Dose adjustment of paroxetine based on CYP2D6 activity score inferred metabolizer status in Chinese Han patients with depressive or anxiety disorders: a prospective study and cross-ethnic meta-analysis.

BACKGROUND: Understanding the impact of CYP2D6 metabolism on paroxetine, a widely used antidepressant, is essential for precision dosing. METHODS: We conducted an 8-week, multi-center, single-drug, 2-week wash period prospective cohort study in 921 Chinese Han patients with depressive or anxiety disorders (ChiCTR2000038462). We performed CYP2D6 genotyping (single nucleotide variant and copy number variant) to derive the CYP2D6 activity score and evaluated paroxetine treatment outcomes including steady-state concentration, treatment efficacy, and adverse reaction. CYP2D6 metabolizer status was categorized into poor metabolizers (PMs), intermediate metabolizers (IMs), extensive metabolizers (EMs), and ultrarapid metabolizers (UMs). The influence of CYP2D6 metabolic phenotype on paroxetine treatment outcomes was examined using multiple regression analysis and cross-ethnic meta-analysis. The therapeutic reference range of paroxetine was estimated by receiver operating characteristic (ROC) analyses. FINDINGS: After adjusting for demographic factors, the steady-state concentrations of paroxetine in PMs, IMs, and UMs were 2.50, 1.12, and 0.39 times that of EMs, with PM and UM effects being statistically significant (multiple linear regression, P = 0.03 and P = 0.04). Sex and ethnicity influenced the comparison between IMs and EMs. Moreover, poor efficacy of paroxetine was associated with UM, and a higher risk of developing adverse reactions was associated with lower CYP2D6 activity score. Lastly, cross-ethnic meta-analysis suggested dose adjustments for PMs, IMs, EMs, and UMs in the East Asian population to be 35%, 40%, 143%, and 241% of the manufacturer's recommended dose, and 62%, 68%, 131%, and 159% in the non-East Asian population. INTERPRETATION: Our findings advocate for precision dosing based on the CYP2D6 metabolic phenotype, with sex and ethnicity being crucial considerations in this approach. FUNDING: National Natural Science Foundation of China; Academy of Medical Sciences Research Unit.

Features of virtual reality impact effectiveness of VR pain alleviation therapeutics in pediatric burn patients: A randomized clinical trial.

Key features of virtual reality (VR) that impact the effectiveness of pain reduction remain unknown. We hypothesized that specific features of the VR experience significantly impact VR's effectiveness in reducing pain during pediatric burn dressing care. Our randomized controlled trial included children 6 to 17 years (inclusive) who were treated in the outpatient clinic of an American Burn Association-verified pediatric burn center. Participants were randomly assigned (1:1:1) to active VR (playing the VR), passive VR (immersed in the same VR environment without interactions), or standard-of-care. On a scale from 0 to 100, participants rated overall pain (primary outcome) and features of the VR experience (game realism, fun, and engagement). Path analysis assessed the interrelationships among these VR key features and their impact on self-reported pain scores. From December 2016 to January 2019, a total of 412 patients were screened for eligibility, and 90 were randomly assigned (31 in the active VR group, 30 in the passive VR group, and 29 in the standard-of-care group). The current study only included those in the VR groups. The difference in median scores of VR features was not statistically significant between the active (realism, 77.5 [IQR: 50-100]; fun, 100 [IQR: 81-100]; engagement, 90 [IQR: 70-100]) and passive (realism, 72 [IQR: 29-99]; fun, 93.5 [IQR: 68-100]; engagement, 95 [IQR: 50-100]) VR distraction types. VR engagement had a significant direct (-0.39) and total (-0.44) effect on self-reported pain score (p<0.05). Key VR features significantly impact its effectiveness in pain reduction. The path model suggested an analgesic mechanism beyond distraction. Differences in VR feature scores partly explain active VR's more significant analgesic effect than passive VR. Trial Registration: ClinicalTrials.gov Identifier: NCT04544631.

Consuming a Linoleate-Rich Diet Increases Concentrations of Tetralinoleoyl Cardiolipin in Mouse Liver and Alters Hepatic Mitochondrial Respiration.

BACKGROUND: Hepatic mitochondrial dysfunction is a major cause of fat accumulation in the liver. Individuals with fatty liver conditions have hepatic mitochondrial structural abnormalities and a switch in the side chain composition of the mitochondrial phospholipid, cardiolipin, from poly- to monounsaturated fatty acids. Linoleic acid (LA), an essential dietary fatty acid, is required to remodel nascent cardiolipin (CL) to its tetralinoleoyl cardiolipin (L4CL, CL with 4 LA side chains) form, which is integral for mitochondrial membrane structure and function to promote fatty acid oxidation. It is unknown, however, whether increasing LA in the diet can increase hepatic L4CL concentrations and improve mitochondrial respiration in the liver compared with a diet rich in monounsaturated and saturated fatty acids. OBJECTIVES: The main aim of this study was to test the ability of a diet fortified with LA-rich safflower oil (SO), compared with the one fortified with lard (LD), to increase concentrations of L4CL and improve mitochondrial respiration in the livers of mice. METHODS: Twenty-four (9-wk-old) C57 BL/J6 male mice were fed either the SO or LD diets for ∼100 d, whereas food intake and body weight, fasting glucose, and glucose tolerance tests were performed to determine any changes in glycemic control. RESULTS: Livers from mice fed SO diet had higher relative concentrations of hepatic L4CL species compared with LD diet-fed mice (P value = 0.004). Uncoupled mitochondria of mice fed the SO diet, compared with LD diet, had an increased baseline oxygen consumption rate (OCR) and succinate-driven respiration (P values = 0.03 and 0.01). SO diet-fed mice had increased LA content in all phospholipid classes compared with LD-fed mice (P < 0.05). CONCLUSIONS: Our findings reveal that maintaining or increasing hepatic L4CL may result in increased OCR in uncoupled hepatic mitochondria in healthy mice whereas higher oleate content of CL reduced mitochondrial function shown by lower OCR in uncoupled mitochondria.

Success of Pulpal Anesthesia Following Buccal Infiltration of the Maxillary First Molar With 1.8 mL and 3.6 mL of 4% Articaine With 1:100,000 Epinephrine: A Prospective, Randomized Crossover Study.

OBJECTIVE: The purpose of this prospective, randomized crossover study was to compare the peak incidence of success, onset, and incidence over time of pulpal anesthesia in maxillary first molars following a buccal infiltration of 1.8 mL or 3.6 mL of 4% articaine with 1:100 000 epinephrine. METHODS: A total of 118 adults received 1.8 mL or 3.6 mL of 4% articaine with 1:100 000 epinephrine via buccal infiltration of the maxillary first molar at 2 separate appointments. Electric pulp testing (EPT) of the maxillary first molar was performed over 68 minutes. RESULTS: There was no significant difference in the peak incidence of anesthetic success (85% and 92%, respectively) in the maxillary first molar between 1.8 mL and 3.6 mL. The difference in onset times (4.5 min for 1.8 mL vs 4.4 min for 3.6 mL) was not statistically significant. However, the 3.6-mL volume did produce a significantly higher incidence of pulpal anesthesia from minutes 48 to 68 compared with the 1.8-mL volume. CONCLUSION: There was no significant difference in peak incidence or onset of pulpal anesthesia in the maxillary first molar between 1.8 mL and 3.6 mL of articaine with epinephrine. The incidence of pulpal anesthesia was significantly higher with 3.6 mL of articaine at 48 minutes and beyond, but neither volume provided complete pulpal anesthesia for all subjects that lasted at least 60 minutes.

Articaine Infiltrations of the Mandibular Lateral Incisor-Is It Volume or Location of the Infiltrations That Affect Success? A Prospective, Randomized Crossover Study.

INTRODUCTION: A combination labial infiltration (1.8 mL) plus lingual infiltration (1.8 mL) of 4% articaine with 1:100,000 epinephrine in the mandibular lateral incisor was found superior to a labial infiltration of 1.8 mL of the same solution. However, it is not known whether the volume or the location had the greatest effect. Therefore, the purpose of this prospective, randomized crossover study was to determine the anesthetic efficacy of a labial infiltration of a 3.6 mL volume of 4% articaine with 1:100,000 epinephrine compared with labial infiltration (1.8 mL) plus lingual infiltration (1.8 mL) of 4% articaine with 1:100,000 epinephrine in the mandibular lateral incisor. METHODS: One hundred subjects randomly received 2 sets of injections, using 4% articaine with 1:100,000 epinephrine, consisting of labial and lingual infiltrations of 1.8 mL (3.6 mL total) and 2 labial infiltrations of 1.8 mL (3.6 mL total) of the mandibular lateral incisor in 2 separate appointments. Electric pulp testing was used to determine anesthetic success (highest 80/80 reading). The data were analyzed statistically. RESULTS: The labial and lingual combination exhibited a significantly higher anesthetic success rate (97%) when compared with the 2 labial infiltrations (74%) and had significantly higher 80/80s readings from 1 minute to 58 minutes. CONCLUSIONS: Within the limitations of this clinical study, a combination labial plus lingual infiltration using a 3.6-mL volume of 4% articaine with 1:100,000 epinephrine significantly increased pulpal anesthetic success for the mandibular lateral incisor when compared with a labial infiltration using a 3.6-mL volume of articaine. Therefore, location of the infiltrations was more important than volume.

BatMan: Mitigating Batch Effects Via Stratification for Survival Outcome Prediction.

Reproducible translation of transcriptomics data has been hampered by the ubiquitous presence of batch effects. Statistical methods for managing batch effects were initially developed in the setting of sample group comparison and later borrowed for other settings such as survival outcome prediction. The most notable such method is ComBat, which adjusts for batches by including it as a covariate alongside sample groups in a linear regression. In survival prediction, however, ComBat is used without definable groups for survival outcome and is done sequentially with survival regression for a potentially batch-confounded outcome. To address these issues, we propose a new method called BATch MitigAtion via stratificatioN (BatMan). It adjusts batches as strata in survival regression and uses variable selection methods such as the regularized regression to handle high dimensionality. We assess the performance of BatMan in comparison with ComBat, each used either alone or in conjunction with data normalization, in a resampling-based simulation study under various levels of predictive signal strength and patterns of batch-outcome association. Our simulations show that (1) BatMan outperforms ComBat in nearly all scenarios when there are batch effects in the data and (2) their performance can be worsened by the addition of data normalization. We further evaluate them using microRNA data for ovarian cancer from the Cancer Genome Atlas and find that BatMan outforms ComBat while the addition of data normalization worsens the prediction. Our study thus shows the advantage of BatMan and raises caution about the use of data normalization in the context of developing survival prediction models. The BatMan method and the simulation tool for performance assessment are implemented in R and publicly available at LXQin/PRECISION.survival-GitHub.

Comparison of maxillary anterior tooth movement between Invisalign and fixed appliances.

INTRODUCTION: This research project aimed to compare the number of maxillary incisors and canine movement between Invisalign and fixed orthodontic appliances using artificial intelligence and identify any limitations of Invisalign. METHODS: Sixty patients (Invisalign, n = 30; braces, n = 30) were randomly selected from the Ohio State University Graduate Orthodontic Clinic archive. Peer Assessment Rating (PAR) analysis was used to indicate the severity of the patients in both groups. To analyze the incisors and canine movement, specific landmarks were identified on incisors and canines using an artificial intelligence framework, two-stage mesh deep learning. Total average tooth movement in the maxilla and individual (incisors and canine) tooth movement in 6 directions (buccolingual, mesiodistal, vertical, tipping, torque, rotation) were then analyzed at a significance level of α = 0.05. RESULTS: Based on the posttreatment Peer Assessment Rating scores, the quality of finished patients in both groups was similar. In maxillary incisors and canines, there was a significant difference in movement between Invisalign and conventional appliances for all 6 movement directions (P <0.05). The greatest differences were with rotation and tipping of the maxillary canine, along with incisor and canine torque. The smallest statistical differences observed for incisors and canines were crown translational tooth movement in the mesiodistal and buccolingual directions. CONCLUSIONS: When comparing fixed orthodontic appliances to Invisalign, patients treated with fixed appliances were found to have significantly more maxillary tooth movement in all directions, especially with rotation and tipping of the maxillary canine.

Targeting NFE2L2/KEAP1 Mutations in Advanced NSCLC With the TORC1/2 Inhibitor TAK-228.

INTRODUCTION: Increased insight into the mutational landscape of squamous cell lung cancers (LUSCs) in the past decade has not translated into effective targeted therapies for patients with this disease. NRF2, encoded by NFE2L2, and its upstream regulator, KEAP1, control key aspects of redox balance and are frequently mutated in NSCLCs. METHODS: Here, we describe the specific potent activity of TAK-228, a TORC1/2 inhibitor, in NSCLC models harboring NRF2-activating alterations and results of a phase 2 clinical trial of TAK-228 in patients with advanced NSCLC harboring NRF2-activating alterations including three cohorts (NFE2L2-mutated LUSC, KEAP1-mutated LUSC, KRAS/NFE2L2- or KEAP1-mutated NSCLC). RESULTS: TAK-228 was most efficacious in a LUSC cohort with NFE2L2 alterations; the overall response rate was 25% and median progression-free survival was 8.9 months. Additional data suggest that concurrent inhibition of glutaminase with the glutaminase inhibitor CB-839 might overcome metabolic resistance to therapy in these patients. CONCLUSIONS: TAK-228 has single-agent activity in patients with NRF2-activated LUSC. This study reframes oncogenic alterations as biologically relevant based on their downstream effects on metabolism. This trial represents, to the best of our knowledge, the first successful attempt at metabolically targeting NSCLC and identifies a promising targeted therapy for patients with LUSC, who are bereft of genotype-directed therapies.

Surviving the shift: College student satisfaction with emergency online learning during COVID-19 pandemic.

BACKGROUND: The coronavirus disease 2019 (COVID-19) epidemic disrupted education systems by forcing systems to shift to emergency online leaning. Online learning satisfaction affects academic achievement. Many factors affect online learning satisfaction. However there is little study focused on personal characteristics, mental status, and coping style when college students participated in emergency online courses. AIM: To assess factors related to satisfaction with emergency online learning among college students in Hebei province during the COVID-19 pandemic. METHODS: We conducted a cross-sectional survey of 1600 college students. The collected information included demographics, psychological aspects of emergent public health events, and coping style. Single factor, correlation, and multiple linear regression analyses were performed to identify factors that affected online learning satisfaction. RESULTS: Descriptive findings indicated that 62.9% (994/1580) of students were satisfied with online learning. Factors that had significant positive effects on online learning satisfaction were online learning at scheduled times, strong exercise intensity, good health, regular schedule, focusing on the epidemic less than one hour a day, and maintaining emotional stability. Positive coping styles were protective factors of online learning satisfaction. Risk factors for poor satisfaction were depression, neurasthenia, and negative coping style. CONCLUSION: College students with different personal characteristics, mental status, and coping style exhibited different degrees of online learning satisfaction. Our findings provide reference for educators, psychologists, and school administrators to conduct health education intervention of college students during emergency online learning.

Assessment of malalignment factors related to the Invisalign treatment time aided by automated imaging processes.

OBJECTIVES: To identify predictors regarding the type and severity of malocclusion that affect total Invisalign treatment duration based on an intraoral digital scan. MATERIALS AND METHODS: The subjects of this retrospective clinical cohort were 116 patients treated with Invisalign. A deep learning method was used for automated tooth segmentation and landmark identification of the initial and final digital models. The changes in the six degrees of freedom (DOF), representing types of malalignment, were measured. Linear regression was performed to find the contributing factors associated with treatment time. In addition, the Peer Assessment Rating (PAR) score and a composite score combining 6 DOF were correlated separately to the treatment time. RESULTS: The number of trays differed between sexes (P = .0015). The absolute maximum torque was marginally associated with the total number of trays (P = .0518), while the rest of the orthodontic tooth movement showed no correlation. The composite score showed a higher correlation with the total number of trays (P = .0045) than did individual tooth movement. Pretreatment upper and lower anterior segment PAR scores were positively associated with the treatment time (P < .001). CONCLUSIONS: There is not enough evidence to conclude that certain types of tooth movement affect the total aligner treatment time. A composite score seems to be a better predictor for total treatment time than do individual malalignment factors in aligner treatment. Upper and lower anterior malalignment factors have a significant effect on the treatment duration.

Contrast weighted learning for robust optimal treatment rule estimation.

Personalized medicine aims to tailor medical decisions based on patient-specific characteristics. Advances in data capturing techniques such as electronic health records dramatically increase the availability of comprehensive patient profiles, promoting the rapid development of optimal treatment rule (OTR) estimation methods. An archetypal OTR estimation approach is the outcome weighted learning, where OTR is determined under a weighted classification framework with clinical outcomes as the weights. Although outcome weighted learning has been extensively studied and extended, existing methods are susceptible to irregularities of outcome distributions such as outliers and heavy tails. Methods that involve modeling of the outcome are also sensitive to model misspecification. We propose a contrast weighted learning (CWL) framework that exploits the flexibility and robustness of contrast functions to enable robust OTR estimation for a wide range of clinical outcomes. The novel value function in CWL only depends on the pairwise contrast of clinical outcomes between patients irrespective of their distributional features and supports. The Fisher consistency and convergence rate of the estimated decision rule via CWL are established. We illustrate the superiority of the proposed method under finite samples using comprehensive simulation studies with ill-distributed continuous outcomes and ordinal outcomes. We apply the CWL method to two datasets from clinical trials on idiopathic pulmonary fibrosis and COVID-19 to demonstrate its real-world application.

Mobile phone virtual reality game for pediatric home burn dressing pain management: a randomized feasibility clinical trial.

BACKGROUND: Virtual reality (VR) gaming is considered a safe and effective alternative to standard pain alleviation in the hospital. This study addressed the potential effectiveness and feasibility of a VR game that was developed by our research team for repeated at-home burn dressing changes. METHODS: A randomized clinical trial was conducted among patients recruited from the outpatient burn clinic of a large American Burn Association-verified pediatric burn center between September 2019 and June 2021. We included English-speaking burn patients aged 5-17 years old requiring daily dressing changes for at least 1 week after first outpatient dressing change. One group played an interactive VR game during dressing changes, while the other utilized standard distraction techniques available in the home for up to a week. Both child and caretaker were asked to assess perceived pain on a numerical rating scale (NRS) of 0-10. For the VR group, patients were also asked to rate various aspects of the VR game on a NRS of 0-10 and caregivers were asked questions assessing ease of use. RESULTS: A total of 35 children were recruited for this study with 24 fully completing study measures. The majority of participants were male (n=19, 54.3%), White (n=29, 82.9%), and with second degree burns (n=32, 91.4%). Children and caregivers in the VR group reported less pain than the control group at the 4th dressing change. Participants in the VR group showed a clinically meaningful (≥30%) reduction in child-reported overall pain (33.3%) and caregiver-reported worst pain (31.6%) in comparison with subjects in the control group. Children's satisfaction with the VR remained at a high level across dressing changes over the 1-week period, with reported realism and engagement increasing over time. Over half of the children (54.5%) enjoyed playing the game and did not report any challenges nor any side effects. CONCLUSIONS: Subjects found the VR to be a useful distraction during home dressing changes and reported no challenges/side effects. VR should be considered as a nonpharmacologic companion for pain management during at-home burn dressing changes. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04548635. Registered September 14, 2020-retrospectively registered.

Statistical methods of indirect comparison with real-world data for survival endpoint under non-proportional hazards.

In clinical studies that utilize real-world data, time-to-event outcomes are often germane to scientific questions of interest. Two main obstacles are the presence of non-proportional hazards and confounding bias. Existing methods that could adjust for NPH or confounding bias, but no previous work delineated the complexity of simultaneous adjustments for both. In this paper, a propensity score stratified MaxCombo and weighted Cox model is proposed. This model can adjust for confounding bias and NPH and can be pre-specified when NPH pattern is unknown in advance. The method has robust performance as demonstrated in simulation studies and in a case study.

Linoleic Acid-Rich Oil Alters Circulating Cardiolipin Species and Fatty Acid Composition in Adults: A Randomized Controlled Trial.

SCOPE: Higher circulating linoleic acid (LA) and muscle-derived tetralinoleoyl-cardiolipin (LA4 CL) are each associated with decreased cardiometabolic disease risk. Mitochondrial dysfunction occurs with low LA4 CL. Whether LA-rich oil fortification can increase LA4 CL in humans is unknown. The aims of this study are to determine whether dietary fortification with LA-rich oil for 2 weeks increases: 1) LA in plasma, erythrocytes, and peripheral blood mononuclear cells (PBMC); and 2) LA4 CL in PBMC in adults. METHODS AND RESULTS: In this randomized controlled trial, adults are instructed to consume one cookie per day delivering 10 g grapeseed (LA-cookie, N = 42) or high oleate (OA) safflower (OA-cookie, N = 42) oil. In the LA-cookie group, LA increases in plasma, erythrocyte, and PBMC by 6%, 7%, and 10% respectively. PBMC and erythrocyte OA increase by 7% and 4% in the OA-cookie group but is unchanged in the plasma. PBMC LA4 CL increases (5%) while LA3 OA1 CL decreases (7%) in the LA-cookie group but are unaltered in the OA-cookie group. CONCLUSIONS: LA-rich oil fortification increases while OA-oil has no effect on LA4 CL in adults. Because LA-rich oil fortification reduces cardiometabolic disease risk and increases LA4 CL, determining whether mitochondrial dysfunction is repaired through dietary fortification is warranted.

Comparison of Maxillary Lateral Incisor Infiltration Pain Using the Dentapen and a Traditional Syringe: A Prospective Randomized Study.

INTRODUCTION: The anterior maxillary infiltration is one of the more painful dental injections. The Dentapen is an electronic syringe that uses computer-controlled delivery technology to administer dental local anesthesia at a slow controlled rate. The purpose of this prospective, randomized, single-blind study was to evaluate solution deposition pain of a maxillary lateral incisor infiltration using the Dentapen with the slow flow rate (1.8 mL/162 sec) and ramp-up setting compared with a traditional syringe infiltration at a flow rate of 1.8 mL/60 sec. METHODS: One hundred thirty adults were administered a maxillary lateral incisor infiltration with the Dentapen and a traditional syringe at 2 separate appointments in a single-blind manner. The infiltrations of 2% lidocaine with 1:100,000 epinephrine were given at a rate of 1.8 mL/162 sec with the ramp-up feature for the Dentapen and 1.8 mL/60 sec for the traditional infiltration. The pain of solution deposition was recorded on a visual analogue scale. At the conclusion of the study, subjects selected their preferred injection technique. The data were analyzed statistically using paired t tests, a mixed-effect model, and odds ratio. RESULTS: The pain of solution deposition was significantly less for the Dentapen injection than the traditional injection (P < .001). With the Dentapen device, 16% experienced moderate pain, and for the traditional syringe, 39% experienced moderate pain. Overall, 75% of subjects preferred the Dentapen injection over the traditional injection. CONCLUSIONS: The Dentapen, using the slow flow rate and ramp-up mode, significantly reduced the pain of solution deposition for maxillary lateral incisor infiltrations.

Titanium as a Possible Modifier of Inflammation Around Dental Implants.

PURPOSE: The exact etiopathogenesis of peri-implant diseases remains unclear. While significant information on molecular markers is available, studies on biomarkers related to possible biocorrosion are sparse. This study aimed to evaluate periimplant crevicular fluid (PICF) for possible titanium (Ti) contamination and explore associations between clinical findings, inflammatory mediators, and Ti levels. MATERIALS AND METHODS: Patients with implant-supported restoration (≥ 1 year in function) were recruited for this cross-sectional study. Demographics, systemic, and periodontal health history were recorded. Clinical evaluations were conducted to reach peri-implant/periodontal diagnoses and grade severity of peri-implant soft tissue inflammation. Crevicular fluid (CF) was collected from both implants and adjacent teeth (PICF, gingival crevicular fluid [GCF]) and analyzed for Ti (inductively coupled plasma mass spectrometry) and inflammatory mediators (V-plex assays). Multiple regression analysis with a linear mixed effect model was used to analyze possible associations between clinical diagnosis, PICF/GCF cytokine, and Ti concentrations. RESULTS: Seventy-seven patients (aged 62 ± 2 years; 39 male) with 117 implants (9 ± 1 years in function) were recruited. Diabetes, positive periodontitis history, and current/former smoking were reported by 8%, 39%, and 39% of subjects, respectively. Seventy-nine implant sites (63 patients) were included in CF cytokine analysis, and 45 of these sites (42 patients) were paired with Ti analysis. Statistically significant increases from health to disease were noted in log-transformed PICF concentrations of IL-1ß, IL-6, IL-10, and INF-γ (P ≤ .05). Also, statistically significant increases from health to severe clinical inflammation were detected in log-transformed PICF concentrations of IL-8, IL-13, and TNF-α (P ≤ .05). Ti was detected in the majority (82%) of PICF and GCF samples. There was no statistically significant difference in log-transformed Ti concentration based on disease status. However, log-transformed Ti concentration was positively correlated to IL-1ß, IL-2, IL-4, IL-8, IL-13, and INF-γ concentrations when data were adjusted for site-specific health (P ≤ .05). CONCLUSION: Ti was detectable in PICF and adjacent GCF, even in health. Specific inflammatory mediator concentrations were increased in peri-implant disease and significantly associated with Ti concentrations, even when data were adjusted for peri-implant health status. Increased GCF inflammatory mediator concentrations were also associated with increased Ti concentrations. Ti effects on peri-implant as well as periodontal tissues require additional longitudinal investigations.

A multifactorial intervention to increase adherence to oral appliance therapy with a titratable mandibular advancement device for obstructive sleep apnea: a randomized controlled trial.

PURPOSE: Obstructive sleep apnea (OSA) is a common chronic condition, associated with several conditions that account for leading causes of mortality. Adherence to treatment of a chronic condition is, along with treatment efficacy, a major determinant of treatment outcome. The aim of this study was to test whether or not a multifactorial intervention in addition to standard care increases adherence rates in patients using a titratable oral appliance for OSA. METHODS: All subjects were 18 years old or older, had a diagnosis of OSA, and were treated with an oral appliance with an embedded sensor to measure appliance wear time objectively. The control group received routine care, while the experimental subjects received an additional multifactorial intervention. Comparison of adherence was at 30 days (Phase I) and 90 days (Phase II) after appliance delivery. RESULTS: Data are reported for 82 subjects in Phase I (control 43; experimental 39) and 66 subjects in Phase II (control 36; experimental 30). There were no significant differences for age, sex, body mass index, and apnea-hypopnea index (p > 0.05) between groups. In both Phase I and Phase II, the mean number of nights the appliance was worn 4 or more hours and the mean time the appliance was worn nightly were significantly greater in the experimental than in the control group (p < 0.05). CONCLUSIONS: Interventions were well received by subjects and can be carried out by auxiliary personnel. The experimental interventions resulted in clinically important and statistically significant improvements in patient adherence to treatment.

Combined oncolytic adenovirus carrying MnSOD and mK5 genes both regulated by survivin promoter has a synergistic inhibitory effect on gastric cancer.

Gastric cancer (GC) is one of the major causes of cancer-related mortality. The use of oncolytic virus for cancer gene-virotherapy is a new approach for the treatment of human cancers. In this study, a novel Survivin promoter-driven recombinant oncolytic adenovirus carrying mK5 or MnSOD gene was constructed, which was modified after deletion of the E1B gene. Human plasminogen Kringle 5 mutant (mK5) and manganese superoxide dismutase (MnSOD) are both potential tumor suppressor genes. By constructing Ad-Surp-mK5 and Ad-Surp-MnSOD oncolytic adenoviruses, we hypothesized that the combination of the two viruses would enhance the therapeutic efficacy of GC as compared to the one virus alone. The results of the in vitro experiments revealed that the combination of adenovirus carrying mK5 and MnSOD gene exhibited stronger cytotoxicity to GC cell lines as compared to the virus alone. Additionally, the virus could selectively kill cancer cells and human somatic cells. Cell staining, flow cytometry, and western blot analysis showed that the combination of two adenoviruses containing therapeutic genes could promote the apoptosis of cancer cells. In vivo experiments further verified that Ad-Surp-mK5 in combination with Ad-Surp-MnSOD exhibited a significant inhibitory effect on the growth of GC tumor xenograft as compared to the virus alone, and no significant difference was observed in the bodyweight of treatment and the normal mice. In conclusion, the combination of our two newly constructed recombinant oncolytic adenoviruses containing mK5 or MnSOD therapeutic genes could significantly inhibit gastric cancer growth by inducing apoptosis, suggestive of its potential for GC therapy.

Zanubrutinib, obinutuzumab, and venetoclax with minimal residual disease-driven discontinuation in previously untreated patients with chronic lymphocytic leukaemia or small lymphocytic lymphoma: a multicentre, single-arm, phase 2 trial.

BACKGROUND: We hypothesised that combining zanubrutinib with obinutuzumab and venetoclax (BOVen) as an initial therapy for chronic lymphocytic leukaemia and small lymphocytic lymphoma would lead to high rates of undetectable minimal residual disease (MRD), and we explored MRD as a biomarker for directing treatment duration. METHODS: This multicenter, investigator-initiated, single-arm, phase 2 trial took place at two two academic medical centres in the USA. Patients were eligible for the primary cohort if they had treatment-naive chronic lymphocytic leukaemia or small lymphocytic lymphoma, required therapy, and were at least 18 years of age with an Eastern Cooperative Oncology Group performance status up to 2. BOVen was administered in 28 day cycles (oral zanubrutinib at 160 mg twice per day starting in cycle 1 on day 1; intravenous obinutuzumab at 1000 mg on day 1 [split over day 1 with 100 mg and day 2 with 900 mg for an absolute lymphocyte count >25 000 cells per µL or lymph nodes >5 cm in diameter], day 8, and day 15 of cycle 1, and day 1 of cycles 2-8; and oral venetoclax ramp up to 400 mg per day starting in cycle 3 on day 1) and discontinued after 8-24 cycles when prespecified undetectable MRD criteria were met in the peripheral blood and bone marrow. The primary endpoint was the proportion of patients that reached undetectable MRD in both the peripheral blood and bone marrow (flow cytometry cutoff less than one chronic lymphocytic leukaemia cell per 10 000 leukocytes [<10-4]) assessed per protocol. This trial is registered at clinicaltrials.gov (NCT03824483). The primary cohort is closed to recruitment, and recruitment continues in the TP53-mutated mantle cell lymphoma cohort. FINDINGS: Between March 14, 2019, and Oct 10, 2019, 47 patients were screened for eligibility, and 39 patients were enrolled and treated. Median age was 62 years (IQR 52-70) with 30 (77%) of 39 male participants and nine (23%) of 39 female participants. 28 (72%) of 39 patients had unmutated immunoglobulin heavy-chain variable-region and five (13%) of 39 had 17p deletion or TP53 mutation. After a median follow-up of 25·8 months (IQR 24·0-27·3), 33 (89%) of 37 patients (95% CI 75-97) had undetectable MRD in both blood and bone marrow, meeting the prespecified undetectable MRD criteria to stop therapy after a median of ten cycles (IQR 8-12), which includes two cycles of zanubrutinib and obinutuzumab before starting venetoclax. After median surveillance after treatment of 15·8 months (IQR 13·0-18·6), 31 (94%) of 33 patients had undetectable MRD. The most common adverse events were thrombocytopenia (23 [59%] of 39), fatigue (21 [54%]), neutropenia (20 [51%]), and bruising (20 [51%]), and the most common adverse event at grade 3 or worse was neutropenia (seven [18%]) in the intention-to-treat population. One death occurred in a patient with intracranial haemorrhage on day 1 of cycle 1 after initiating intravenous heparin for pulmonary emboli. INTERPRETATION: BOVen was well tolerated and met its primary endpoint, with 33 (89%) of 37 previously untreated patients with chronic lymphocytic leukaemia or small lymphocytic lymphoma reaching undetectable MRD in both peripheral blood and bone marrow despite a median treatment duration of only 10 months, owing to our undetectable MRD-driven treatment discontinuation design. These data support further evaluation of the BOVen regimen in chronic lymphocytic leukaemia and small lymphocytic lymphoma with treatment duration guided by early MRD response kinetics. FUNDING: Beigene, Genentech (Roche), Grais-Cutler Fund, Lymphoma Research Fund, Lymphoma Research Foundation, American Cancer Society, Farmer Family Foundation, and the National Instititutes of Health and National Cancer Institute.

Stratified Restricted Mean Survival Time Model for Marginal Causal Effect in Observational Survival Data.

Time to event outcomes is commonly encountered in epidemiologic research. Multiple papers have discussed the inadequacy of using the hazard ratio as a causal effect measure due to its noncollapsibility and the time-varying nature. In this paper, we further clarified that the hazard ratio might be used as a conditional causal effect measure, but it is generally not a valid marginal effect measure, even under randomized design. We proposed to use the restricted mean survival time (RMST) difference as a causal effect measure, since it essentially measures the mean difference over a specified time horizon and has a simple interpretation as the area under survival curves. For observational studies, propensity score adjustment can be implemented with RMST estimation to remove observed confounding bias. We proposed a propensity score stratified RMST estimation strategy, which performs well in our simulation evaluation and is relatively easy to implement for epidemiologists in practice. Our stratified RMST estimation includes two different versions of implementation, depending on whether researchers want to involve regression modeling adjustment, which provides a powerful tool to examine the marginal causal effect with observational survival data.