Alterations of oral microbiota and impact on the gut microbiome in type 1 diabetes mellitus revealed by integrated multi-omic analyses.

BACKGROUND: Alterations to the gut microbiome have been linked to multiple chronic diseases. However, the drivers of such changes remain largely unknown. The oral cavity acts as a major route of exposure to exogenous factors including pathogens, and processes therein may affect the communities in the subsequent compartments of the gastrointestinal tract. Here, we perform strain-resolved, integrated meta-genomic, transcriptomic, and proteomic analyses of paired saliva and stool samples collected from 35 individuals from eight families with multiple cases of type 1 diabetes mellitus (T1DM). RESULTS: We identified distinct oral microbiota mostly reflecting competition between streptococcal species. More specifically, we found a decreased abundance of the commensal Streptococcus salivarius in the oral cavity of T1DM individuals, which is linked to its apparent competition with the pathobiont Streptococcus mutans. The decrease in S. salivarius in the oral cavity was also associated with its decrease in the gut as well as higher abundances in facultative anaerobes including Enterobacteria. In addition, we found evidence of gut inflammation in T1DM as reflected in the expression profiles of the Enterobacteria as well as in the human gut proteome. Finally, we were able to follow transmitted strain-variants from the oral cavity to the gut at the individual omic levels, highlighting not only the transfer, but also the activity of the transmitted taxa along the gastrointestinal tract. CONCLUSIONS: Alterations of the oral microbiome in the context of T1DM impact the microbial communities in the lower gut, in particular through the reduction of "mouth-to-gut" transfer of Streptococcus salivarius. Our results indicate that the observed oral-cavity-driven gut microbiome changes may contribute towards the inflammatory processes involved in T1DM. Through the integration of multi-omic analyses, we resolve strain-variant "mouth-to-gut" transfer in a disease context. Video Abstract.

Validation of the Hamilton Program for Schizophrenia Voices Questionnaire: Associations with emotional distress and wellbeing, and invariance across diagnosis and sex.

BACKGROUND: Voice-hearing is a transdiagnostic experience with evident negative effects on patients. Good quality measurement is needed to further elucidate the nature, impact and treatment of voice-hearing experiences across patient groups. The Hamilton Program for Schizophrenia Voices Questionnaire (HPSVQ) is a brief self-report measure which requires further psychometric evaluation. METHODS: Using data from a transdiagnostic sample of 401 adult UK patients, the fit of a conceptual HPSVQ measurement model, proposing a separation between physical and emotional voice-hearing characteristics, was tested. A structural model was examined to test associations between voice-hearing, general emotional distress (depression, anxiety, stress) and wellbeing. The invariance of model parameters was examined across diagnosis and sex. RESULTS: The final measurement model comprised two factors named 'voice severity' and 'voice-related distress'. The former comprised mainly physical voice characteristics and the latter mainly distress and other negative impacts. Structural model results supported voice-related distress as mediating the associations between voice severity and emotional distress and wellbeing. Model parameters were invariant across psychosis versus non-psychosis diagnosis and partially invariant across sex. Females experienced more severe and distressing voices and a more direct association between voice severity and general anxiety was evident. CONCLUSIONS: The HPSVQ is a useful self-report measure of voice-hearing with some scope for further exploration and refinement. Voice-related distress appears a key mechanism by which voice severity predicts general distress and wellbeing. Whilst our data broadly support interventions targeting voice-related distress for all patients, females may benefit especially from interventions targeting voice severity and strategies for responding.

Pre-surgical lung biopsy in management of solitary pulmonary nodules: a cost effectiveness analysis.

Objectives: Tissue diagnosis prior to thoracic surgery with curative intent is vital in thoracic lesions concerning for lung cancer. Methods of obtaining tissue diagnosis are variable within the United Kingdom.Methods: We performed a model-based analysis to identify the most efficient method of diagnosis using both a health care perspective. Our analysis concerns adults in the UK presenting with a solitary pulmonary nodule suspicious for a primary lung malignancy, patients with more advanced disease (for example lymph node spread) were not considered. Model assumptions were derived from published sources and expert reviews, cost data were obtained from healthcare research group cost estimates (2016-17). Outcomes were measured in terms of costs experienced to healthcare trusts.Results: Our results show that CT guided percutaneous lung biopsy using an ambulatory approach, is the most cost-effective method of diagnosis. Indeed, using this approach, trust experience approximately half of the cost of an approach of surgical lung biopsy performed at the time of potential resection ('frozen section').Limitations and conclusions: Whilst this analysis is limited to the specific scenario of a solitary pulmonary nodule, these findings have implications for the implementation of lung cancer screening in the UK, which is likely to result in increased numbers of patients with such early disease.

Right on track? Performance of satellite telemetry in terrestrial wildlife research.

Satellite telemetry is an increasingly utilized technology in wildlife research, and current devices can track individual animal movements at unprecedented spatial and temporal resolutions. However, as we enter the golden age of satellite telemetry, we need an in-depth understanding of the main technological, species-specific and environmental factors that determine the success and failure of satellite tracking devices across species and habitats. Here, we assess the relative influence of such factors on the ability of satellite telemetry units to provide the expected amount and quality of data by analyzing data from over 3,000 devices deployed on 62 terrestrial species in 167 projects worldwide. We evaluate the success rate in obtaining GPS fixes as well as in transferring these fixes to the user and we evaluate failure rates. Average fix success and data transfer rates were high and were generally better predicted by species and unit characteristics, while environmental characteristics influenced the variability of performance. However, 48% of the unit deployments ended prematurely, half of them due to technical failure. Nonetheless, this study shows that the performance of satellite telemetry applications has shown improvements over time, and based on our findings, we provide further recommendations for both users and manufacturers.

Evaluation of the protection against norovirus afforded by E. coli monitoring of shellfish production areas under EU regulations.

EC Regulation 854/2004 requires the classification of bivalve mollusc harvesting areas according to the faecal pollution status of sites. It has been reported that determination of Escherichia coli in bivalve shellfish is a poor predictor of norovirus (NoV) contamination in individual samples. We explore the correlation of shellfish E. coli data with norovirus presence using data from studies across 88 UK sites (1,184 paired samples). We investigate whether current E. coli legislative standards could be refined to reduce NoV infection risk. A significant relationship between E. coli and NoV was found in the winter months (October to February) using data from sites with at least 10 data pairs (51 sites). We found that the ratio of arithmetic means (log10 E. coli to log10 NoV) at these sites ranged from 0.6 to 1.4. The lower ratios (towards 0.6) might typically indicate situations where the contribution from UV disinfected sewage discharges was more significant. Conversely, higher ratios (towards 1.4) might indicate a prevalence of animal sources of pollution; however, this relationship did not always hold true and so further work is required to fully elucidate the factors of relevance. Reducing the current class B maximum (allowed in 10% of samples) from 46,000 E. coli per 100 g (corresponding NoV value of 75750 ± 103) to 18,000 E. coli per 100 g (corresponding NoV value of 29365 ± 69) reduces maximum levels of NoV by a factor of 2.6 to 1; reducing the upper class B limit to 100% compliance with 4,600 E. coli per 100 g (corresponding NoV value of 7403 ± 39) reduces maximum levels of NoV by a factor of 10.2 to 1. We found using the UK filtered winter dataset that a maximum of 200 NoV corresponded to a maximum of 128 ± 7 E. coli per 100 g. A maximum of 1,000 NoV corresponded to a maximum of 631 ± 14 E. coli per 100 g.

Is pneumonectomy a justified procedure in patients with persistent N2 nonsmall cell lung cancer disease following induction therapy.

Optimal management and the role of surgery in multimodality treatment for N2 disease nonsmall cell lung cancer (NSCLC) are controversial. In this review, we focus on the possible role of pneumonectomy as a justified procedure in patients with persistent N2 disease following induction therapy. We have conducted an OVID PubMedbased search including manuscripts published in English for relevant studies. The interpretation of these trials highlights the lack of clarity and consistency in our management and leaves areas of controversy. There are no Level 1 data to support either performing or not performing pneumonectomy in this setting. The majority of the literature reviewed stresses the high risk of mortality and morbidity following pneumonectomy as a part of a trimodality approach to Stage IIIA/N2 NSCLC disease. However, selected highvolume institutions do follow this strategy with the level of risk seemingly justifying it for a highly selected group of patients, and this approach to Stage III/N2 NSCLC can be offered safely with acceptable mortality. Patient selection, response rate to induction therapy, and R0 resection are crucial for survival in experienced centers.

An Exploration of the Reliability and Validity of the Spanish Version of the 'Voice and You' (VAY): A Scale for Measuring the Relationship with Voices.

UNLABELLED: The purpose of this study was to adapt the 'Voice and You' Scale (VAY) (Hayward, Denney, Vaughan, & Fowler, 2008) to Spanish and explore its psychometric properties for measuring the perceived relationship with voices. A sample of 50 psychiatric patients with verbal auditory hallucinations (48 had a psychotic disorder and two a borderline personality disorder) was used. Its reliability was calculated using the Cronbach's α and test-retest, and concurrent validity by the Pearson correlation coefficient of the VAY with the Beliefs About Voices Questionnaire and the Psychotic Symptom Rating Scales. The results showed that internal consistency of the Spanish version of the VAY ranged from 0.74 to 0.84 on the various subscales, and test-retest reliability varied from 0.74 to 0.83 on three subscales (voice 'dominance', 'intrusiveness' and hearer 'dependence'), and was lower (0.68) on the hearer 'distance' subscale. Concurrent validity was acceptable as significant associations were found with the Beliefs About Voices Questionnaire and the Psychotic Symptom Rating Scales subscales. It is concluded that the Spanish version of the VAY is a reliable and valid instrument that can assist the exploration of voices within relational frameworks across research and clinical domains. KEY PRACTITIONER MESSAGE: The Spanish version of the VAY is a reliable, valid instrument for evaluating the perception a person can have about his or her relationship with the voices and how the person relates to them. Voices that are perceived as relating dominantly and intrusively, and from whom distance is sought, seem to be distressing and cause disturbance. Voices that are related to dependently are perceived as having benevolent intent and are engaged with. Benevolent or neutral voices may be considered as intrusive because of the intensity and frequency with which they are experienced.

Durability of giant hiatus hernia repair in 455 patients over 20 years.

INTRODUCTION: The surgical management of symptomatic giant hiatus hernia (GHH) aims to improve quality of life (QoL) and reduce the risk of life threatening complications. Previous reports are predominantly those with small sample sizes and short follow-up periods. The present study sought to assess a large cohort of patients for recurrence and QoL over a longer time period. METHODS: This was a follow-up study of a prospectively collected database of 455 consecutive patients. Primary repair of GHH was evaluated by endoscopy/barium meal for recurrence and a standardised symptom questionnaire for QoL. Recurrence was assessed for size, elapsed time, oesophagitis and symptoms. RESULTS: Objective and subjective review was achieved in 91.9% and 68.6% of patients. The median age was 69 years (range: 15-93 years) and 64% were female. Laparoscopic repair was completed in 95% (mesh in 6% and Collis gastroplasty in 7%). The 30-day mortality rate was 0.9%. The proportion of patients alive at five and ten years were 90% and 75% respectively. Postoperative QoL scores improved from a mean of 95 to 111 (p<0.01) and were stable over time (112 at 10 years). The overall recurrence rate was 35.6% (149/418) at 42 months; this was 11.5% (48/418) for hernias >2cm and 24.2% (101/418) for <2cm. The rate of new recurrence at 0-1 years was 13.7% (>2cm = 3.4%, <2cm = 10.3%), at 1-5 years it was 30.8% (>2cm = 9.5%, <2cm = 21.3%), at 5-10 years it was 40.1% (>2cm = 13.8%, <2cm = 26.3%) and at over 10 years it was 50.0% (>2cm = 25.0%, <2cm = 25.0%). Recurrence was associated with oesophagitis but not decreased QoL. Revision surgery was required in 4.8% of cases (14.8% with recurrence). There were no interval major GHH complications. CONCLUSIONS: Surgery has provided sustained QoL improvements irrespective of recurrence. Recurrence occurred progressively over ten years and may predispose to oesophagitis.

Thymectomy: role in the treatment of myasthenia gravis.

Thymectomy is a frequently used treatment for myasthenia gravis (MG) and is virtually always indicated in MG patients who have a thymoma. However, the evidence for thymectomy in non-thymomatous MG remains less certain-no randomised controlled trials have been published to date, although one is currently underway. We reviewed the management and clinical outcome of patients with MG who underwent thymectomy over a 12 year period. Eighty-nine patients who underwent transsternal thymectomy were identified. A thymoma was identified on histology in 24 %, whereas 48, 9 and 19 % had hyperplastic, atrophic and normal thymic histology, respectively. One patient developed post operative myasthenic crisis but generally the procedure was well tolerated. Outcome was favourable for the majority of patients, with 34 % achieving complete stable remission (CSR) and an additional 33 % achieving pharmacological remission. Moreover, steroid requirements fell progressively during follow-up. Patients with a hyperplastic gland had a significantly greater chance of achieving CSR compared to other histological subtypes and the incidence of CSR increased with a longer duration of follow-up. Thymectomy for MG is generally safe and well tolerated and is associated with a sustained improvement of symptoms in the majority of patients.

Different cellular p16(INK4a) localisation may signal different survival outcomes in head and neck cancer.

BACKGROUND: Recently, the management of head and neck squamous cell carcinoma (HNSCC) has focused considerable attention on biomarkers, which may influence outcomes. Tests for human papilloma infection, including direct assessment of the virus as well as an associated tumour suppressor gene p16, are considered reproducible. Tumours from familial melanoma syndromes have suggested that nuclear localisation of p16 might have a further role in risk stratification. We hypothesised p16 staining that considered nuclear localisation might be informative for predicting outcomes in a broader set of HNSCC tumours not limited to the oropharynx, human papilloma virus (HPV) status or by smoking status. METHODS: Patients treated for HNSCC from 2002 to 2006 at UNC (University of North Carolina at Chapel Hill) hospitals that had banked tissue available were eligible for this study. Tissue microarrays (TMA) were generated in triplicate. Immunohistochemical (IHC) staining for p16 was performed and scored separately for nuclear and cytoplasmic staining. Human papilloma virus staining was also carried out using monoclonal antibody E6H4. p16 expression, HPV status and other clinical features were correlated with progression-free (PFS) and overall survival (OS). RESULTS: A total of 135 patients had sufficient sample for this analysis. Median age at diagnosis was 57 years (range 20-82), with 68.9% males, 8.9% never smokers and 32.6% never drinkers. Three-year OS rate and PFS rate was 63.0% and 54.1%, respectively. Based on the p16 staining score, patients were divided into three groups: high nuclear, high cytoplasmic staining group (HN), low nuclear, low cytoplasmic staining group (LS) and high cytoplasmic, low nuclear staining group (HC). The HN and the LS groups had significantly better OS than the HC group with hazard ratios of 0.10 and 0.37, respectively, after controlling for other factors, including HPV status. These two groups also had significantly better PFS than the HC staining group. This finding was consistent for sites outside the oropharynx and did not require adjustment for smoking status. CONCLUSION: Different p16 protein localisation suggested different survival outcomes in a manner that does not require limiting the biomarker to the oropharynx and does not require assessment of smoking status.

Modulation of gastric pH by a buffered soluble effervescent formulation: A possible means of improving gastric tolerability of alendronate.

Gastrointestinal side-effects of alendronate (ALN) are believed to be associated with oesophageal lodging of tablets and perhaps reflux of gastric contents with alendronate under strongly acidic pH conditions. This leads to unfavourable posture restrictions when dosing. This clinical study evaluated gastric emptying and gastric pH after administration of Fosamax(®) tablets and a novel effervescent ALN formulation with a high buffering capacity. This novel formulation, EX101, was developed to potentially improve gastric tolerance. Gastric pH was monitored by nasogastric probes. Gastric emptying was determined simultaneously by scintigraphic imaging of (99m)Tc-DTPA labelled formulations. Both formulations tested rapidly cleared the oesophagus and there were no statistically significant or physiologically relevant differences in gastric emptying times. Mean pH at time to 50% gastric emptying of the radiolabel was significantly higher in EX101-treated subjects compared to those treated with Fosamax(®). At time to 90% gastric emptying of the radiolabel, mean pH values were comparable. Mucosal exposure to ALN at pH less than 3 is irritating to gastro-oesophageal tissue. Ingestion of Fosamax(®) resulted in ALN being present in the stomach at a pH below 3 within minutes. EX101 minimised the possibility of exposing the oesophagus (in case of reflux) to acidified ALN.

Expectations and illusions: a position paper on the relationship between mental health practitioners and social exclusion.

Over the last 10 years, the social inclusion agenda has been gaining momentum as a policy driver in mental health services. Prior to the seminal Social Exclusion Unit (SEU) report, Mental Health and Social Exclusion, there was a lack of awareness concerning the pervasive links between social exclusion and mental health problems. In the report, the SEU suggested that mental health practitioners themselves may actually be contributing to this social exclusion. This finding has been given limited coverage in both social inclusion literature and research. The current paper is a positioned commentary further exploring the relationship between practitioners and the social exclusion of mental health service users. A literature review was conducted in order to identify themes among factors which appear to moderate and contribute to this relationship. These factors are presented and implications for inclusive practice are explored.

Atomic-scale structure of biogenic materials by total X-ray diffraction: a study of bacterial and fungal MnOx.

Biogenic materials are produced by microorganisms and are typically found in a nanophase state. As such, they are difficult to characterize structurally. In this report, we demonstrate how high-energy X-ray diffraction and atomic pair distribution function analysis can be used to determine the atomic-scale structures of MnO(x) produced by bacteria and fungi. These structures are well-defined, periodic, and species-specific, built of Mn-O(6) octahedra forming birnessite-type layers and todorokite-type tunnels, respectively. The inherent structural diversity of biogenic material may offer opportunities for practical applications.

Organization of ventricular fibrillation in the human heart: experiments and models.

Sudden cardiac death is a major health problem in the industrialized world. The lethal event is typically ventricular fibrillation (VF), during which the co-ordinated regular contraction of the heart is overthrown by a state of mechanical and electrical anarchy. Understanding the excitation patterns that sustain VF is important in order to identify potential therapeutic targets. In this paper, we studied the organization of human VF by combining clinical recordings of electrical excitation patterns on the epicardial surface during in vivo human VF with simulations of VF in an anatomically and electrophysiologically detailed computational model of the human ventricles. We find both in the computational studies and in the clinical recordings that epicardial surface excitation patterns during VF contain around six rotors. Based on results from the simulated three-dimensional excitation patterns during VF, which show that the total number of electrical sources is 1.4 +/- 0.12 times greater than the number of epicardial rotors, we estimate that the total number of sources present during clinically recorded VF is 9.0 +/- 2.6. This number is approximately fivefold fewer compared with that observed during VF in dog and pig hearts, which are of comparable size to human hearts. We explain this difference by considering differences in action potential duration dynamics across these species. The simpler spatial organization of human VF has important implications for treatment and prevention of this dangerous arrhythmia. Moreover, our findings underline the need for integrated research, in which human-based clinical and computational studies complement animal research.

Erythropoietin protects the human myocardium against hypoxia/reoxygenation injury via phosphatidylinositol-3 kinase and ERK1/2 activation.

BACKGROUND AND PURPOSES: Erythropoietin (EPO) has been shown to protect against myocardial infarction in animal studies by activating phosphatidylinositol-3 kinase (PI3K)/Akt and ERK1/2. However these pro-survival pathways are impaired in the diabetic heart. We investigated the ability of EPO to protect human atrial trabeculae from non-diabetic and diabetic patients undergoing coronary artery bypass surgery, against hypoxia-reoxygenation injury. EXPERIMENTAL APPROACH: Human atrial trabeculae were exposed to 90min hypoxia and 120min reoxygenation. EPO was administered throughout reoxygenation. The developed force of contraction, calculated as a percentage of baseline force of contraction, was continuously monitored. The involvement of PI3K and ERK1/2 and the levels of activated caspase 3(AC3) were assessed. KEY RESULTS: EPO improved the force of contraction in tissue from non-diabetic patients (46.7+/-1.7% vs. 30.2+/-2.2% in control, p<0.001). These beneficial effects were prevented by the PI3K inhibitor, LY294002 and the ERK1/2 inhibitor, U0126. EPO also significantly improved the force of contraction in the diabetic tissue, although to a lesser degree. The levels of activated caspase 3 were significantly reduced in EPO treated trabeculae from both non-diabetic and diabetic patients, relative to their respective untreated controls. CONCLUSIONS AND IMPLICATIONS: EPO administered at reoxygenation protected human myocardial muscle by activating PI3K and ERK1/2 and reducing the level of activated caspase 3. This cardioprotection was also observed in the diabetic group. This data supports the potential of EPO being used as a novel cardioprotective strategy either alone or as an adjunct in the clinical setting alongside existing reperfusion therapies.

Distribution of human endogenous retrovirus type W receptor in normal human villous placenta.

BACKGROUND: The fusion of trophoblast cells into the villous syncytiotrophoblast is crucial for appropriate placental function and fetal development. Fusion occurs following the interaction of syncytin-1, an envelope protein of the endogenous retrovirus HERV-W, and the RD114/mammalian type D retrovirus receptor (RDR/ASCT2) on adjacent cell membranes. This process must be tightly regulated in order to maintain the proliferative pool of cytotrophoblast cells as well as the function of the syncytia. AIM: We sought to investigate whether syncytial fusion of placental cytotrophoblast cells may be regulated via modulation of RDR/ASCT2 expression. METHODS: Expression of RDR/ASCT2 in term and first trimester villous placenta was assessed along with a number of molecular markers using immunofluorescent staining. In a complementary approach, Western blotting was used to investigate RDR/ASCT2 expression in a panel of choriocarcinoma cell lines before and after stimulation of fusion. RESULTS: Villous placental RDR/ASCT2 expression was found to be restricted to the cytotrophoblast compartment, being largely absent in the syncytiotrophoblast. Local variations in RDR/ASCT2 expression were not associated with the proliferative status of cytotrophoblast cells. RDR/ASCT2 expression was also shown to be down-regulated in BeWo choriocarcinoma cells after stimulation of syncytial fusion. CONCLUSION: This first report of the localisation and distribution of RDR/ASCT2 in human placental villi suggests that the fusion of placental trophoblast cells is not regulated by local or temporal variations of RDR/ASCT2 expression in villous cytotrophoblast cells.

Aortic stenosis in cardiovascular ochronosis.

Alkaptonuria (endogenous ochronosis) is a rare metabolic disorder caused by a deficiency of homogentisic acid oxidase, an enzyme responsible for the metabolic degradation of tyrosine. Patients with alkaptonuria commonly present with joint pain owing to degenerative arthritis. Other affected patients may present with pigmentation of the ear cartilage and sclera. This article reports a case of aortic stenosis associated with ochronosis in a 48-year-old man who presented with severe cardiac failure. He had no previous diagnosis of alkaptonuria, which was confirmed by mass spectrometry analysis of urine. The pathogenesis of cardiovascular ochronosis is unclear, but is probably related to the extensive extracellular deposits of ochronotic pigment in the cardiac tissue.