Steven R. Gill

MethodsData from the NIH/NIAID-funded (NCT03389893 [ADRN09]) multicenter study that enrolled adults with moderate-severe AD were analyzed. Bulk RNA-sequencing gene expression counts (rlog normalized) of skin biopsies were compared to bacterial colony forming units (CFU/cm 2) or associated PCR (rCFU/cm 2) in lesional (n= 57) and non-lesional (n= 55) pre-treatment samples. Genes of interest (GOIs) were determined based on association with CFU level (upper vs lower tertile) or early response to dupilumab and rCFU correlation (R 2≥ 0.10, p< 0.05).ResultsPre-treatment lesional vs non-lesional skin revealed increased S. aureus with remarkable variance in bacterial load between subjects (non-lesional 1.90±1.37 vs lesional 3.27±1.82 log 10 CFU/cm 2, p< 0.05). Multiple linear regression (rCFU∼ GOIs+ Sex+ Age±Lesion) identified a selective positive association of CERS1 (ceramide synthase 1 …

IntroductionThis study aimed to identify social, psychological, and contextual factors that influenced attendance at routine oral health visits in a cohort of 189 preschool children who were followed over a 2-year period.MethodsGeneralized estimating equation was used to examine the association between clinic attendance and the predictors. ORs and 95% CIs were reported in the multiple logistic regression models. The study was conducted in Rochester, New York, between February 2016 and February 2021.ResultsPrior to the COVID-19 pandemic declaration, the rate of canceled and no-show appointments was greater for routine clinic visits (20% and 24%, respectively) than for research visits (14% and 9%, respectively) for the same participants; these rates increased during the pandemic. After adjusting for sociodemographic factors, the likelihood of a canceled or no-show appointment was associated with …

Composition of the vaginal microbiome in pregnancy is associated with adverse maternal, obstetric, and child health outcomes. Identifying the sources of individual differences in the vaginal microbiome is therefore of considerable clinical and public health interest. The current study tested the hypothesis that vaginal microbiome composition during pregnancy is associated with an individual's experience of affective symptoms and stress exposure. Data were based on a prospective longitudinal study of a diverse and medically healthy community sample of 275 mother-infant pairs. Affective symptoms and stress exposure and select measures of associated biomarkers (diurnal salivary cortisol, serum measures of sex hormones) were collected at each trimester; self-report, clinical and medical records were used to collect detailed data on socio-demographic factors and health behavior, including diet and sleep. Vaginal microbiome samples were collected in the third trimester (34-40 weeks) and characterized by 16S rRNA sequencing. Identified taxa were clustered into three community state types (CST1-3) based on dissimilarity of vaginal microbiota composition. Results indicate that depressive symptoms during pregnancy were reliably associated with individual taxa and CST3 in the third trimester. Prediction of functional potential from 16S taxonomy revealed a differential abundance of metabolic pathways in CST1-3 and individual taxa, including biosynthetic pathways for the neuroactive metabolites, serotonin and dopamine. With the exception of bioavailable testosterone, no significant associations were found between symptoms- and stress …

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Musculoskeletal infections (MSKI), which are a major problem in orthopedics, occur when the pathogen eludes or overwhelms the host immune system. While effective vaccines and immunotherapies to prevent and treat MSKI should be possible, fundamental knowledge gaps in our understanding of protective, nonprotective, and pathogenic host immunity are prohibitive. We also lack critical knowledge of how host immunity is affected by the microbiome, implants, prior infection, nutrition, antibiotics, and concomitant therapies, autoimmunity, and other comorbidities. To define our current knowledge of these critical topics, a Host Immunity Section of the 2023 Orthopaedic Research Society MSKI International Consensus Meeting (ICM) proposed 78 questions. Systematic reviews were performed on 15 of these questions, upon which recommendations with level of evidence were voted on by the 72 ICM delegates, and …

Critical knowledge gaps of orthopaedic infections pertain to bacterial colonization. The established dogma termed the Race for the Surface posits that contaminating bacteria compete with host cells for the implant post-op, which remains unproven without real time in vivo evidence. Thus, we modified the murine longitudinal intravital imaging of the bone marrow (LIMB) system to allow real time quantification of GFP+ host cells and ECFP+ or RFP+ methicillin-resistant Staphylococcus aureus (MRSA) proximal to a transfemoral implant. Following inoculation with~ 10 5 CFU, an L-shaped metal implant was press-fit through the lateral cortex at a 90 angle~ 0.150 mm below a gradient refractive index (GRIN) lens. We empirically derived a volume of interest (VOI)= 0.0161±0.000675 mm 3 during each imaging session by aggregating the Z-stacks between the first (superior) and last (inferior) in-focus LIMB slice. LIMB post-implantation revealed very limited bacteria detection at 1hr, but by 3hrs 56.8% of the implant surface was covered by ECFP+ bacteria and the rest covered by GFP+ host cells. 3D volumetric rendering of the GFP+ and ECFP+ or RFP+ voxels demonstrated exponential MRSA growth between 3-6hrs in the Z plane, which was validated with cross-sectional ex vivo bacterial burden analyses demonstrating significant growth by~ 2 x 10 4 CFU/hr on the implant from 2 to 12hrs post-op (p< 0.05; r 2> 0.98). Collectively, these results show the competition at the surface is completed by 3hrs in this model and demonstrate the potential of LIMB to elucidate mechanisms of bacterial colonization, the host immune response, and efficacy of antimicrobials …

Early childhood caries prevention through a developmental origins model of the oral microbiome, host and oral environment, and sociodemographic influences. - Abstract - Europe PMC Sign in | Create an account https://orcid.org Europe PMC Menu About Tools Developers Help Contact us Helpdesk Feedback Twitter Blog Tech blog Developer Forum Europe PMC plus Search life-sciences literature (42,895,960 articles, preprints and more) Search Advanced search Feedback This website requires cookies, and the limited processing of your personal data in order to function. By using the site you are agreeing to this as outlined in our privacy notice and cookie policy. Abstract Full text Early childhood caries prevention through a developmental origins model of the oral microbiome, host and oral environment, and sociodemographic influences. Gill SR , O'Connor TG , Kopycka-Kedzierawski DT Quintessence …

Purpose: Osteoarthritis (OA) is the leading cause of physical disability in the US and globally. Among the various etiologies (eg, age, obesity, genetics), trauma as an initiator is common, with posttraumatic OA (PTOA) accounting for 12-15% of all OA cases. Recently, it has been suggested that the gut microbiome may play a role in OA, with evidence suggesting that in the context of obesity gut microbiome dysbiosis accelerates disease. It is not known if the gut microbiome is involved in other types of OA, and we set out to determine if there are changes in the gut microbial community in the specific context of PTOA. In this work, we hypothesized that progressive PTOA is associated with signature changes in the gut microbiome that can be termed as a PTOA-associated dysbiosis. The gut microbiome's role in promoting osteoarthritis may be explained by these microbial changes.Methods: All mouse experiments were …

Pregnancy initiates a temporary transition in the maternal physiological state, with a shift in the oral microbiome and a potential increase in frequency of oral diseases. The risk of oral disease is higher among populations of Hispanic and Black women and those with lower socioeconomic status (low SES), demonstrating a need for intervention within these high-risk populations. To further our understanding of the oral microbiome of high-risk pregnant women, we characterized the oral microbiome in 28 nonpregnant and 179 pregnant low-SES women during their third trimester living in Rochester, New York. Unstimulated saliva and supragingival plaque samples were collected cross-sectionally, followed by assessment of the bacterial (16S ribosomal RNA) and fungal (18S ITS) microbiota communities. Trained and calibrated dentists performed oral examinations to determine the number of decayed teeth and plaque …

The gut microbiota regulates multiple facets of host metabolism and immunity through the production of signaling metabolites, such as polyamines which are small organic compounds that are essential to host cell growth and lymphocyte activation. Polyamines are most abundant in the intestinal lumen, where their synthesis by the gut microbiota is influenced by microbiome composition and host diet. Disruption of the host gut microbiome in metabolic syndrome and obesity-related type 2 diabetes (obesity/T2D) results in potential dysregulation of polyamine synthesis. A growing body of evidence suggests that restoration of the dysbiotic gut microbiota and polyamine synthesis is effective in ameliorating metabolic syndrome and strengthening the impaired immune responses of obesity/T2D. In this review, we discuss existing studies on gut microbiome determinants of polyamine synthesis, polyamine production in obesity/T2D, and evidence that demonstrates the potential of polyamines as a nutraceutical in obesity/T2D hosts.

Studies have demonstrated that bleach baths improve atopic dermatitis (AD) severity; however, the effects on itch, skin barrier, and cutaneous microbial composition are less clear. We examined whether bleach baths reduce itch, normalize skin barrier function, reduce S. aureus absolute abundance, and increase microbial diversity in adults with AD who were colonized with S. aureus on their non-lesional skin. This was an open label, non-randomized, controlled trial performed at a single academic center. Fifteen AD and five non-atopic healthy controls (NA) were instructed to take two bleach baths (0.005% NaClO; 5–10 min duration) per week for a total of 12 weeks as add-on therapy. Adults 18 to 65 years (inclusive) with mild to severe AD were recruited with EASI score > 6.0, S. aureus culture positivity, access to a bathtub, and ability and willingness to maintain current topical or systemic treatments. They were …

Atopic dermatitis (AD) is characterized by type 2 inflammation, chronic pruritus and Staphylococcus aureus (SA) skin colonization and infections. SA is thought to play a role in AD severity. We characterized the changes in the host-microbial interface in AD subjects following type 2 blockade. Participants (N= 71) with moderate-severe AD were enrolled in a RDBPC study (dupilumab vs placebo; 2: 1) at Atopic Dermatitis Research Network centers. Bioassays were performed at multiple timepoints: SA and virulence factor quantification, 16s rRNA microbiome, serum biomarkers, barrier function, skin transcriptomic analyses and PBMC phenotyping. Dupilumab treatment resulted in significant SA reductions after only 3 days; 11 days before clinical improvement. Those with the greatest SA reductions had the best clinical outcomes, and reductions correlated with CCL17 reductions. Reductions in SA cytotoxins (day 7 …

BackgroundAtopic dermatitis (AD) is an inflammatory disorder characterized by dominant type 2 inflammation leading to chronic pruritic skin lesions, allergic comorbidities, and Staphylococcus aureus skin colonization and infections. S aureus is thought to play a role in AD severity.ObjectivesThis study characterized the changes in the host-microbial interface in subjects with AD following type 2 blockade with dupilumab.MethodsParticipants (n = 71) with moderate-severe AD were enrolled in a randomized (dupilumab vs placebo; 2:1), double-blind study at Atopic Dermatitis Research Network centers. Bioassays were performed at multiple time points: S aureus and virulence factor quantification, 16s ribosomal RNA microbiome, serum biomarkers, skin transcriptomic analyses, and peripheral blood T-cell phenotyping.ResultsAt baseline, 100% of participants were S aureus colonized on the skin surface. Dupilumab …

BackgroundSuboptimal maternal oral health during pregnancy is potentially associated with adverse birth outcomes and increased dental caries risks in children. This study aimed to assess the oral microbiome and immune response following an innovative clinical regimen, Prenatal Total Oral Rehabilitation (PTOR), that fully restores women’s oral health to a “disease-free status” before delivery.MethodsThis prospective cohort study assessed 15 pregnant women at baseline and 3 follow-up visits (1 week, 2 weeks, and 2 months) after receiving PTOR. The salivary and supragingival plaque microbiomes were analyzed using metagenomic sequencing. Multiplexed Luminex cytokine assays were performed to examine immune response following PTOR. The association between salivary immune markers and oral microbiome was further examined.ResultsPTOR was associated with a reduction of periodontal …

IntroductionEarly childhood caries (ECC) is a complex oral disease that is prevalent in US children.ObjectivesThe purpose of this 2-y prospective cohort study was to examine baseline and time-dependent risk factors for ECC onset in initially caries-free preschool children.MethodsA cohort of 189 initially caries-free children aged 1 to 3 y was recruited. At each 6-mo study visit, children were examined using the ICDAS index; salivary samples were collected to assess mutans streptococci (MS), lactobacilli, Candida species, salivary cortisol (prior and after a stressor), and salivary IgA. Diet and oral health behavior were assessed from parent report. Child and family stress exposure was assessed from measures of psychological symptoms, stressful life event exposure, family organization and violence exposure, and social support. Sociodemographic factors were also considered. A Kaplan-Meier estimator of survival …

Purpose: he leading cause of disability in the United States is osteoarthritis (OA), which has a monetary impact of more than $303 billion annually. With no disease-modifying treatments for OA, the need for a therapeutic intervention is an unmet need. Obesity is a risk factor for the development of OA and is known to drive systemic inflammation, a factor that ultimately leads to joint degeneration. We have previously shown that the OA of obesity leads to a dysbiosis of the gut microbiome that, when corrected, is protective against the OA of obesity. This protection coincides with a reduction in both systemic and colonic inflammation, with the colonic phenotype driven by a reduction in the pro-inflammatory macrophage signature. Previous studies in the obesity field have demonstrated that correction of the inflammatory cascade within the colon reduces systemic inflammation. Monocyte chemoattractant protein one (MCP1 …

Wiskott–Aldrich Syndrome (WAS) is characterized by recurrent infections, thrombocytopenia, and eczema. Here, we show that WASp-deficient mice on a BALB/c background have dysregulated cutaneous immune homeostasis with increased leukocyte accumulation in the skin, 1 week after birth. Increased cutaneous inflammation was associated with epithelial abnormalities, namely, altered keratinization, abnormal epidermal tight junctional morphology and increased trans-epidermal water loss; consistent with epidermal barrier dysfunction. Immune and physical barrier disruption was accompanied by progressive skin dysbiosis, highlighting the functional significance of the disrupted cutaneous homeostasis. Interestingly, the dysregulated immunity in the skin preceded the systemic elevation in IgE and lymphocytic infiltration of the colonic lamina propria associated with WASp deficiency. Mechanistically, the enhanced immune cell accumulation in the skin was lymphocyte dependent. Elevated levels of both Type 2 (IL-4, IL-5) and Type 17 (IL-17, IL-22, IL-23) cytokines were present in the skin, as well as the ‘itch’ factor IL-31. Unexpectedly, the canonical WAS-associated cytokine IL-4 did not play a role in the immune dysfunction. Instead, IL-17 was critical for skin immune infiltration and elevation of both Type 2 and Type 17 cytokines. Our findings reveal a previously unrecognized IL-17-dependent breakdown in immune homeostasis and cutaneous barrier integrity in the absence of WASp, targeting of which may provide new therapeutic possibilities for the treatment of skin pathologies in WAS patients.

Atopic dermatitis (AD) severity correlates with S. aureus (SA) colonization and barrier dysfunction. To address the importance of IL-4&-13 on these parameters, the Atopic Dermatitis Research Network designed a 6wk, RDBPC trial (Dupilumab [DPL]: placebo/2: 1) with sampling (at 0, 3, 7, 14, 21, 28 & 42 days [d]) to quantify SA, barrier and severity (EASI, NRS, IGA & SCORAD). Seventy-two moderate-severe adult AD subjects were randomized. There was a> 7-fold reduction in SA (qPCR) on lesional (L) skin in DPL vs placebo group (1 o endpoint [28d]; P< 0.001). SA abundance (qPCR) on L skin was reduced by 3d (P= 0.019) and qPCR & culture quantification were more robustly reduced at 14-42d (P≤ 0.004). SA reductions (qPCR) in nonlesional (NL) skin were seen≥ 7d (P≤ 0.033), but were greater at later timepoints (≥ 21d; P≤ 0.025). Shannon diversity increased as early as 14d (L skin)(P< 0.001) in DPL …

MethodsWe used stored house dust samples from homes of 100 asthmatic children from 5 cities across the United States who participated in the Childhood Asthma Management Program (CAMP) clinical trial. We sequenced the 16S rRNA V1 to V3 regions of bacteria and the 18S and ITS regions of fungi. We studied whether the presence of dogs and cats in the home affected the indoor microbiota, and whether features of the house dust microbiota were associated with asthma exacerbations over the 4 years of the trial (defined as an emergency room visit or hospitalization for asthma).ResultsAn extremely rich diversity of bacteria and fungi from dust samples collected more than 20 years ago was observed. Microbial composition differed by city of residence, with fungal communities being able to differentiate better between locations than bacterial communities. A pet dog in the home contributed to increased bacterial …

Neonatal immune-microbiota co-development is poorly understood, yet age-appropriate recognition of – and response to – pathogens and commensal microbiota is critical to health. In this longitudinal study of 148 preterm and 119 full-term infants from birth through one year of age, we found that postmenstrual age or weeks from conception is a central factor influencing T cell and mucosal microbiota development. Numerous features of the T cell and microbiota functional development remain unexplained; however, by either age metric and are instead shaped by discrete perinatal and postnatal events. Most strikingly, we establish that prenatal antibiotics or infection disrupt the normal T cell population developmental trajectory, influencing subsequent respiratory microbial colonization and predicting respiratory morbidity. In this way, early exposures predict the postnatal immune-microbiota axis trajectory, placing …