Recent Submissions

  • The Role of Descending Pain Modulation in Chronic Primary Pain: Potential Application of Drugs Targeting Serotonergic System

    Tao, Z.-Y.; Wang, P.-X.; Traub, R.J. (Hindawi Limited, 2019)
    Chronic primary pain (CPP) is a group of diseases with long-term pain and functional disorders but without structural or specific tissue pathologies. CPP is becoming a serious health problem in clinical practice due to the unknown cause of intractable pain and high cost of health care yet has not been satisfactorily addressed. During the past decades, a significant role for the descending pain modulation and alterations due to specific diseases of CPP has been emphasized. It has been widely established that central sensitization and alterations in neuroplasticity induced by the enhancement of descending pain facilitation and/or the impairment of descending pain inhibition can explain many chronic pain states including CPP. The descending serotonergic neurons in the raphe nuclei target receptors along the descending pain circuits and exert either pro- or antinociceptive effects in different pain conditions. In this review, we summarize the possible underlying descending pain regulation mechanisms in CPP and the role of serotonin, thus providing evidence for potential application of analgesic medications based on the serotonergic system in CPP patients. Copyright 2019 Zhuo-Ying Tao et al.
  • Mss51 deletion enhances muscle metabolism and glucose homeostasis in mice

    Moyer, A.L.; Lovering, R.; Rovira Gonzalez, Y.I. (American Society for Clinical Investigation, 2019)
    Myostatin is a negative regulator of muscle growth and metabolism and its inhibition in mice improves insulin sensitivity, increases glucose uptake into skeletal muscle, and decreases total body fat. A recently described mammalian protein called MSS51 is significantly downregulated with myostatin inhibition. In vitro disruption of Mss51 results in increased levels of ATP, ?-oxidation, glycolysis, and oxidative phosphorylation. To determine the in vivo biological function of Mss51 in mice, we disrupted the Mss51 gene by CRISPR/Cas9 and found that Mss51-KO mice have normal muscle weights and fiber-type distribution but reduced fat pads. Myofibers isolated from Mss51-KO mice showed an increased oxygen consumption rate compared with WT controls, indicating an accelerated rate of skeletal muscle metabolism. The expression of genes related to oxidative phosphorylation and fatty acid ?-oxidation were enhanced in skeletal muscle of Mss51-KO mice compared with that of WT mice. We found that mice lacking Mss51 and challenged with a high-fat diet were resistant to diet-induced weight gain, had increased whole-body glucose turnover and glycolysis rate, and increased systemic insulin sensitivity and fatty acid ?-oxidation. These findings demonstrate that MSS51 modulates skeletal muscle mitochondrial respiration and regulates whole-body glucose and fatty acid metabolism, making it a potential target for obesity and diabetes.
  • Recognizing Hemiparetic Ankle Deficits Using Wearable Pressure Sensors

    Ramadan, A.; Roy, A.; Smela, E. (Institute of Electrical and Electronics Engineers Inc., 2019)
    Objective: To provide proof-of-concept for a novel method to recognize impaired push-off and foot-drop deficits in hemiparetic gait using analog pressure sensors. These data may enhance feedback from a modular ankle exoskeleton (such as Anklebot) for stroke rehabilitation, which now employs on/off foot switches under the foot. Methods: A pressure sensor was positioned on the posterior side of the calcaneus. Experiments were conducted on two healthy subjects with normal walking and with hip circumduction and foot drop, the latter to mimic hemiparetic gait post-stroke. Results: Unlike the foot switches, the pressure sensor yielded data during swing. The initial swing and terminal stance readings followed local foot-shoe dynamics and were thus able to detect foot drop swing deficits while also providing push-off information during stance. Discussion: The analog pressure sensors provided more information than foot switches, even during stance. This system may provide clinicians with a tool to monitor foot drop and push-off.
  • Classical Schizophrenia: Liddle and the Core of Schizophrenia

    Carpenter, W.T. (SAGE Publications Inc., 2019)
  • Interleukin 1 receptor antagonist (IL1RN) gene variants predict radiographic severity of knee osteoarthritis and risk of incident disease.

    Attur, Mukundan; Yau, Michelle; Mitchell, Braxton D. (BMJ, 2019-12-18)
    In these studies, we examined the association of single nucleotide polymorphisms (SNPs) of the IL1RN gene with radiographic severity of symptomatic knee osteoarthritis (SKOA) and the risk of incident OA. We also explored these genetic polymorphisms in patients with new onset rheumatoid arthritis (RA). This is an open access article distributed in accordance with the Creative Commons Attribution 4.0 Unported (CC BY 4.0) license.
  • Molecular Neuropathology in Practice: Clinical Profiling and Integrative Analysis of Molecular Alterations in Glioblastoma

    Nasrallah, M.P.; Binder, Z.A.; Sukhadia, S. (SAGE Publications Ltd, 2019)
    Molecular profiling of glioblastoma has revealed complex cytogenetic, epigenetic, and molecular abnormalities that are necessary for diagnosis, prognosis, and treatment. Our neuro-oncology group has developed a data-driven, institutional consensus guideline for efficient and optimal workup of glioblastomas based on our routine performance of molecular testing. We describe our institution�s testing algorithm, assay development, and genetic findings in glioblastoma, to illustrate current practices and challenges in neuropathology related to molecular and genetic testing. We have found that coordination of test requisition, tissue handling, and incorporation of results into the final pathologic diagnosis by the neuropathologist improve patient care. Here, we present analysis of O6-methylguanine-DNA-methyltransferase promoter methylation and next-generation sequencing results of 189 patients, obtained utilizing our internal processes led by the neuropathology team. Our institutional pathway for neuropathologist-driven molecular testing has streamlined the management of glioblastoma samples for efficient return of results for incorporation of genomic data into the pathological diagnosis and optimal patient care. Copyright The Author(s) 2019.
  • Measurement of Retinal Microvascular Blood Velocity Using Erythrocyte Mediated Velocimetry

    Tracey, B.M.; Le, C.T.; Chen, V.Y.; Renner, C.Y.; Li, J.; Kalarn, S.P.; Mohammed, T.K.; Mohammed, I.S.K.; Thompson, G.M.; Im, L.T.; et al. (Nature Research, 2019)
    Changes in retinal blood flow may be involved in the pathogenesis of glaucoma and other ocular diseases. Erythrocyte mediated velocimetry (EMV) is a novel technique where indocyanine green (ICG) dye is sequestered in erythrocyte ghosts and autologously re-injected to allow direct visualization of erythrocytes for in vivo measurement of speed. The purpose of this study is to determine the mean erythrocyte speed in the retinal microvasculature, as well as the intravisit and intervisit variability of EMV. Data from 23 EMV sessions from control, glaucoma suspect, and glaucoma patients were included in this study. In arteries with an average diameter of 43.11 µm ± 6.62 µm, the mean speed was 7.17 mm/s ± 2.35 mm/s. In veins with an average diameter of 45.87 µm ± 12.04 µm, the mean speed was 6.05 mm/s ± 1.96 mm/s. Intravisit variability, as measured by the mean coefficient of variation, was 3.57% (range 0.44–9.68%). Intervisit variability was 4.85% (range 0.15–8.43%). EMV may represent reliable method for determination of retinal blood speed, potentially allowing insights into the effects of pharmacologic agents or pathogenesis of ocular diseases. Copyright 2019, The Author(s).
  • Maintenance of Deep Lung Architecture and Automated Airway Segmentation for 3D Mass Spectrometry Imaging

    Scott, A.J.; Chandler, C.E.; Ernst, R.K. (Nature Research, 2019)
    Mass spectrometry imaging (MSI) is a technique for mapping the spatial distributions of molecules in sectioned tissue. Histology-preserving tissue preparation methods are central to successful MSI studies. Common fixation methods, used to preserve tissue morphology, can result in artifacts in the resulting MSI experiment including delocalization of analytes, altered adduct profiles, and loss of key analytes due to irreversible cross-linking and diffusion. This is especially troublesome in lung and airway samples, in which histology and morphology is best interpreted from 3D reconstruction, requiring the large and small airways to remain inflated during analysis. Here, we developed an MSI-compatible inflation containing as few exogenous components as possible, forgoing perfusion, fixation, and addition of salt solutions upon inflation that resulted in an ungapped 3D molecular reconstruction through more than 300 microns. We characterized a series of polyunsaturated phospholipids (PUFA-PLs), specifically phosphatidylinositol (-PI) lipids linked to lethal inflammation in bacterial infection and mapped them in serial sections of inflated mouse lung. PUFA-PIs were identified using spatial lipidomics and determined to be determinant markers of major airway features using unsupervised hierarchical clustering. Deep lung architecture was preserved using this inflation approach and the resulting sections are compatible with multiple MSI modalities, automated interpretation software, and serial 3D reconstruction. Copyright 2019, The Author(s).
  • Nonsurgical endodontic management of dens invaginatus: a report of two cases

    Abu, Hasna, A.; Ungaro, D.M.T.; Martinho, F.C. (F1000Research, 2019)
    Dens invaginatus is a malformation affecting mainly the superior lateral incisors. It is defined as an infolding of the crown hard tissues, including the enamel and dentin, and can extend up to the root apex. Root canal treatment of this abnormality is considered difficult due to the complex anatomy presented by these teeth. This case series presents nonsurgical endodontic treatment in two cases of dens invaginatus (type II and III) in maxillary lateral incisors. This nonsurgical or conventional endodontic treatment results in healing of the periapical lesions associated with both cases, with no need for extra intervention e.g. surgical or invasive management. The manual instrumentation associated with sodium hypochlorite and calcium hydroxide were able to completely heal the lesions. Radiographic exams were carried out to control and asses the healing. Nonsurgical treatment was successful in both cases with adequate repair after a 6-year follow-up with radiographic and tomographic assessments. Copyright: 2019 Abu Hasna A et al.
  • Marital Status and Overall Survival in Patients with Resectable Pancreatic Cancer: Results of an Ancillary Analysis of NRG Oncology/RTOG 9704

    Reyngold, M.; Winter, K.A.; Regine, W.F. (Wiley-Blackwell, 2019)
    Background: Several registry-based analyses suggested a survival advantage for married versus single patients with pancreatic cancer. The mechanisms underlying the association of marital status and survival are likely multiple and complex and, therefore, may be obscured in analyses generated from large population-based databases. The goal of this research was to characterize this potential association of marital status with outcomes in patients with resected pancreatic cancer who underwent combined modality adjuvant therapy on a prospective clinical trial. Materials and Methods: This is an ancillary analysis of 367 patients with known marital status treated on NRG Oncology/RTOG 97-04. Survival analysis was performed using the Kaplan-Meier method and compared using the log-rank test. Multivariate analysis was performed using the Cox proportional hazards regression model. Results: Of 367 patients, 271 (74%) were married or partnered and 96 (26%) were single. Married or partnered patients were more likely to be male. There was no association between marital status and overall survival (OS) or disease-free survival (DFS) on univariate (hazard ratio [HR], 1.09 and 1.01, respectively) or multivariate analyses (HR, 1.05 and 0.98, respectively). Married or partnered male patients did not have improved survival compared with female or single patients. Conclusion: Ancillary analysis of data from NRG Oncology/RTOG 97-04 demonstrated no association between marital and/or partner status and OS or DFS in patients with resected pancreatic cancer who received adjuvant postoperative chemotherapy followed by concurrent external beam radiation therapy and chemotherapy. Clinical trial identification number. NCT00003216. Implications for Practice: Several population-based studies have shown an epidemiological link between marital status and survival in patients with pancreatic cancer. A better understanding of this association could offer an opportunity to improve outcomes through psychosocial interventions designed to mitigate the negative effects of not being married. Based on the results of this analysis, patients who have undergone a resection and are receiving adjuvant therapy on a clinical trial are unlikely to benefit from such interventions. Further efforts to study the association between marital status and survival should be focused on less selected subgroups of patients with pancreatic cancer.
  • Catecholaminergic manipulation alters dynamic network topology across cognitive states

    Shine, J.M.; van den Brink, R.L.; Hernaus, D. (MIT Press Journals, 2017)
    The human brain is able to flexibly adapt its information processing capacity to meet a variety of cognitive challenges. Recent evidence suggests that this flexibility is reflected in the dynamic reorganization of the functional connectome. The ascending catecholaminergic arousal systems of the brain are a plausible candidate mechanism for driving alterations in network architecture, enabling efficient deployment of cognitive resources when the environment demands them. We tested this hypothesis by analyzing both resting-state and task-based fMRI data following the administration of atomoxetine, a noradrenaline reuptake inhibitor, compared with placebo, in two separate human fMRI studies. Our results demonstrate that the manipulation of central catecholamine levels leads to a reorganization of the functional connectome in a manner that is sensitive to ongoing cognitive demands.
  • Multiple-Ascending-Dose Phase 1 Clinical Study of the Safety, Tolerability, and Pharmacokinetics of CRS3123, a Narrow-Spectrum Agent with Minimal Disruption of Normal Gut Microbiota

    Lomeli, B.K.; Galbraith, H.; Ravel, J. (American Society for Microbiology, 2019)
    CRS3123 is a novel small molecule that potently inhibits methionyl-tRNA synthetase of Clostridioides difficile, inhibiting C. difficile toxin production and spore formation. CRS3123 has been evaluated in a multiple-ascending-dose placebo-controlled phase 1 trial. Thirty healthy subjects, ages 18 to 45 years, were randomized into three cohorts of 10 subjects each, receiving either 200, 400, or 600 mg of CRS3123 (8 subjects per cohort) or placebo (2 subjects per cohort) by oral administration twice daily for 10 days. CRS3123 was generally safe and well tolerated, with no serious adverse events (SAEs) or severe treatment-emergent adverse events (TEAEs) reported. All subjects completed their assigned treatment and follow-up visits, and there were no trends in systemic, vital sign, or laboratory TEAEs. There were no QTcF interval changes or any clinically significant changes in other electrocardiogram (ECG) intervals or morphology. CRS3123 showed limited but detectable systemic uptake; although absorption increased with increasing dose, the increase was less than dose proportional. Importantly, the bulk of the oral dose was not absorbed, and fecal concentrations were substantially above the MIC90 value of 1 μg/ml at all dosages tested. Subjects receiving either of the two lower doses of CRS3123 exhibited minimal disruption of normal gut microbiota after 10 days of twice-daily dosing. CRS3123 was inactive against important commensal anaerobes, including Bacteroides, bifidobacteria, and commensal clostridia. Microbiome data showed favorable differentiation compared to other CDI therapeutics. These results support further development of CRS3123 as an oral agent for the treatment of CDI. (This study has been registered at Clinicaltrials.gov under identifier NCT02106338.). Copyright 2019 Lomeli et al.
  • Effects of Single Nucleotide Polymorphisms in Human KCNMA1 on BK Current Properties

    Plante, A.E.; Lai, M.H.; Lu, J.; Meredith, A.L. (Frontiers Media S.A., 2019)
    BK Ca2+-activated K+ channels are important regulators of membrane excitability. Multiple regulatory mechanisms tailor BK current properties across tissues, such as alternative splicing, posttranslational modifications, and auxiliary subunits. Another potential mechanism for modulating BK channel activity is genetic variation due to single nucleotide polymorphisms (SNPs). The gene encoding the human BK α subunit, KCNMA1, contains hundreds of SNPs. However, the variation in BK channel activity due to SNPs is not well studied. Here, we screened the effects of four SNPs (A138V, C495G, N599D, and R800W) on BK currents in HEK293T cells, selected based on predicted protein pathogenicity or disease linkage. We found that the SNPs C495G and R800W had the largest effects on BK currents, affecting the conductance–voltage relationship across multiple Ca2+ conditions in the context of two BK channel splice variants. In symmetrical K+, C495G shifted the V1/2 to more hyperpolarized potentials (by −15 to −20 mV) and accelerated activation, indicating C495G confers some gain-of-function properties. R800W shifted the V1/2 to more depolarized potentials (+15 to +35 mV) and slowed activation, conferring loss-of-function properties. Moreover, the C495G and R800W effects on current properties were found to persist with posttranslational modifications. In contrast, A138V and N599D had smaller and more variable effects on current properties. Neither application of alkaline phosphatase to patches, which results in increased BK channel activity attributed to channel dephosphorylation, nor bidirectional redox modulations completely abrogated SNP effects on BK currents. Lastly, in physiological K+, C495G increased the amplitude of action potential (AP)-evoked BK currents, while R800W had a more limited effect. However, the introduction of R800W in parallel with the epilepsy-linked mutation D434G (D434G/R800W) decreased the amplitude of AP-evoked BK currents compared with D434G alone. These results suggest that in a physiological context, C495G could increase BK activation, while the effects of the loss-of-function SNP R800W could oppose the gain-of-function effects of an epilepsy-linked mutation. Together, these results implicate naturally occurring human genetic variation as a potential modifier of BK channel activity across a variety of conditions. Copyright 2019 Plante, Lai, Lu and Meredith.
  • Comorbidities of hidradenitis suppurativa: A review of the literature

    Cartron, A.; Driscoll, M.S. (Elsevier Inc, 2019)
    Background: Hidradenitis suppurativa (HS) is a chronic inflammatory skin condition that affects the follicular portion of folliculopilosebaceous units. It causes painful nodules, abscesses, and draining sinus tracts throughout multiple regions of the body. HS primarily affects women; the overall HS prevalence in women is three times that in men. Although cutaneous disease itself causes substantial morbidity, recent evidence has shown that HS is a systemic inflammatory disease with multiple associated comorbidities. Objective: A review of the literature was conducted to elucidate existing information on this topic to assist in clinical decision-making for dermatologists. Methods: A review of the literature using the PubMed database was conducted with the search term “hidradenitis suppurativa comorbidities”. The search was conducted from March 3, 2019 to March 20, 2019, and yielded 55 articles, case reports, and reviews. Results: Metabolic and cardiovascular comorbidities were the most commonly associated with HS. HS has a significant comorbidity burden beyond the skin, including metabolic, cardiovascular, endocrine, gastrointestinal, rheumatologic, and psychiatric disorders, which collectively decrease the quality of life of patients. Conclusions: Dermatologists should be aware of these associations to encourage appropriate screening and referral for management of these disorders.
  • Validation of a predictive model for operative trauma experience to facilitate selection of trauma sustainment military-civilian partnerships

    Hall, A.; Qureshi, I.; Scalea, T. (BMJ Publishing Group, 2019)
    Background: Trauma readiness is a Department of Defense requirement for military healthcare providers. Surgeons must maintain readiness to optimize surgical care on the battlefield and minimize preventable death. The objective of this study was to validate a predictive model for trauma operative exposure by applying the model prospectively. Methods: The predictive model for operative trauma exposure was prospectively applied to predict the number of emergent operative cases that would be experienced over predetermined time periods at four separate trauma sustainment military-civilian partnerships (TS-MCP). Notional courses were designed to be 2 or 4 weeks long and consisting of 5 and 12 overnight call periods, respectively. A total of 51 separate 2-week courses and 49 4-week courses were evaluated using the model. The outcome measure was the number of urgent (occurring within a day of arrival) operative trauma cases. Results: Trauma/general surgery case volumes during call periods of notional courses were within the predicted range at least 98% of the time. Orthopedic volumes were more variable with a range of 82%-98% meeting expectation depending on the course length and institution. Conclusion: The previously defined model accurately predicted the number of urgent trauma/general surgery cases course participants would likely experience when applied prospectively to TS-MCP; however, the model was less accurate in predicting acute orthopedic trauma exposure. While it remains unknown how many cases need to be performed meet a trauma sustainment requirement, having a model with a predictive capability for case volume will facilitate metric development. This model may be useful when planning for future TS-MCP. Level of evidence Economic and Value Based Evaluations Level II. Copyright Author(s) (or their employer(s)) 2019.
  • Minimally invasive chest wall stabilization: A novel surgical approach to video-assisted rib plating (VARP)

    DIaz, J.J.; Azar, F.K. (BMJ Publishing Group, 2019)
    The current morbidity of rib plating is due to the size of the incision required to perform an open procedure. We describe a minimally invasive laparoscopic approach to rib plating. A cadaver model was used to develop the surgical technique by performing both left and right posterior-lateral rib plating. A small incision was made over the auscultatory triangle. The potential working space is developed under the posterior shoulder girdle and the scapula. A table-based retractor was used to elevate the scapula and the muscles. Two separate ports were placed: one camera port and one working port. In three cadaver models, 12 rib fractures were plated and the surgical technique is described. This novel technique will likely allow for faster recovery and was especially useful in the subscapular space. Level of evidence II. © © Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.
  • Neural and behavioral changes driven by observationally-induced hypoalgesia

    Raghuraman, N.; Wang, Y.; Furman, A.J.; Tricou, C.; Seminowicz, D.A.; Colloca, L. (Nature Research, 2019)
    Observing successful pain treatment in others can induce anticipatory neural processes that, in turn, relieve pain. Previous studies have suggested that social learning and observation influence placebo hypoalgesia. Here, we used electroencephalography (EEG) to determine the neurophysiological changes associated with pain relief acquired through the observation. Thirty-one participants observed a demonstrator undergo painful heat stimulations paired with a “control” cream and non-painful ones paired with a “treatment” cream, which actually were both Vanicreams. After their observation, the participants then received the same creams and stimulations. We found that the treatment cream led to lower self-reported pain intensity ratings than the control cream. Anticipatory treatment cues elicited smaller P2 in electrodes F1, Fz, FC1, and FCz than the control condition. The P2 component localization indicated a higher current density in the right middle frontal gyrus, a region associated with attentional engagement. In placebo responders, the sensorimotor cortex activity captured in electrodes C3, Cz, and C4 indicated that hypoalgesia was positively correlated with resting state peak alpha frequency (PAF). These results suggest that observationally-induced placebo hypoalgesia may be driven by anticipatory mechanisms that modulate frontal attentional processes. Furthermore, resting state PAF could serve as a predictor of observationally-induced hypoalgesia. Copyright 2019, The Author(s).
  • Value in Hepatitis C Virus Treatment: A Patient-Centered Cost-Effectiveness Analysis

    Mattingly, T.J.; II; Slejko, J.F.; Onukwugha, E.; Perfetto, E.M.; Kottilil, S.; Mullins, C.D. (Adis, 2019)
    Background: Innovations in hepatitis C virus (HCV) therapy included in traditional comparative evaluations focus on sustained virologic response (SVR) without addressing challenges patients report beyond virologic cure. This study aims to evaluate the cost-effectiveness of HCV drug therapy with a patient-centered approach. Methods: An individual-based Markov model was constructed using guidance from a stakeholder advisory board (SAB), a patient Delphi panel, and published literature to evaluate direct-acting antivirals (DAAs) compared to no treatment. The United States (US) health sector and societal perspectives were considered for 10- and 20-year time horizons. Inputs for treatment costs and effectiveness reflect a generic regimen. Indirect costs used for the societal model included estimates from self-reported productivity in a matched-control sample. Beyond the traditional quality-adjusted life-year (QALY) health outcome, this study included two novel measures developed from the Delphi panel and SAB: infected life-years and workdays missed. All costs were measured in 2018 US dollars. Results: Health sector costs and QALYs were higher in the treatment group in both 10- and 20-year models. Total infected life-years and workdays missed were reduced in the treatment group for both models. When costs of absenteeism, presenteeism, and patient/caregiver time were included, the DAA intervention was cost-saving at both 10 and 20 years. Health sector results were sensitive to drug costs and utility estimates for post-SVR health states. Societal results were sensitive to presenteeism estimates and drug costs. Conclusion: Treatment was cost-effective from a health sector perspective and cost-saving when including non-health costs such as patient/caregiver time and productivity. Copyright 2019, The Author(s).
  • Effects of S. mutans gene-modification and antibacterial calcium phosphate nanocomposite on secondary caries and marginal enamel hardness

    Chen, H.; Tang, Y.; Weir, M.D.; Masri, R.; Oates, T.W.; Zhang, K.; Xu, H.H.K. (Royal Society of Chemistry, 2019)
    Secondary caries at the restoration-tooth margins is a main reason for dental restoration failures. Gene-modification for Streptococcus mutans (S. mutans) and composites containing dimethylaminohexadecyl methacrylate (DMAHDMA) and nanoparticles of amorphous calcium phosphate (NACP) all have the potential to suppress bacterial acids and promote remineralization. However, there has been no report of their effects on marginal caries-inhibition and enamel hardness. The objective of this study was to investigate the effects of gene-modification and DMAHDM-NACP composite restoration on enamel demineralization and hardness at the margins under biofilm acids for the first time. Parent S. mutans and rnc gene-deleted S. mutans were tested side by side. The bioactive composite contained 3% DMAHDM and 30% NACP. Mechanical properties and calcium (Ca) and phosphate (P) ion releases were measured. Colony-forming units (CFU), MTT, lactic acid and polysaccharide of biofilms were evaluated. Demineralization of bovine enamel with composite restorations was induced via biofilms, then enamel hardness was measured. The dual strategy of combining rnc-deletion with DMAHDM+30NACP: (1) achieved the strongest biofilm-inhibition, with the greatest reduction in biofilm CFU by 6 logs; (2) decreased biofilm lactic acid and polysaccharide production by more than 80%; (3) achieved enamel hardness that was 140% higher than that of a commercial fluoride-releasing composite under 30 days of biofilm acids. Therefore, the novel dual approach of rnc gene-deletion and DMAHDM+NACP nanocomposite is promising to inhibit secondary caries at the margins and increase the longevity of tooth restorations.

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