites received Nd:YAG laser (first entrance to pocket: 3 W, 100 µs, 20 Hz; second entrance: 4 W, 600 µs, 20 Hz) and control sites received placebo (laser off). Periodontal probing depth (PPD), clinical attachment level (CAL), gingival recession (GR), bleeding on probing (BOP), and plaque index (PI) were recorded at baseline and 1, 2, 3, 4 and 6-month visits. RESULTS: Twenty patients completed the 6-month period. Significant reductions in PPD, CAL, BOP, and PI values and a significant increase in GR at all follow-up visits compared to the baseline (all P < 0.001) were revealed in both groups. Test sites showed significantly greater improvement in PPD (P = 0.0002) and greater increase in GR (P < 0.0001) compared to the control sites at 6-month visit. There was no difference between two groups regarding CAL gain through the study period (P = 0.23). CONCLUSION: NSPT+Nd:YAG laser with the current protocol results in greater PPD reduction compared to NSPT alone. However, this reduction is likely because of greater GR rather than attachment gain. Therefore, the adjunction of Nd:YAG laser (with the current setting) to the NSPT for the treatment of residual periodontal pockets did not ameliorate the clinical outcomes (ClinicalTrials.gov ID: NCT03365167).

The association of co-morbid asthma and overweight/obese status with healthcare utilization and caregiver perception of health in children 4-17 years, a NHANES study.

OBJECTIVE: Asthma and obesity are two of the most common chronic childhood illnesses. The purpose of this study was to better understand the relationship between co-morbid asthma and obesity in children aged 4-17 and whether it impacts the caregiver's perception of health and/or healthcare utilization. METHODS: This was a secondary analysis of the National Health and Nutrition Examination Surveys (NHANES) datasets from 2007 to 2018. Cumulative logistic regression models were used to analyze the caregiver's perception of health, received healthcare, and overnight hospital stay as dependent variables. Asthma and weight status were included as covariates, with adjustment for age, income, head of the household's education, gender, race, and insurance. RESULTS: The sample included 15,386 children. When looking at weight status in addition to asthma, compared to caregivers of children with current asthma and normal weight, caregivers of children with current asthma and with obesity are more likely to perceive their children as having worse health (OR = 1.73, 95%CI = [1.30, 2.32], p = 0.0003), and are more likely to have more frequent healthcare utilization but the results did not reach a statistical significance. CONCLUSIONS: Caregiver's perception of overall health was worse in caregivers of those with co-morbid obesity/asthma than in caregivers of children with asthma alone. This indicates that caregivers of children with co-morbid asthma and obesity have insight into their children's condition and may be primed for discussion and counseling in the healthcare setting.

Diode Laser Light Scattering and Temperature Changes Due to Anesthesia Injection in Bovine Tongue Mucosa.

Background and objective: Diode lasers are used in periodontal therapy. Parameters such as wavelength and application mode can affect the laser/tissue interactions, quality of incision, and final outcomes. This study set out to assess the temperature changes in tissue when diode lasers are used for incisions on tissues injected with local anesthetics. Materials and methods: Incisions were made on the surface of bovine tongue parallel to the tongue axis (ex vivo). The tissue was divided into three groups (lidocaine, saline, and a control group with no infiltration). Irradiation was performed with 810 and 980 nm diode lasers. Trials were further divided using noninitiated and initiated tips. A microprobe thermocouple was placed to evaluate the temperature changes. Linear mixed-model with Tukey adjustment was used to make comparisons and p < 0.05 was denoted as statistically significant. Results: The overall group comparisons reveal that the control group mean rise in temperature is lower than both the lidocaine group (p < 0.0001) and the saline group (p < 0.0001). When combining the data in and across each group, the average temperature rise that occurred for incisions made with initiated tips was significantly lower than incisions made with noninitiated tips (p < 0.0001). Combining the data of tip initiation shows that incisions made with a 980 nm laser produced lower temperature changes, than incisions made with an 810 nm laser (p < 0.0001). Conclusions: Infiltration of water-based liquids, such as local anesthetics or saline, causes an increase in tissue temperature during irradiation, especially when noninitiated tips are used. In addition, temperature significantly rises with the use of the 810 compared with the 980 nm diode laser. Therefore, to avoid photothermal damage to the tissue, the use of initiated tips is encouraged and local anesthetics in conjunction with 810 nm diode lasers should be minimized.

Therapeutic potential of a novel semi-synthetic-sulfated-polysaccharide to suppress inflammatory mediators in P. gingivalis LPS stimulated human monocytes/macrophages.

BACKGROUND: Chronic periodontitis is associated with an increased risk for systemic conditions such as cardiovascular disease, diabetes, and osteoporosis. During chronic periodontitis, endotoxin (lipopolysaccharide, LPS) produced by P. gingivalis provokes monocyte accumulation and differentiation into macrophages and increased secretion of pro-inflammatory cytokines and matrix metalloproteases (MMPs). While normal levels of MMPs are important in cellular function, increased levels of cytokines and MMPs can cause connective tissue destruction. RESULTS: In the current study, we investigated the therapeutic capability of a novel semi-synthetic sulfated polysaccharide (SAGE) on the production of cytokines and MMPs by cultured human mononuclear cells and macrophages stimulated with endotoxin LPS produced by P. gingivalis, a periodontally-relevant cell culture model. Our research demonstrated SAGE inhibited the LPS induced synthesis of inflammatory mediators including TNF-α, IL-1ß, PGE2, and MMP-9 in this periodontal-relevant cell culture model. In addition, TLR-2 and TLR-4 levels were also reduced with the SAGE treatment. CONCLUSIONS: The therapeutic potential of this novel semi-synthetic sulfated polysaccharide compound may help to prevent tissue damage and bone loss in patients with periodontal disease or other inflammatory diseases.

Orthopaedic Surgeon Mental Health During the COVID-19 Pandemic.

Introduction: This study compares rates of depression, suicidal ideation, and burnout among resident/fellow and attending physicians in orthopaedic surgery to other specialties during height/end of the first wave of the coronavirus disease 2019 (COVID-19) pandemic at our institution. Main outcomes and measures included suicidal ideation, Patient Health Questionnaire for Depression (PHQ-9) scores for depression, and 2 single-item measures for emotional exhaustion and depersonalization. This study provides valuable information regarding orthopaedic surgeon mental health during world crises. Methods: This is a cross-sectional survey-based study of resident, fellow, and attending physicians from 26 specialties during and after the first wave of the COVID-19 pandemic at our institution from April 24, 2020 to May 15, 2020. The survey contained 22 items. This includes consent, demographics and general data, 2 single-item questions of emotional exhaustion and depersonalization, and the PHQ-9. Subjects were eligible if they were a resident/fellow or attending physician at our institution. Results: The response rate for the study was 16.31%. Across all specialties rates were 6.2% depression, 19.6% burnout, and 6.6% suicidal ideation. The results for orthopaedic surgeons are as follows: 0% tentative diagnosis of depression, 3.8% suicidal ideation, and 4% burnout. Anesthesiology had the highest rate of depression (14.3%). Internal medicine and other non-surgical specialties had the highest rate of suicidal ideation (10.2%). Orthopaedic surgeons were significantly more likely to achieve work-life balance and experience less burnout than anesthesiologists and pediatricians. Discussion: Depression, suicidal ideation, and burnout continue to affect physicians across all specialties. These issues are amplified in light of crisis. Job satisfaction and rigorous training may be protective factors that allow orthopaedic surgeons to adapt to novel clinical settings under stress when compared to anesthesiologists and pediatricians. Resilience training and stress management strategies should continue to be investigated to better prepare physicians for world crises.

Depression, Suicidal Thoughts, and Burnout Among Physicians During the COVID-19 Pandemic: a Survey-Based Cross-Sectional Study.

OBJECTIVES: Frontline workers have been a bulwark in the fight against COVID-19, while being subject to major unexpected stressors. These include conflicting news, evolving guidelines, perceived inadequate personal protective equipment, overflow of patients with rising death counts, absence of disaster training, and limitations in the implementation of social distancing. This study investigates the incidence and associated factors of depression, suicidal thoughts, and burnout among physicians during the COVID-19 pandemic. METHODS: In a cross-sectional survey-based study of resident, fellow, and attending physicians from a tertiary university hospital during the height of the COVID-19 pandemic in New York from April 24 to May 15, 2020, demographics and practice specialty, attending vs. resident/fellow status, call frequency, emotional exhaustion, depersonalization, and depression severity were examined. RESULTS: Two hundred twenty-five subjects completed the survey (response rate of 16.3%), with rates of 6.2% depression, 6.6% suicidal ideation, and 19.6% burnout. Depression, suicidal ideation, and burnout were all associated with history of prior depression/anxiety and frequency of on call. Suicidal ideation and burnout were also associated with younger age. There was no difference in rates of depression, suicidal ideation, or burnout between attending and resident physicians. Female physicians reported less work-life balance and more burnout. CONCLUSIONS: These findings highlight the importance of considering physician mental health during times of peak stress, such as natural or man-made disasters. The prominence of premorbid depression/anxiety as a relevant factor underscores the need to further understand physician mental health and provide early screening and treatment.

Impact of Multidisciplinary Team Management on the Survival Rate of Head and Neck Cancer Patients: A Cohort Study Meta-analysis.

Background: Head and neck cancer (HNC) is one of the more common malignant tumors that threaten human health worldwide. Multidisciplinary team management (MDTM) in HNC treatment has been introduced in the past several decades to improve patient survival rates. This study reviewed the impact of MDTM on survival rates in patients with HNC compared to conventional treatment methods. Methods: Only cohort studies were identified for this meta-analysis that included an exposure group that utilized MDTM and a control group. Heterogeneity and sensitivity also were assessed. Survival rate data for HNC patients were analyzed using RevMan 5.2 software. Results: Five cohort studies (n = 39,070) that examined survival rates among HNC patients were included. Hazard ratios (HR) were calculated using the random effect model. The results revealed that exposure groups treated using MDTM exhibited a higher survival rate [HR = 0.84, 95% CI (0.76-0.92), P = 0.0004] with moderate heterogeneity (I 2 = 68%, p = 0.01). For two studies that examined the effect of MDTM on the survival rate for patients specifically with stage IV HNC, MDTM did not produce any statistically significant improvement in survival rates [HR = 0.81, 95% CI (0.59-1.10), p = 0.18]. Conclusions: The application of MDTM based on conventional surgery, radiotherapy, and chemotherapy improved the overall survival rate of patients with HNC. Future research should examine the efficacy of MDTM in patients with cancer at different stages.

Anti-inflammatory effect of salt water and chlorhexidine 0.12% mouthrinse after periodontal surgery: a randomized prospective clinical study.

OBJECTIVES: The purpose of this study was to compare the anti-inflammatory efficacy of sodium chloride- and a 0.12% chlorhexidine mouth rinses in patients undergoing minimal invasive periodontal surgery. MATERIALS AND METHODS: Forty-seven patients with a diagnosis of periodontitis and indication for access flap procedure were randomly selected. Group A: a sodium chloride (salt)water-based mouth rinse (test group) or group B: a 0.12% chlorhexidine mouth rinse (control group) administered after surgery. Gingival Index (GI) were evaluated in the whole mouth and in the surgical site at baseline (T1), a week later (T2), and 12 weeks (T3) after the treatment. Total MMP activity was measured in GCF using a commercial kit and plate reader. Medians of total MMP activity and GI were compared for time intervals T1 vs. T2, T1 vs. T3, and T2 vs T3 using Friedman tests and Wilcoxon signed rank tests, and were also compared between test and control using Mann-WhitneyU tests at each timepoint. RESULTS: The average GI values showed significant differences between baseline and T2 (p = 0.0005) and baseline and T3 (p = 0.003) in the test group. CONCLUSION: The sodium chloride-mouth rinse use after periodontal surgery seems to have similar anti-inflammatory properties as CHX mouth rinse and can be used regularly postoperatively after periodontal surgical procedures. CLINICAL RELEVANCE: The use of salt water mouthwash showed an anti-inflammatory effect similar to CHX 0.12% after minimal invasive periodontal surgery. Salt water mouthwash is accessible to the world population and can contribute on the healing process after periodontal surgery.

Examination of physician factors influencing psychiatric assessment of acutely suicidal patients.

Suicide risk assessment is a subjective process and remains a clinical challenge in psychiatry. We aimed to examine physicians' characteristics that influence management of acutely suicidal patients. In a cross-sectional design, we performed an anonymous internet survey of psychiatry residents and attendings from four academic centers. Gender, years of experience, practice setting, prior patient suicide, and personal exposure to suicide were characterized. Participants were presented with three clinical vignettes and asked to rate suicide risk and clinical disposition. The relationship between responses to the vignettes and physician characteristics were examined with generalized linear models. Fifty-four residents and 49 attendings completed the survey. Four (7%) residents and 24 (49%) attendings had patients die by suicide, whereas 32 (59%) and 36 (74%), respectively, knew somebody outside their practice who died by suicide. Among residents, lower rating of acute suicide risk was associated with prior exposure to non-patient suicide. Less hospitalization chosen by attendings was associated with greater perceived difficulty of suicide risk assessment. In the combined resident and attending sample, less proneness to hospitalize was associated with number of previous patients die by suicide and with outpatient practice. Our results suggest that previous exposure to suicide is associated with more risk-averse management.

Meta-analysis of randomized controlled trials of galantamine in schizophrenia: significant cognitive enhancement.

Cognitive impairments are core features of schizophrenia and the best predictor of functional outcome. Cholinergic system and alpha-7 nicotinic acetylcholine (α7nACh) receptors are strongly implicated in the pathophysiologic mechanisms associated with cognitive impairments in schizophrenia. Galantamine is not only a reversible, competitive inhibitor of acetylcholinesterase but also a type I positive allosteric modulator of α7nACh receptors. The objective of this meta-analysis was to examine the efficacy of galantamine for cognitive symptoms of schizophrenia. In the meta-analysis that included six randomized controlled trials (RCTs, N=226), cognitive impairments significantly improved with galantamine compared to placebo, with a small Hedges' g effect size of 0.233. This finding is consistent with other RCTs in schizophrenia with medications with a similar mechanism of action. On the basis of the results from all the failed (although some efficacy has been shown) RCTs to date in schizophrenia, targeting only one pathophysiologic mechanism may be insufficient to detect a clinically meaningful signal. Nicotinergic medications, like any other add-on medications, are unlikely to be effective as stand-alone medications. Hence, these medications may have to be combined with other medications with complementary mechanisms such as glutamatergic/N-methyl-D-aspartate systems to detect a meaningful effect size for the three domains of psychopathology.

Chemically-Modified Curcumin 2.24: A Novel Systemic Therapy for Natural Periodontitis in Dogs.

PURPOSE: To determine the effect of a pleiotropic MMP-inhibitor, a novel chemically-modified curcumin 2.24 (CMC2.24), on the clinical and biological measures of naturally-occurring periodontitis in the beagle dog. METHODS: Eight adult female dogs with generalized periodontitis were distributed into two groups: Placebo and Treatment (n=4/group). After a 1-hr full-mouth scaling and root planing (SRP) at time 0, placebo or CMC2.24 (10mg/kg) capsules were orally administered once/day for 3 months. Various clinical periodontal parameters (e.g., pocket depth, gingival index) were measured at different time periods (0, 1, 2 and 3 months), and gingival crevicular fluid (GCF) samples and gingival tissue biopsies (3-month) were analyzed for cytokines, MMPs and cell-signaling molecules. Standardized radiographs were taken at 0 and 3-month; in addition, peripheral blood monocytes/macrophages from these dogs at 3-month were cultured and analyzed for the pro-, activated-, and total-forms of both MMP-2 and MMP-9. RESULTS: CMC2.24 treatment significantly reduced gingival inflammation (gingival index, GCF flow), pocket depth (PD), and the numbers of pockets (PD≥4mm), compared to placebo. CMC2.24 also significantly reduced MMP-9 and MMP-2 (primarily in the activated-form) in gingival tissue, alveolar bone loss, and reduced GCF IL-1ß. Cell-signaling molecules, TLR-2 (but not TLR-4) and p38 MAPK, responded to CMC2.24 in a pattern consistent with reductions in inflammation and collagenolysis. In culture, CMC2.24 had no effect on pro-MMP-9 but essentially completely blocked the conversion of pro- to activated-MMP-9 in systemic blood-derived monocytes/macrophages from these dogs. CONCLUSION: In the beagle dog model of natural periodontitis, orally administered CMC2.24 (a novel triketonic phenylaminocarbonyl-curcumin) significantly decreased clinical measures of periodontitis as well as pro-inflammatory cytokines, MMPs, and cell-signaling molecules. These and previous studies, using other in vitro and in vivo models, support the clinical potential of CMC2.24 as a novel adjunct to SRP in the treatment of chronic periodontitis.