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David A Isaacs,1,2 Kemberlee Bonnet,3 Michelle R Eckland,1 Kimberly Markowitz,4 Maria Pena,5 David G Schlundt3 1Department of Neurology, Vanderbilt University Medical Center, Nashville, TN, USA; 2Department of Pediatrics, Division of Pediatric Neurology, Monroe Carell Jr. Children’s Hospital at Vanderbilt, Nashville, TN, USA; 3Department of Psychology, Vanderbilt University, Nashville, TN, USA; 4Department of Neuroscience, Vanderbilt University, Nashville, TN, USA; 5College of Nursing, University of Florida, Gainesville, FL, USACorrespondence: David A Isaacs, Department of Neurology, Vanderbilt University Medical Center, 1161 21st Ave South, A-0118 MCN, Nashville, TN, 37232, USA, Tel +1 615 936.2025, Fax +1 615 936 1229, Email david.a.isaacs@vumc.orgPurpose: Adults with Tourette syndrome (TS) have worse mental health, physical health, and quality of life than the general population. The factors contributing to negative outcomes across multiple health domains in adults with TS remain uncertain, in part due to a lack of longitudinal studies in this population. In attempt to address these knowledge gaps, our center has initiated development of a regional registry for adults with TS. During the goal-setting and design phase of registry development, we conducted focus groups with adults with TS to identify research issues of greatest importance to this population and to obtain feedback on design and implementation of an adult TS registry.Patients and Methods: Participants were recruited from a tertiary care adult TS clinic and from institutional research registries. Focus groups were conducted online and were moderated by a qualitative research expert. Qualitative data analysis was performed using an iterative inductive/deductive approach.Results: Across four focus groups, adult TS participants (n=22) expressed a variety of research priorities, including developing more effective treatments for tics, identifying risk factors for tic persistence into adulthood, clarifying the interaction between TS symptoms and women’s health, clarifying the relationships between TS and other mental and physical health disorders, and addressing day-to-day living issues. Focus group participants were generally enthusiastic about creation of an adult TS registry. They indicated that adults with TS are more likely to engage with a registry that logistically accommodates participants (eg, by offering a wide range of visit times, by providing telehealth options) and that fosters bidirectional interaction (eg, by disseminating results regularly, by involving participants in registry design and implementation, by notifying participants of support resources).Conclusion: Focus group input clarifies the research priorities of adults with TS and will inform the ongoing development of an adult TS registry.Keywords: tic disorder, patient registry, neurodevelopmental disorder, movement disorder

Background: Among the innate defense mechanisms in the oral cavity, lactoferrin (LF) is a vital antimicrobial that can modify the host response against periodontopathogens. Aggregatibacter actinomycetemcomitans is the main periodontopathogen of localized aggressive periodontitis. The aim of this study is to evaluate the role of LF during A. actinomycetemcomitans-induced periodontitis. Methods: Differences in the expression levels of cytokines, chemokines, chemokine receptors, and bone loss markers between wild-type (WT) and LF knockout mice (LFKO-/-) were evaluated by real time-PCR. Serum lgG and LF levels were quantified by ELISA. Alveolar bone loss among the groups was estimated by measuring the distance from cemento-enamel junction (CEJ) to the alveolar bone crest (ABC) at 20 molar sites. Results: Oral infection with A. actinomycetemcomitans increased LF levels in periodontal tissue (P= 0.01) and saliva (P = 0.0004) of wild-type infected (WTI) mice compared to wild-type control mice. Pro-inflammatory cytokines such as interferon-γ tumor necrosis factor-α, interleukin (IL)-1β, IL-6, and IL-12 were increased in the infected LF knockout (LFKO-/-I) mice compared to the WTI mice, whereas the anti-inflammatory cytokines IL-4 and IL-10 were decreased. Chemokines and chemokine receptors showed different expression patterns between WTI and LFKO-/-I mice. The LFKO-/-I mice developed increased bone loss (P = 0.002), in conjunction with increased expression of receptor activator of nuclear factor-κB ligand and decrease in osteoprotegerin, compared to WTI mice. Conclusions: These results demonstrate that the infected LFKO-/- mice were more susceptible to A. actinomycetemcomitans- induced alveolar bone loss, with different patterns of immune responses compared to those of WTI mice. [ABSTRACT FROM AUTHOR]

Objective: Black American (BA) multiple sclerosis (MS) patients experience greater disability compared to White American (WA) patients. Here, we investigated the role of paramagnetic rim lesions (PRLs), a subset of chronic active lesions, on race-related disability in MS., Methods: We conducted a retrospective observational study comparing BA and WA MS patients. PRLs were identified through Quantitative Susceptibility Mapping (QSM) MRI. A causal mediation analysis explored the impact of PRLs on the relationship between race and disability, as measured by the Expanded Disability Status Scale (EDSS)., Results: The prevalence of PRLs in BA patients with MS was higher at 55% compared to WA patients at 39% (p = 0.022). A higher percentage of PRLs among all white matter lesions was observed with BA (8.01%) patients compared to WA (3.4%) patients (p = 0.003). In a regression analysis, controlling for significant patient-level covariates and income-level demographics, the percentage of PRLs was, on average, 4.61 points higher for BA patients than for WA patients (p = 0.003). In a separate regression analysis, accounting for covariates, BA patients exhibited significantly higher EDSS scores (p < 0.001). Further analysis demonstrated that the percentage of PRLs was a mediator in the association between BA patients and greater disability (p = 0.031). Higher proportion of PRLs in BA population accounted for 14% of the total effect of race on disability., Interpretation: BA patients exhibit greater disability, in part, due to their higher proportion of PRLs. This study underscores the substantial impact of chronic active lesions on disability outcomes in this specific minority MS patient population., (© 2024 The Author(s). Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Oral disease interventions primarily focus on behavioral changes like dietary improvements and ensuring better oral hygiene. However, recognizing the influence of biological factors, including genetics and early-life nutrition, is crucial. Iron deficiency (ID) and its advanced form, iron deficiency anemia (IDA), affect nearly two billion people globally, especially children and pregnant women. We conducted a comprehensive search using Medline via EndNote and Web of Science, employing keywords related to iron deficiency anemia (IDA), and we identified 36 studies deemed relevant for inclusion in this literature review. IDA prevalence is notably high among pregnant women and young children. Both IDA and early-childhood caries (ECC) disproportionately affect impoverished populations, highlighting the socioeconomic dimension of this issue. IDA presents with various oral mucosal changes and is closely linked to candidiasis. Additionally, IDA can hinder tooth development and weaken the immune response. Multiple population surveys have revealed a significant association between ECC and IDA. While some studies have explored the IDA-periodontal disease link, the current evidence is relatively limited in its robustness. In conclusion, more comprehensive longitudinal studies are essential to deepen our understanding of the IDA-oral disease connection. Investigating the underlying biological mechanisms is critical to developing effective interventions, particularly for vulnerable populations affected by IDA.

T cell infiltration into tumors is a favorable prognostic feature, but most solid tumors lack productive T cell responses. Mechanisms that coordinate T cell exclusion are incompletely understood. Here we identify hepatocyte activation via interleukin-6/STAT3 and secretion of serum amyloid A (SAA) proteins 1 and 2 as important regulators of T cell surveillance of extrahepatic tumors. Loss of STAT3 in hepatocytes or SAA remodeled the tumor microenvironment with infiltration by CD8 + T cells, while interleukin-6 overexpression in hepatocytes and SAA signaling via Toll-like receptor 2 reduced the number of intratumoral dendritic cells and, in doing so, inhibited T cell tumor infiltration. Genetic ablation of SAA enhanced survival after tumor resection in a T cell-dependent manner. Likewise, in individuals with pancreatic ductal adenocarcinoma, long-term survivors after surgery demonstrated lower serum SAA levels than short-term survivors. Taken together, these data define a fundamental link between liver and tumor immunobiology wherein hepatocytes govern productive T cell surveillance in cancer., (© 2024. The Author(s), under exclusive licence to Springer Nature America, Inc.)

We previously showed that chimeric antigen receptor (CAR) T-cell therapy targeting epidermal growth factor receptor variant III (EGFRvIII) produces upregulation of programmed death-ligand 1 (PD-L1) in the tumor microenvironment (TME). Here we conducted a phase 1 trial (NCT03726515) of CAR T-EGFRvIII cells administered concomitantly with the anti-PD1 (aPD1) monoclonal antibody pembrolizumab in patients with newly diagnosed, EGFRvIII + glioblastoma (GBM) (n = 7). The primary outcome was safety, and no dose-limiting toxicity was observed. Secondary outcomes included median progression-free survival (5.2 months; 90% confidence interval (CI), 2.9-6.0 months) and median overall survival (11.8 months; 90% CI, 9.2-14.2 months). In exploratory analyses, comparison of the TME in tumors harvested before versus after CAR + aPD1 administration demonstrated substantial evolution of the infiltrating myeloid and T cells, with more exhausted, regulatory, and interferon (IFN)-stimulated T cells at relapse. Our study suggests that the combination of CAR T cells and PD-1 inhibition in GBM is safe and biologically active but, given the lack of efficacy, also indicates a need to consider alternative strategies., (© 2024. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Microbes are an integral component of the tumor microenvironment. However, determinants of microbial presence remain ill-defined. Here, using spatial-profiling technologies, we show that bacterial and immune cell heterogeneity are spatially coupled. Mouse models of pancreatic cancer recapitulate the immune-microbial spatial coupling seen in humans. Distinct intra-tumoral niches are defined by T cells, with T cell-enriched and T cell-poor regions displaying unique bacterial communities that are associated with immunologically active and quiescent phenotypes, respectively, but are independent of the gut microbiome. Depletion of intra-tumoral bacteria slows tumor growth in T cell-poor tumors and alters the phenotype and presence of myeloid and B cells in T cell-enriched tumors but does not affect T cell infiltration. In contrast, T cell depletion disrupts the immunological state of tumors and reduces intra-tumoral bacteria. Our results establish a coupling between microbes and T cells in cancer wherein spatially defined immune-microbial communities differentially influence tumor biology., Competing Interests: Declaration of interests W.J.H. reports royalties from Rodeo/Amgen; grants from Sanofi, NeoTX, and Circle Pharma; and prior consulting fees from Exelixis. G.L.B. reports prior and active roles as a consultant/advisory board member for Seattle Genetics (now Seagen), Adicet Bio, Aduro Biotech, AstraZeneca, BiolineRx, BioMarin Pharmaceuticals, Bristol-Myers Squibb, Cantargia, Cour Pharmaceuticals, Boehinger Ingelheim, Genmab, Hibercell, HotSpot Therapeutics, Incyte Corporation, Janssen, Merck, Molecular Partners, NanoGhost, Pancreatic Cancer Action Network, Shattuck Labs, and Verastem and reports receiving commercial research grants from Incyte Corporation, Bristol-Myers Squibb, Verastem, Halozyme, Biothera, Newlink, Novartis, Arcus Biosciences, and Janssen. G.L.B. is an inventor of intellectual property related to chimeric antigen receptor (CAR) T cells that is licensed by the University of Pennsylvania to Novartis and Tmunity Therapeutics., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Myeloid cells facilitate T cell immune evasion in cancer yet are pliable and have antitumor potential. Here, by cotargeting myeloid activation molecules, we leveraged the myeloid compartment as a therapeutic vulnerability in mouse models of pancreatic cancer. Myeloid cells in solid tumors expressed activation receptors including the pattern recognition receptor Dectin-1 and the TNF receptor superfamily member CD40. In mouse models of checkpoint inhibitor-resistant pancreatic cancer, coactivation of Dectin-1, via systemic β-glucan therapy, and CD40, with agonist antibody treatment, eradicated established tumors and induced immunological memory. Antitumor activity was dependent on cDC1s and T cells but did not require classical T cell-mediated cytotoxicity or blockade of checkpoint molecules. Rather, targeting CD40 drove T cell-mediated IFN-γ signaling, which converged with Dectin-1 activation to program distinct macrophage subsets to facilitate tumor responses. Thus, productive cancer immune surveillance in pancreatic tumors resistant to checkpoint inhibition can be invoked by coactivation of complementary myeloid signaling pathways.

Although macrophages contribute to cancer cell dissemination, immune evasion, and metastatic outgrowth, they have also been reported to coordinate tumor-specific immune responses. We therefore hypothesized that macrophage polarization could be modulated therapeutically to prevent metastasis. Here, we show that macrophages respond to β-glucan (odetiglucan) treatment by inhibiting liver metastasis. β-glucan activated liver-resident macrophages (Kupffer cells), suppressed cancer cell proliferation, and invoked productive T cell-mediated responses against liver metastasis in pancreatic cancer mouse models. Although excluded from metastatic lesions, Kupffer cells were critical for the anti-metastatic activity of β-glucan, which also required T cells. Furthermore, β-glucan drove T cell activation and macrophage re-polarization in liver metastases in mice and humans and sensitized metastatic lesions to anti-PD1 therapy. These findings demonstrate the significance of macrophage function in metastasis and identify Kupffer cells as a potential therapeutic target against pancreatic cancer metastasis to the liver., (© 2023. Springer Nature Limited.)

9.4 million People have swallowing problems in the US. In special needs populations, routine oral hygiene procedures such as tooth brushing can result in aspiration of microbial laden fluids leading to a significant systemic challenge. Aspiration may lead to pneumonia in susceptible populations. These circumstances indicate the need for innovative approaches to oral hygiene for special needs, convalescent, the elderly populations, and young children learning to brush who can ingest excess fluoride which causes mottled enamel. Methods include describing some of the design considerations of the new prototype fabrication and microbiological evaluation of this new device, as well a comparison study of the versions 2 and 3 of the oral care device. Results concluded that version 3.0 regarding patient ease of use was better in comparison to version 2, which was the major difference, and 90% in both groups said they would recommend the new toothbrush. In the microbiological evaluation no growth was seen on any plates containing samples from either the experimental or the control after 48 h of incubation.

Article Title and Bibliographic Information: The efficacy of analgesics in controlling orthodontic pain: a systematic review and meta- analysis. Cheng C, Xie T, Wang J. BMC Oral Health 2020; 20:259., Source of Funding: The systematic review was funded by grants from the National Natural Science Foundation of China (No. 81771114 and No. 81970967). The authors have no actual or potential conflicts of interest., Type of Study/design: Systematic review with meta-analysis of data., (Copyright © 2022 Elsevier Inc. All rights reserved.)

The rise of antibiotic resistant bacteria due to overuse and misuse of antibiotics in medicine and dentistry is a growing concern. New approaches are needed to combat antibiotic resistant (AR) bacterial infections. There are a number of methods available and in development to address AR infections. Dentists conventionally use chemicals such as chlorohexidine and calcium hydroxide to kill oral bacteria, with many groups recently developing more biocompatible antimicrobial peptides (AMPs) for use in the oral cavity. AMPs are promising candidates in the treatment of (oral) infections. Also known as host defense peptides, AMPs have been isolated from animals across all kingdoms of life and play an integral role in the innate immunity of both prokaryotic and eukaryotic organisms by responding to pathogens. Despite progress over the last four decades, there are only a few AMPs approved for clinical use. This review summarizes an Introduction to Oral Microbiome and Oral Infections, Traditional Antibiotics and Alternatives & Antimicrobial Peptides. There is a focus on cationic AMP characteristics and mechanisms of actions, and an overview of animal-derived natural and synthetic AMPs, as well as observed microbial resistance.

Objectives: To determine the effect of human lactoferrin (hLF) in experimental oral candidiasis and examine the host-pathogen interactions in a mouse model., Design: Experimental groups comprised of 4-6-week-old wild type (C57BL/6J) or lactoferrin knockout (ltf -/- ) immunosuppressed mice. Six mice in each group were inoculated with C. albicans or sham infection by swabbing the oral cavity. To determine the effect of hLF on infection and host response, we added hLF (0.5 g/kg/day) to the drinking water. Candida and mice RNA were isolated from gingival tissue and analyzed by qRT-PCR for virulence genes and host expression of inflammatory mediators., Results: Administration of hLF significantly reduced the C. albicans CFUs in both WT and ltf -/- mice (P < .001). Examination of the oral cavity of ltf -/- I mice revealed lesions characterized by white patches and inflammation when compared to WTI mice. Several Candida virulence genes (als, ece, efg, sap) were significantly downregulated on administration of hLF to WTI and ltf -/- I mice (P < .001). The WTI+hLF mice had significantly increased expression of toll-like receptors (TLRs) compared to other group. We observed that hLF increased expression of interleukins, IL-1β, IL-6, IL-12, IL-17, tumor necrosis factor alpha (TNF-α), transforming growth factor beta (TGF-β), inducible nitric oxide synthase (iNOS) and myeloperoxidase (MPO) compared to untreated gingival tissue., Conclusion: Our study highlights the protective effect of hLF against oral C. albicans infection by its actions on both microbial and host factors. HLF may be of therapeutic value to protect against oral candidiasis., (Copyright © 2022. Published by Elsevier Ltd.)

Severe acute respiratory syndrome-related coronavirus (SARS-CoV-2) is detectable in saliva from asymptomatic individuals, suggesting a potential benefit from the use of mouth rinses to suppress viral load and reduce virus spread. Published studies on the reduction of SARS-CoV-2-induced cytotoxic effects by mouth rinses do not exclude antiseptic mouth rinse-associated cytotoxicity. Here, we determined the effect of commercially available mouth rinses and antiseptic povidone-iodine on the infectivity of replication-competent SARS-CoV-2 viruses and of pseudotyped SARS-CoV-2 viruses. We first determined the effect of mouth rinses on cell viability to ensure that antiviral activity was not a consequence of mouth rinse-induced cytotoxicity. Colgate Peroxyl (hydrogen peroxide) exhibited the most cytotoxicity, followed by povidone-iodine, chlorhexidine gluconate (CHG), and Listerine (essential oils and alcohol). The potent antiviral activities of Colgate Peroxyl mouth rinse and povidone-iodine were the consequence of rinse-mediated cellular damage when the products were present during infection. The potency of CHG was greater when the product was not washed off after virus attachment, suggesting that the prolonged effect of mouth rinses on cells impacts the antiviral outcome. To minimalize mouth rinse-associated cytotoxicity, mouth rinse was largely removed from treated viruses by centrifugation prior to infection of cells. A 5% ( v / v ) dilution of Colgate Peroxyl or povidone-iodine completely blocked viral infectivity. A similar 5% ( v / v ) dilution of Listerine or CHG had a moderate suppressive effect on the virus, but a 50% ( v / v ) dilution of Listerine or CHG blocked viral infectivity completely. Mouth rinses inactivated the virus without prolonged incubation. The new infectivity assay, with limited impacts of mouth rinse-associated cytotoxicity, showed the differential effects of mouth rinses on SARS-CoV-2 infection. Our results indicate that mouth rinses can significantly reduce virus infectivity, suggesting a potential benefit for reducing SARS-CoV-2 spread.

Data sources The authors searched Medline via PubMed, Scopus, Web of Science, the Cochrane Library and ClinicalTrials.gov for published and unpublished clinical trials. Only randomised clinical trials, with either a parallel or crossover design, reporting the tooth sensitivity of participants undergoing in-office dental bleaching and comparing pain frequency and severity with oral premedication of a non-steroidal or other anti-inflammatory drug compared with a placebo were used in the review. Studies that evaluated the topical administration of drugs or desensitising agents were not reviewed.Study selection In total,5,050 randomised clinical studies were screened and 11 studies were included in the various meta-analyses. Nine studies examined the effect of pre-emptive analgesics on the risk of sensitivity and ten studies evaluated the effect of drugs on the severity of sensitivity; seven of these studies were assessed as having a low risk of bias.Data extraction and synthesis This systematic review and meta-analysis was conducted a priori and registered at the International Prospective Register of Systematic Reviews. There were two reviewers who extracted data from the study tables and independently performed quality assessments of the selected trials using the Office of Health Assessment and Translation risk of bias rating tool for human and animal studies. Risk ratios were calculated for the dichotomous sensitivity risk data and mean difference for measures of sensitivity intensity.Results The authors found no effect of the drugs on the risk of sensitivity. Using a visual analogue scale, the authors identified a small but clinically insignificant reduction in the level of sensitivity in the drug-treated group evaluated up to one hour after bleaching. This was not observed when a numerical rating scale was used to measure pain intensity. For the 24-hour pain data, the authors did not find any significant intensity difference between groups. Mean pain intensity scores were generally low in both experimental groups in all randomised controlled trials reviewed. Based on a visual inspection of the funnel plots of all outcomes, the authors concluded that there was no publication bias.Conclusions The data did not support the pre-emptive use of anti-inflammatory drugs in preventing or reducing the intensity of pain caused by in-office tooth bleaching.

Article Title and Bibliographic Information: Estimation of the asymptomatic ratio of novel coronavirus infections (COVID-19). Nishiura H, Kobayashi T, Miyama T, et al.Int J Infect Dis 2020;94:154-155. https://doi.org/10.1016/j.ijid.2020.03.020., Source of Funding: Self-funded., Type of Study/design: Cross-sectional population study., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Objective: The objective of this study was to examine the relationship between iron deficiency and caries susceptibility in a mouse model., Materials and Methods: Three-week-old C57BL/J6 mice were fed a cariogenic diet containing either standard iron (48 ppm Fe) or low iron (4 ppm Fe) levels. Concurrently, groups of mice with both diets were orally inoculated with Streptococcus mutans (1 × 10 8 ) cells on three consecutive days. At the end of the 5th week after infection, mice were sacrificed and jaws were collected for caries scoring, rating the number and severity of lesions using a modified Keyes method applicable to mice., Results: Blood analysis by the end of the 5th week revealed marked reduction in the hemoglobin and hematocrit levels of the mice fed the iron deficient diet (IDA and IDA-S. mutans). Anemic mice in both groups lacked the incisor enamel pigmentation observed in mice fed an iron deficient diet. Anemic infected mice had the highest caries severity scores reflecting extensive deep lesions (P < 0.05). S. mutans infected mice fed a standard iron diet had similar numbers of lesions and severity scores as un-infected IDA animals (p < 0.05). IDA did not alter S. mutans CFU counts in infected animals (P < 0.05)., Conclusion: These results demonstrated that IDA mice are at a higher risk of developing deep dental caries compared to non-anemic mice; highlighting the protective role of iron against dental caries., (Copyright © 2019. Published by Elsevier Ltd.)