Acetaldehyde Production by Rothia Mucilaginosa Isolates from Patients with Oral Leukoplakia.

Rothia mucilaginosa has been found at high abundance on oral leukoplakia (OLK). The ability of clinical isolates to produce acetaldehyde (ACH) from ethanol has not been investigated. The objective of the current study was to determine the capacity of R. mucilaginosa isolates recovered from OLK to generate ACH. Analysis of R. mucilaginosa genomes (n = 70) shows that this species does not normally encode acetaldehyde dehydrogenase (ALDH) required for detoxification of ACH. The predicted OLK metagenome also exhibited reduced ALDH coding capacity. We analysed ACH production in 8 isolates of R. mucilaginosa and showed that this species is capable of generating ACH in the presence of ethanol. The levels of ACH produced (mean = 53 µM) were comparable to those produced by Neisseria mucosa and Candida albicansin parallel assays. These levels were demonstrated to induce oxidative stress in cultured oral keratinocytes. This study shows that R. mucilaginosa can generate ACH from ethanol in vitro at levels which can induce oxidative stress. This organism likely contributes to oral ACH levels following alcohol consumption and the significance of the increased abundance of R. mucilaginosa in patients with potentially malignant disorders requires further investigation

Biomedical Applications of Vibrational Spectroscopy: Oral Cancer Diagnostics

Vibrational spectroscopy, based on either infrared absorption or Raman scattering, has attracted increasing attention for biomedical applications. Proof of concept explorations for diagnosis of oral potentially malignant disorders and cancer are reviewed, and recent advances critically appraised. Specific examples of applications of Raman microspectroscopy for analysis of histological, cytological and saliva samples are presented for illustrative purposes, and the future prospects, ultimately for routine, chairside in vivo screening are discussed

Post-mortem culture of Balamuthia mandrillaris from the brain and cerebrospinal fluid of a case of granulomatous amoebic meningoencephalitis, using human brain microvascular endothelial cells

The first isolation in the UK of Balamuthia mandrillaris amoebae from a fatal case of granulomatous amoebic meningoencephalitis is reported. Using primary cultures of human brain microvascular endothelial cells (HBMECs), amoebae were isolated from the brain and cerebrospinal fluid (CSF). The cultures showed a cytopathic effect at 20–28 days, but morphologically identifiable B. mandrillaris amoebae were seen in cleared plaques in subcultures at 45 days. The identification of the organism was later confirmed using PCR on Chelex-treated extracts. Serum taken while the patient was still alive reacted strongly with slide antigen prepared from cultures of the post-mortem isolate, and also with those from a baboon B. mandrillaris strain at 1 : 10 000 in indirect immunofluorescence, but with Acanthamoeba castellanii (Neff) at 1 : 160, supporting B. mandrillaris to be the causative agent. If the presence of amoebae in the post-mortem CSF reflects the condition in life, PCR studies on CSF and on biopsies of cutaneous lesions may also be a valuable tool. The role of HBMECs in understanding the interactions of B. mandrillaris with the blood–brain barrier is discussed

Drivers of potentially avoidable emergency admissions in Ireland: an ecological analysis

Background: Many emergency admissions are deemed to be potentially avoidable in a well-performing health system. Objective: To measure the impact of population and health system factors on county-level variation in potentially avoidable emergency admissions in Ireland over the period 2014–2016. Methods: Admissions data were used to calculate 2014–2016 age-adjusted emergency admission rates for selected conditions by county of residence. Negative binomial regression was used to identify which a priori factors were significantly associated with emergency admissions for these conditions and whether these factors were also associated with total/other emergency admissions. Standardised incidence rate ratios (IRRs) associated with a 1 SD change in risk factors were reported. Results: Nationally, potentially avoidable emergency admissions for the period 2014–2016 (266 395) accounted for 22% of all emergency admissions. Of the population factors, a 1 SD change in the county-level unemployment rate was associated with a 24% higher rate of potentially avoidable emergency admissions (IRR: 1.24; 95% CI 1.04 to 1.41). Significant health system factors included emergency admissions with length of stay equal to 1 day (IRR: 1.20; 95% CI 1.11 to 1.30) and private health insurance coverage (IRR: 0.92; 95% CI 0.89 to 0.96). The full model accounted for 50% of unexplained variation in potentially avoidable emergency admissions in each county. Similar results were found across total/other emergency admissions. Conclusion: The results suggest potentially avoidable emergency admissions and total/other emergency admissions are primarily driven by socioeconomic conditions, hospital admission policy and private health insurance coverage. The distinction between potentially avoidable and all other emergency admissions may not be as useful as previously believed when attempting to identify the causes of regional variation in emergency admission rates

Case fatality ratios for serious emergency conditions in the Republic of Ireland: a longitudinal investigation of trends over the period 2002-2014 using joinpoint analysis

Background: In the past decade, the Republic of Ireland has undertaken significant reconfiguration programmes to improve emergency services. During this time the public healthcare system experienced a large real decrease in resources. This study assesses national and regional population outcomes over the period 2002–2014, and whether changes coincide with system reconfiguration and the financial restrictions imposed by the 2008 recession. Methods: Case fatality ratios (CFRs) were constructed for emergency conditions for 2002–2014. Total emergency conditions and individual condition trends were analysed nationally using joinpoint analysis. National results informed the investigation of trends at a regional and county level using an inverse standard error weighted generalised linear model with a log link to construct funnel plots. County-level CFRs were compared for the first and last 3 years of the period to further investigate the changes to county results over the 13 year period, specifically in comparison to the national-level CFR. Results: Nationally, there was an annual fall in CFRs (2.1%). The decline was faster from 2002 to 2007 (annual percentage change = − 3.4; 95% CI-4.4, − 2.4), compared to 2007–2014 (annual percentage change = − 1.2; 95% CI -1.9, − 0.5). The South-East had a lower rate of decrease and the West had a higher rate. Cross sectional analysis of two periods (2002–2004 and 2012–2014) showed high consistency in the counties performance relative to the national CFR in both periods. Conclusion: Change in the national trend coincided with the onset of economic stress on the public health system. Attributing the decline in CFR improvement to economic factors is weakened by the uneven nature of the trend change. No distinct pattern of change was identified among regions which underwent substantial reconfiguration of emergency services

Increasing HPV Vaccination in a Network of Pediatric Clinics using a Multi-component Approach

Background: Despite continued public health efforts to increase human papillomavirus (HPV) vaccination among adolescents, initiation remains below the level needed to reach the Healthy People 2020 goal of 80% series completion by age 13. Methods: We developed, implemented, and evaluated a multi-component program that used evidence-based strategies to increase HPV vaccine initiation in a network of 51 pediatric clinics in Houston, Texas. Our target populations were the clinic network, healthcare providers, male and female patients ages 11-17, and their parents. The program, called the Adolescent Vaccination Program (AVP), was conducted from March 2016 through March 2019 and contained strategies to increase vaccination including: HPV immunization champions; provider assessment and feedback; provider continuing education; provider reminders; and patient reminders. We used a single group pre/post design with an external comparison – NIS-Teen. Our primary outcome was initiation of the HPV vaccine based on the electronic health record. We used interrupted time series analysis (ITSA) to measure change in initiation over time. We calculated monthly, quarterly, and annual rates of initiation for each physician, clinic, and the network. We examined patterns of initiation by patient age, sex, race/ethnicity, and type of insurance. Results: By the end of the project, the 51 clinics averaged 77.4% initiation. Rates increased annually from September 2015 through March 2019. ITSA analysis over 75 months showed an increase in vaccine initiation of 0.396% per month from the introduction of the program in March 2016. Average individual clinic improvement was 0.37% per month ranging from -0.04% to 0.68% through March 2019. Data for the 11-12 year olds, the target age group for initiating the vaccine, showed a greater percentage increase (54.2%) compared with the 13-17 year olds (29.6%). Hispanics and African Americans had the highest initiation rates in all years while non-Hispanic whites had the lowest. Families without insurance had the lowest rates while those with Medicaid/Medicare had the highest. Conclusions: We observed a secular trend upward in both the network and NIS-Teen data; however, the network showed a steeper increase. The AVP is a promising program of strategies to increase HPV vaccination in a clinic setting

Prediction of Small for Gestational Age Infants in Healthy Nulliparous Women Using Clinical and Ultrasound Risk Factors Combined with Early Pregnancy Biomarkers

Objective Most small for gestational age pregnancies are unrecognised before birth, resulting in substantial avoidable perinatal mortality and morbidity. Our objective was to develop multivariable prediction models for small for gestational age combining clinical risk factors and biomarkers at 15±1 weeks’ with ultrasound parameters at 20±1 weeks’ gestation. Methods Data from 5606 participants in the Screening for Pregnancy Endpoints (SCOPE) cohort study were divided into Training (n = 3735) and Validation datasets (n = 1871). The primary outcomes were All-SGA (small for gestational age with birthweight <10th customised centile), Normotensive-SGA (small for gestational age with a normotensive mother) and Hypertensive-SGA (small for gestational age with an hypertensive mother). The comparison group comprised women without the respective small for gestational age phenotype. Multivariable analysis was performed using stepwise logistic regression beginning with clinical variables, and subsequent additions of biomarker and then ultrasound (biometry and Doppler) variables. Model performance was assessed in Training and Validation datasets by calculating area under the curve. Results 633 (11.2%) infants were All-SGA, 465(8.2%) Normotensive-SGA and 168 (3%) Hypertensive-SGA. Area under the curve (95% Confidence Intervals) for All-SGA using 15±1 weeks’ clinical variables, 15±1 weeks’ clinical+ biomarker variables and clinical + biomarkers + biometry /Doppler at 20±1 weeks’ were: 0.63 (0.59–0.67), 0.64 (0.60–0.68) and 0.69 (0.66–0.73) respectively in the Validation dataset; Normotensive-SGA results were similar: 0.61 (0.57–0.66), 0.61 (0.56–0.66) and 0.68 (0.64–0.73) with small increases in performance in the Training datasets. Area under the curve (95% Confidence Intervals) for Hypertensive-SGA were: 0.76 (0.70–0.82), 0.80 (0.75–0.86) and 0.84 (0.78–0.89) with minimal change in the Training datasets. Conclusion Models for prediction of small for gestational age, which combine biomarkers, clinical and ultrasound data from a cohort of low-risk nulliparous women achieved modest performance. Incorporation of biomarkers into the models resulted in no improvement in performance of prediction of All-SGA and Normotensive-SGA but a small improvement in prediction of Hypertensive-SGA. Our models currently have insufficient reliability for application in clinical practice however, they have potential utility in two-staged screening tests which include third trimester biomarkers and or fetal biometry

Divergent neuroinflammatory regulation of microglial TREM expression and involvement of NF-κB

The triggering receptor expressed on myeloid cells (TREM) family of proteins are cell surface receptors with important roles in regulation of myeloid cell inflammatory activity. In the central nervous system, TREM2 is implicated in further roles in microglial homeostasis, neuroinflammation and neurodegeneration. Different TREM receptors appear to have contrasting roles in controlling myeloid immune activity therefore the relative and co-ordinated regulation of their expression is important to understand but is currently poorly understood. We sought to determine how microglial TREM expression is affected under neuroinflammatory conditions in vitro and in vivo. Our data show that microglial Trem1 and Trem2 gene expression are regulated in an opposing manner by lipopolysaccharide (LPS) in vitro in both adult murine and human microglia. LPS caused a significant induction of Trem1 and a contrasting suppression of Trem2 expression. We also observed similar divergent Trem1 and Trem2 responses in vivo in response to acute brain inflammation and acute cerebral ischaemia. Our data show that inhibition of NF-κB activation prevents the LPS-induced alterations in both Trem1 and Trem2 expression in vitro indicating NF-κB as a common signaling intermediate controlling these divergent responses. Distinct patterns of microglial Trem1 induction and Trem2 suppression to different Toll-like receptor (TLR) ligands were also evident, notably with Trem1 induction restricted to those ligands activating TLRs signaling via TRIF. Our data show co-ordinated but divergent regulation of microglial TREM receptor expression with a central role for NF-κB. Neuroinflammatory conditions that alter the balance in TREM expression could therefore be an important influence on microglial inflammatory and homeostatic activity with implications for neuroinflammatory and neurodegenerative disease

Prediction of survival of HPV16-negative, p16-negative oral cavity cancer patients using a 13-gene signature: A multicenter study using FFPE samples

Objectives: To WA the performance of an oral cancer prognostic 13-gene signature for the prediction of survival of patients diagnosed with HPV-negative and p16-negative oral cavity cancer. Materials and Methods: Diagnostic formalin-fixed paraffin-embedded oral cavity cancer tumor samples were obtained from the Fred Hutchinson Cancer Research Center/University of Washington, University of Calgary, University of Michigan, University of Utah, and seven ARCAGE study centers coordinated by the International Agency of Research on Cancer. RNA from 638 Human Papillomavirus (HPV)-negative and p16-negative samples was analyzed for the 13 genes using a NanoString assay. Ridge-penalized Cox regressions were applied to samples randomly split into discovery and validation sets to build models and evaluate the performance of the 13-gene signature in predicting 2-year oral cavity cancer-specific survival overall and separately for patients with early and late stage disease. Results: Among AJCC stage I/II patients, including the 13-gene signature in the model resulted in substantial improvement in the prediction of 2-year oral cavity cancer-specific survival. For models containing age and sex with and without the 13-gene signature score, the areas under the Receiver Operating Characteristic Curve (AUC) and partial AUC were 0.700 vs. 0.537 (p < 0.001), and 0.046 vs. 0.018 (p < 0.001), respectively. Improvement in predicting prognosis for AJCC stage III/IV disease also was observed, but to a lesser extent. Conclusions: If confirmed using tumor samples from a larger number of early stage oral cavity cancer patients, the 13-gene signature may inform personalized treatment of early stage HPV-negative and p16-negative oral cavity cancer patients

Genetic Contributions to the Association between Adult Height and Head and Neck Cancer : A Mendelian Randomization Analysis

Acknowledgements: The authors thank the Italian Association for Research on Cancer (AIRC, IG 2013 n. 14211) and the PRECeDI project (Marie Skłodowska-Curie Research and Innovation Staff Exchange - RISE N°645740) for supporting the work of Roberta Pastorino and Anna Puggina.Peer reviewedPublisher PD