Evaluating enteric methane emissions within a herd of genetically divergent grazing dairy cows.

Enteric methane (CH4) emissions of 3 genetic groups (GG) of dairy cows were recorded across the grazing season (early March to late October). The 3 GG were (1) high economic breeding index (EBI) Holstein-Friesian (HF) representative of the top 1% of dairy cows in Ireland at the time of the study (elite), (2) national average (NA) EBI, which were representative of the average HF dairy cow in Ireland, and (3) purebred Jersey (JE) cows. Enteric CH4 was recorded using GreenFeed technology. Seasonal variation in CH4 was observed, with the lowest daily CH4 emissions and CH4 expressed per unit of dry matter intake occurring in spring (253 g/d and 15.56 g/kg, respectively), intermediate in summer (303 g/d and 18.26 g/kg, respectively), and greatest in autumn (324 g/d and 19.80 g/kg, respectively). Seasonal variation was also observed in the proportion of gross energy intake converted to CH4 (Ym); in the spring the Ym was lowest at 0.046, increasing to 0.053 and 0.058 in the summer and autumn, respectively. There was no difference in daily CH4 between the elite and NA, whereas JE had lower CH4 emissions compared with the elite. When expressed per unit of milk solids (fat + protein yield; MS), the elite and JE produced 6.8% and 9.7% less CH4 per kilogram of MS, respectively, compared with NA. There was no difference between the GG for CH4 per unit of DMI or the Ym. This research emphasizes the variation in CH4 emissions across the grazing season and among cows of differing genetic merit for CH4 emission intensities but not for CH4 per unit of DMI or the Ym.

Exploring the importance of work outcomes in gynaecological patients.

BACKGROUND: There has been increasing evidence that physicians in gynaecology are not routinely enquiring about work during consultations. AIMS: To explore the effect gynaecological conditions can have on work functioning, the importance of work outcomes among patients and whether work considerations are discussed during clinical consultations. METHODS: A cross-sectional survey was administered to employed patients attending a gynaecological clinic at Guy's Hospital. The survey assessed four areas: demographics, gynaecological condition (including self-assessed severity), work status and perceived impact of the condition on work functioning and job satisfaction. Simple descriptive analysis and statistical techniques were used to interpret the data. RESULTS: One hundred and six participants participated (mean age: 37.49 ±â€…9.09). About 95% found it important to be able to work whilst receiving treatment and 82% of patients had reported at least a slight impact on their working ability due to their condition. Of the 31 patients for whom it was their first appointment, 77% said it would be useful to discuss the possible impacts their gynaecological condition could have on their work. About 66% (19/29) of the participants attending a follow-up appointment reported that their doctor had not discussed their work with them. CONCLUSIONS: The symptoms of gynaecological conditions can impact patients' ability to work. There is a lack of useful discussion from doctors about the perceived impact gynaecological conditions can have on a patient's ability to work, despite patients finding it important to be able to remain or return to work.

Longitudinal tracking of 97 esophageal adenocarcinomas using liquid biopsy sampling.

BACKGROUND: The incidence of esophageal adenocarcinoma (EAC) is rapidly rising and has a 5-year survival rate of <20%. Beyond TNM (tumor-node-metastasis) staging, no reliable risk stratification tools exist and no large-scale studies have profiled circulating tumor DNA (ctDNA) at relapse in EAC. Here we analyze the prognostic potential of ctDNA dynamics in EAC, taking into account clonal hematopoiesis with indeterminate potential (CHIP). PATIENTS AND METHODS: A total of 245 samples from 97 patients treated with neoadjuvant chemotherapy and surgery were identified from the prospective national UK Oesophageal Cancer Clinical and Molecular Stratification (OCCAMS) consortium data set. A pan-cancer ctDNA panel comprising 77 genes was used. Plasma and peripheral blood cell samples were sequenced to a mean depth of 7082× (range 2196-28 524) and ctDNA results correlated with survival. RESULTS: Characteristics of the 97 patients identified were as follows: 83/97 (86%) male, median age 68 years (SD 9.5 years), 100% cT3/T4, 75% cN+. EAC-specific drivers had higher variant allele fractions than passenger mutations. Using stringent quality criteria 16/79 (20%) were ctDNA positive following resection; recurrence was observed in 12/16 (75%) of these. As much as 78/97 (80%) had CHIP analyses that enabled filtering for CHIP variants, which were found in 18/78 (23%) of cases. When CHIP was excluded, 10/63 (16%) patients were ctDNA positive and 9/10 of these (90%) recurred. With correction for CHIP, median cancer-specific survival for ctDNA-positive patients was 10.0 months versus 29.9 months for ctDNA-negative patients (hazard ratio 5.55, 95% confidence interval 2.42-12.71; P = 0.0003). Similar outcomes were observed for disease-free survival. CONCLUSIONS: We demonstrate in a large, national, prospectively collected data set that ctDNA in plasma following surgery for EAC is prognostic for relapse. Inclusion of peripheral blood cell samples can reduce or eliminate false positives from CHIP. In future, post-operative ctDNA could be used to risk stratify patients into high- and low-risk groups for intensification or de-escalation of adjuvant chemotherapy.

Macroalgal protein hydrolysates from Palmaria palmata influence the 'incretin effect' in vitro via DPP-4 inhibition and upregulation of insulin, GLP-1 and GIP secretion.

PURPOSE: This study investigated metabolic benefits of protein hydrolysates from the macroalgae Palmaria palmata, previously shown to inhibit dipeptidylpeptidase-4 (DPP-4) activity in vitro. METHODS: Previously, Alcalase/Flavourzyme-produced P. palmata protein hydrolysate (PPPH) improved glycaemia and insulin production in streptozotocin-induced diabetic mice. Here the PPPH, was compared to alternative Alcalase, bromelain and Promod-derived hydrolysates and an unhydrolysed control. All PPPH's underwent simulated gastrointestinal digestion (SGID) to establish oral bioavailability. PPPH's and their SGID counterparts were tested in pancreatic, clonal BRIN-BD11 cells to assess their insulinotropic effect and associated intracellular mechanisms. PPPH actions on the incretin effect were assessed via measurement of DPP-4 activity, coupled with GLP-1 and GIP release from GLUTag and STC-1 cells, respectively. Acute in vivo effects of Alcalase/Flavourzyme PPPH administration on glucose tolerance and satiety were assessed in overnight-fasted mice. RESULTS: PPPH's (0.02-2.5 mg/ml) elicited varying insulinotropic effects (p < 0.05-0.001). SGID of the unhydrolysed protein control, bromelain and Promod PPPH's retained, or improved, bioactivity regarding insulin secretion, DPP-4 inhibition and GIP release. Insulinotropic effects were retained for all SGID-hydrolysates at higher PPPH concentrations. DPP-4 inhibitory effects were confirmed for all PPPH's and SGID counterparts (p < 0.05-0.001). PPPH's were shown to directly influence the incretin effect via upregulated GLP-1 and GIP (p < 0.01-0.001) secretion in vitro, largely retained after SGID. Alcalase/Flavourzyme PPPH produced the greatest elevation in cAMP (p < 0.001, 1.7-fold), which was fully retained post-SGID. This hydrolysate elicited elevations in intracellular calcium (p < 0.01) and membrane potential (p < 0.001). In acute in vivo settings, Alcalase/Flavourzyme PPPH improved glucose tolerance (p < 0.01-0.001) and satiety (p < 0.05-0.001). CONCLUSION: Bioavailable PPPH peptides may be useful for the management of T2DM and obesity.

Greenhouse gas emissions and nitrogen efficiency of dairy cows of divergent economic breeding index under seasonal pasture-based management.

Greenhouse gas (GHG) emissions and nitrogen (N) efficiencies were modeled for 2 genetic groups (GG) of Holstein-Friesian cows across 3 contrasting feeding treatments (FT). The 2 GG were (1) high economic breeding index (EBI) animals representative of the top 5% of cows nationally (elite) and (2) EBI representative of the national average (NA). The FT represented (1) generous feeding of pasture, (2) a slight restriction in pasture allowance, and (3) a high-concentrate feeding system with adequate pasture allowance. Greenhouse gas and N balance models were parameterized using outputs generated from the Moorepark Dairy Systems model, a stochastic budgetary simulation model, having integrated biological data pertaining to the 6 scenarios (2 GG × 3 FT) obtained from a 4-yr experiment conducted between 2013 and 2016. On a per hectare basis, total system GHG emissions were similar for both elite and NA across the 3 FT. Per unit of product, however, the elite group had 10% and 11% lower GHG emissions per kilogram of fat- and protein-corrected milk and per kilogram of milk solids (MSO; fat + protein kg), respectively, compared with the NA across the 3 FT. The FT incorporating high concentrate supplementation had greater absolute GHG emissions per hectare as well as GHG per kilogram of fat- and protein-corrected milk and MSO. The elite group had a slightly superior N use efficiency (N output/N input) and lower N surplus (N input - N output) compared with the NA group. The high concentrate FT had an inferior N use efficiency and a higher N surplus. The results of the current study demonstrate that breeding for increased EBI will lead to a general improvement in GHG emissions per unit of product as well as improved N efficiency. The results also illustrate that reducing concentrate supplementation will reduce GHG emissions, GHG emissions intensity, while improving N efficiency in the context of pasture-based dairy production.

Machine learning to predict early recurrence after oesophageal cancer surgery.

BACKGROUND: Early cancer recurrence after oesophagectomy is a common problem, with an incidence of 20-30 per cent despite the widespread use of neoadjuvant treatment. Quantification of this risk is difficult and existing models perform poorly. This study aimed to develop a predictive model for early recurrence after surgery for oesophageal adenocarcinoma using a large multinational cohort and machine learning approaches. METHODS: Consecutive patients who underwent oesophagectomy for adenocarcinoma and had neoadjuvant treatment in one Dutch and six UK oesophagogastric units were analysed. Using clinical characteristics and postoperative histopathology, models were generated using elastic net regression (ELR) and the machine learning methods random forest (RF) and extreme gradient boosting (XGB). Finally, a combined (ensemble) model of these was generated. The relative importance of factors to outcome was calculated as a percentage contribution to the model. RESULTS: A total of 812 patients were included. The recurrence rate at less than 1 year was 29·1 per cent. All of the models demonstrated good discrimination. Internally validated areas under the receiver operating characteristic (ROC) curve (AUCs) were similar, with the ensemble model performing best (AUC 0·791 for ELR, 0·801 for RF, 0·804 for XGB, 0·805 for ensemble). Performance was similar when internal-external validation was used (validation across sites, AUC 0·804 for ensemble). In the final model, the most important variables were number of positive lymph nodes (25·7 per cent) and lymphovascular invasion (16·9 per cent). CONCLUSION: The model derived using machine learning approaches and an international data set provided excellent performance in quantifying the risk of early recurrence after surgery, and will be useful in prognostication for clinicians and patients.

ANTECEDENTES: la recidiva precoz del cáncer tras esofaguectomía es un problema frecuente con una incidencia del 20-30% a pesar del uso generalizado del tratamiento neoadyuvante. La cuantificación de este riesgo es difícil y los modelos actuales funcionan mal. Este estudio se propuso desarrollar un modelo predictivo para la recidiva precoz después de la cirugía para el adenocarcinoma de esófago utilizando una gran cohorte multinacional y enfoques con aprendizaje automático. MÉTODOS: Se analizaron pacientes consecutivos sometidos a esofaguectomía por adenocarcinoma y que recibieron tratamiento neoadyuvante en 6 unidades de cirugía esofagogástrica del Reino Unido y 1 de los Países Bajos. Con la utilización de características clínicas y la histopatología postoperatoria se generaron modelos mediante regresión de red elástica (elastic net regression, ELR) y métodos de aprendizaje automático Random Forest (RF) y XG boost (XGB). Finalmente, se generó un modelo combinado (Ensemble) de dichos métodos. La importancia relativa de los factores respecto al resultado se calculó como porcentaje de contribución al modelo. RESULTADOS: En total se incluyeron 812 pacientes. La tasa de recidiva a menos de 1 año fue del 29,1%. Todos los modelos demostraron una buena discriminación. Las áreas bajo la curva ROC (AUC) validadas internamente fueron similares, con el modelo Ensemble funcionando mejor (ELR = 0,791, RF = 0,801, XGB = 0,804, Ensemble = 0,805). El rendimiento fue similar cuando se utilizaba validación interna-externa (validación entre centros, Ensemble AUC = 0,804). En el modelo final, las variables más importantes fueron el número de ganglios linfáticos positivos (25,7%) y la invasión linfovascular (16,9%). CONCLUSIÓN: El modelo derivado con la utilización de aproximaciones con aprendizaje automático y un conjunto de datos internacional proporcionó un rendimiento excelente para cuantificar el riesgo de recidiva precoz tras la cirugía y será útil para clínicos y pacientes a la hora de establecer un pronóstico.

Reproductive efficiency and survival of Holstein-Friesian cows of divergent Economic Breeding Index, evaluated under seasonal calving pasture-based management.

The objective of the current study was to examine phenotypic fertility performance and survival, and to gain insight into underlying factors that may contribute to greater fertility performance in 2 divergent genetic groups (GG) of Holstein-Friesian, selected using the Irish Economic Breeding Index (EBI). The GG were evaluated across 3 spring calving pasture-based feeding treatments (FT) over 4 yr. The 2 divergent GG were (1) high EBI; representative of the top 5% nationally (elite), and (2) EBI representative of the national average (NA). In each year, 90 elite and 45 NA cows were randomly allocated to 1 of 3 FT: control, lower grass allowance, and high concentrate. No interaction between GG and FT was observed for any of the measures of fertility investigated. The elite cows achieved significantly greater pregnancy rate to first service (+14.9 percentage points), and significantly greater pregnancy rates after 21, 42, and 84 d of breeding (+17.3, +15.2, and +9.6 percentage points, respectively) compared with NA. The number of services per cow was fewer for elite (1.57) compared with NA (1.80). The interval from mating start date to pregnancy was significantly shorter for elite cows compared with NA. The elite cows maintained greater mean body condition score than NA throughout the study (2.91 vs. 2.72), and had greater body condition score at calving, artificial insemination, and drying off compared with NA. The elite cows had greater mean circulating concentrations of insulin-like growth factor-1 compared with NA. No significant effect was observed of GG on commencement of luteal activity, or progesterone profile variables. Greater survival to the start of fifth lactation was observed for elite cows. The elite cows were 43% less likely to be culled than NA by the beginning of the fifth lactation. The results highlight the success of the Economic Breeding Index to deliver reproductive performance and longevity consistent with industry targets across a range of seasonal pasture-based FT. The results also clearly demonstrate the potential of appropriate genetic selection to reverse negative fertility trends incurred during previous decades of selection for milk production alone.

A crosssectional analysis of Facebook comments to study public perception of a new diagnostic test called the Cytosponge.

Social media provides a useful platform for informal discussions about healthcare. Acceptability is key to the uptake of diagnostic devices and this can be difficult to gauge from questionnaires and qualitative studies. The aim of this study is to investigate whether Facebook could be used to gauge public perception toward uptake of a new diagnostic test for Barrett's esophagus called the Cytosponge. We retrospectively reviewed Facebook comments relating to a video on the Cytosponge. We categorized comments into: (1) Positive, (2) Negative, (3) Unknown and (4) Questions. Recurring themes that arose were compared to a qualitative study on the Cytosponge. The video received 22.5 million views and 2837 comments within four months. Of these, 525 comments were positive, 215 were unknown, 179 were negative, 71 were questions, and 1847 were 'Tagged' comments. Among positive comments, recurrent themes were that it was innovative, could lead to early cancer-detection, and more favorable than endoscopy. Among negative comments, a recurring theme was concern about the risk of gagging and vomiting. Among 'questions', a recurring theme was related to the risk of Cytosponge detachment. We compared our analysis to a published qualitative study and found similar themes arose across both studies. Facebook provides a rich source of qualitative data, which could be used to augment studies to gauge public perception toward a new diagnostic test.

A biomarker panel predicts progression of Barrett's esophagus to esophageal adenocarcinoma.

Progression from Barrett's esophagus (BE) to esophageal adenocarcinoma (EAC) is uncommon but the consequences are serious. Predictors of progression are essential to optimize resource utilization. This study assessed the utility of a promising panel of biomarkers applicable to routine paraffin embedded biopsies (FFPE) to predict progression of BE to EAC in a large population-based, nested case-control study.We utilized the Amsterdam-based ReBus nested case-control cohort. BE patients who progressed to high-grade dysplasia (HGD)/EAC (n = 130) and BE patients who never progressed (n = 130) were matched on age, sex, length of the BE segment, and duration of endoscopic surveillance. All progressors had minimum 2 years of endoscopic surveillance without HGD/EAC to exclude prevalent neoplasia. We assessed abnormal DNA content, p53, Cyclin A, and Aspergillus oryzae lectin (AOL) in FFPE sections. We performed conditional logistic regression analysis to estimate odds ratio (OR) of progression based on biomarker status.Expert LGD (OR, 8.3; 95% CI, 1.7-41.0), AOL (3 vs. 0 epithelial compartments abnormal; OR, 3.6; 95% CI, 1.2-10.6) and p53 (OR, 2.3; 95% CI, 1.2-4.6) were independently associated with neoplastic progression. Cyclin A did not predict progression and DNA ploidy analysis by image cytometry was unsuccessful in the majority of cases, both were excluded from the multivariate analysis. The multivariable biomarker model had an area under the receiver operating characteristic curve of 0.73.Expert LGD, AOL, and p53 independently predict neoplastic progression in BE patients and are applicable to routine practice. These biomarkers can aid in selecting patients for endoscopic ablation or more intensive surveillance.

International cancer seminars: a focus on esophageal squamous cell carcinoma.

The International Agency for Research on Cancer (IARC) and the US National Cancer Institute (NCI) have initiated a series of cancer-focused seminars [Scelo G, Hofmann JN, Banks RE et al. International cancer seminars: a focus on kidney cancer. Ann Oncol 2016; 27(8): 1382-1385]. In this, the second seminar, IARC and NCI convened a workshop in order to examine the state of the current science on esophageal squamous cell carcinoma etiology, genetics, early detection, treatment, and palliation, was reviewed to identify the most critical open research questions. The results of these discussions were summarized by formulating a series of 'difficult questions', which should inform and prioritize future research efforts.

Multicentre cohort study to define and validate pathological assessment of response to neoadjuvant therapy in oesophagogastric adenocarcinoma.

BACKGROUND: This multicentre cohort study sought to define a robust pathological indicator of clinically meaningful response to neoadjuvant chemotherapy in oesophageal adenocarcinoma. METHODS: A questionnaire was distributed to 11 UK upper gastrointestinal cancer centres to determine the use of assessment of response to neoadjuvant chemotherapy. Records of consecutive patients undergoing oesophagogastric resection at seven centres between January 2000 and December 2013 were reviewed. Pathological response to neoadjuvant chemotherapy was assessed using the Mandard Tumour Regression Grade (TRG) and lymph node downstaging. RESULTS: TRG (8 of 11 centres) was the most widely used system to assess response to neoadjuvant chemotherapy, but there was discordance on how it was used in practice. Of 1392 patients, 1293 had TRG assessment; data were available for clinical and pathological nodal status (cN and pN) in 981 patients, and TRG, cN and pN in 885. There was a significant difference in survival between responders (TRG 1-2; median overall survival (OS) not reached) and non-responders (TRG 3-5; median OS 2·22 (95 per cent c.i. 1·94 to 2·51) years; P < 0·001); the hazard ratio was 2·46 (95 per cent c.i. 1·22 to 4·95; P = 0·012). Among local non-responders, the presence of lymph node downstaging was associated with significantly improved OS compared with that of patients without lymph node downstaging (median OS not reached versus 1·92 (1·68 to 2·16) years; P < 0·001). CONCLUSION: A clinically meaningful local response to neoadjuvant chemotherapy was restricted to the small minority of patients (14·8 per cent) with TRG 1-2. Among local non-responders, a subset of patients (21·3 per cent) derived benefit from neoadjuvant chemotherapy by lymph node downstaging and their survival mirrored that of local responders.

Loss of SRY-box2 (SOX2) expression and its impact on survival of patients with oesophageal adenocarcinoma.

BACKGROUND: Oesophageal adenocarcinoma (OAC) is a highly aggressive malignancy with poor survival, which is highly variable amongst patients with comparable conventional prognosticators. Therefore molecular biomarkers are urgently needed to improve the prediction of survival in these patients. SRY (sex determining region Y)-box 2, also known as SOX2, is a transcription factor involved in embryonal development of the gastrointestinal tract as well as in carcinogenesis. The purpose of this study was to see whether SOX2 expression is associated with survival in patients with OAC. METHODS: SOX2 was studied by immunohistochemistry in patients who had undergone potentially curative oesophagectomy for adenocarcinoma. Protein expression of SOX2 was evaluated using tissue microarrays from resection specimens, and results were analysed in relation to the clinical data by Cox regression analysis. SOX2 was evaluated in two independent OAC cohorts (Rotterdam cohort and a multicentre UK cohort). RESULTS: Loss of SOX2 expression was independently predictive of adverse overall survival in the multivariable analysis, adjusted for known factors influencing survival, in both cohorts (Rotterdam cohort: hazard ratio (HR) 1·42, 95 per cent c.i. 1·07 to 1·89, P = 0·016; UK cohort: HR 1·54, 1·08 to 2·19, P = 0·017). When combined with clinicopathological staging, loss of SOX2 showed an increased effect in patients with pT1-2 tumours (P = 0·010) and node-negative OAC (P = 0·038), with an incrementally adverse effect on overall survival for stage I OAC with SOX2 loss (HR 3·18, 1·18 to 8·56; P = 0·022). CONCLUSION: SOX2 is an independent prognostic factor for long-term survival in OAC, especially in patients with stage I OAC.

Activity measurements of the radionuclides 18F and 64Cu for the NIST, USA in the ongoing comparisons BIPM.RI(II)-K4.F-18 and BIPM.RI(II)-K4.Cu-64.

In 2016, comparisons of activity measurements of 18F and 64Cu using the Transfer Instrument of the International Reference System (SIRTI) took place at the National Institute of Standards and Technology (NIST, USA). This is the first SIRTI comparison for 64Cu. Ampoules containing about 27 kBq of 18F and 100 kBq of 64Cu solutions were measured in the SIRTI for about 5 and 1.5 half-lives, respectively. The NIST standardized the activity in the ampoules by ionization chamber measurements traceable to 4π(LS)ß-γ anticoincidence measurements. The comparisons, identifiers BIPM.RI(II)-K4.F-18 and BIPM.RI(II)-K4.Cu-64, are linked to the corresponding BIPM.RI(II)-K1.F-18 and BIPM.RI(II)-K1.Cu-64 comparisons and degrees of equivalence with the respective key comparison reference values have been evaluated. The NIST replaces its earlier degree of equivalence for 18F obtained in the frame of the CCRI(II)-K3.F-18 comparison in 2001.

Evidence against solar influence on nuclear decay constants.

The hypothesis that proximity to the Sun causes variation of decay constants at permille level has been tested and disproved. Repeated activity measurements of mono-radionuclide sources were performed over periods from 200 days up to four decades at 14 laboratories across the globe. Residuals from the exponential nuclear decay curves were inspected for annual oscillations. Systematic deviations from a purely exponential decay curve differ from one data set to another and are attributable to instabilities in the instrumentation and measurement conditions. The most stable activity measurements of alpha, beta-minus, electron capture, and beta-plus decaying sources set an upper limit of 0.0006% to 0.008% to the amplitude of annual oscillations in the decay rate. Oscillations in phase with Earth's orbital distance to the Sun could not be observed within a 10-6 to 10-5 range of precision. There are also no apparent modulations over periods of weeks or months. Consequently, there is no indication of a natural impediment against sub-permille accuracy in half-life determinations, renormalisation of activity to a distant reference date, application of nuclear dating for archaeology, geo- and cosmochronology, nor in establishing the SI unit becquerel and seeking international equivalence of activity standards.

Dysregulated cytokine expression in lesional and nonlesional skin in hidradenitis suppurativa.

BACKGROUND: There is a dearth of information on the precise pathogenesis of hidradenitis suppurativa (HS), but immune dysregulation is implicated. OBJECTIVES: To determine the nature of the immune response in HS. METHODS: Skin biopsies - lesional, perilesional (2 cm away) and uninvolved (10 cm away) - were obtained from patients with HS and healthy controls. The expression of various cytokines was determined by enzyme-linked immunosorbent assay, flow cytometry and real-time polymerase chain reaction. RESULTS: The expression of the inflammatory cytokines interleukin (IL)-17, IL-1ß and tumour necrosis factor-α was enhanced in lesional skin of patients with HS. In addition, IL17A and IL1B mRNA were enhanced in clinically normal perilesional skin. CD4(+) T cells produced IL-17 in HS, while CD11c(+) CD1a(-) CD14(+) cells were sources of IL-1ß. Activated caspase-1 was detected in HS skin and was associated with enhanced expression of NLRP3 and IL18. Inhibition of caspase-1 decreased IL-1ß and IL-18 production, suggesting that the caspase-1 pathway participates in IL-1ß and IL-18 expression in HS. Abnormal cytokine expression was detected in perilesional and uninvolved skin, which may suggest that subclinical inflammation is present in HS skin prior to the formation of an active lesion. CONCLUSIONS: This study demonstrates that CD4(+) T cells produce IL-17 in HS and that the IL-17 pathway may be important in HS pathogenesis. CD11c(+) CD1a(-) CD14(+) cells are a source of IL-1ß in HS, the production of which was shown to be mediated, in part, via a caspase-1-dependent pathway. These results suggest that IL-17 and the caspase-1-associated cytokines IL-1ß and IL-18 may play a role in the pathogenesis of HS.

Efficient national surveillance for health-care-associated infections.

BACKGROUND: Detecting novel healthcare-associated infections (HCAI) as early as possible is an important public health priority. However, there is currently no evidence base to guide the design of efficient and reliable surveillance systems. Here we address this issue in the context of a novel pathogen spreading primarily between hospitals through the movement of patients. METHODS: Using a mathematical modelling approach we compare the current surveillance system for a HCAI that spreads primarily between hospitals due to patient movements as it is implemented in Scotland with a gold standard to determine if the current system is maximally efficient or whether it would be beneficial to alter the number and choice of hospitals in which to concentrate surveillance effort. RESULTS: We validated our model by demonstrating that it accurately predicts the risk of meticillin-resistant Staphylococcus aureus bacteraemia cases in Scotland. Using the 29 (out of 182) sentinel hospitals that currently contribute most of the national surveillance effort results in an average detection time of 117 days. A reduction in detection time to 87 days is possible by optimal selection of 29 hospitals. Alternatively, the same detection time (117 days) can be achieved using just 22 optimally selected hospitals. Increasing the number of sentinel hospitals to 38 (teaching and general hospitals) reduces detection time by 43 days; however decreasing the number to seven sentinel hospitals (teaching hospitals) increases detection time substantially to 268 days. CONCLUSIONS: Our results show that the current surveillance system as it is used in Scotland is not optimal in detecting novel pathogens when compared to a gold standard. However, efficiency gains are possible by better choice of sentinel hospitals, or by increasing the number of hospitals involved in surveillance. Similar studies could be used elsewhere to inform the design and implementation of efficient national, hospital-based surveillance systems that achieve rapid detection of novel HCAIs for minimal effort.

Variation in warfarin prescribing and dosing in the UK: a national survey of anticoagulation clinics.

WHAT IS KNOWN AND OBJECTIVE: Clinical practice in the initiation, prescribing, dosing and monitoring of warfarin in the UK varies, but this has not been adequately documented. The objective was to undertake a survey on current clinical practice in this area, and how it compares with national guidelines that have been developed by the British Committee for Standards in Haematology. METHODS: A national online survey of anticoagulation clinics was performed using Survey Monkey(®) . The survey was designed to capture data for prescribing, dosing and monitoring of anticoagulation with warfarin. RESULTS: Of 85 clinics who responded to the survey, most were run by secondary care (68%), facilitated by specialist nurses (58%) and followed standard guidelines for the management of warfarin (87%). The majority of clinics indicated their target international normalized ratio (INR) for patients with atrial fibrillation (AF) (69/73; 94·5%) was between 2·0 and 3·0, but the indicated target INR for mechanical heart valves was more variable. Initiation and loading dosing regimens were a major source of variability with uncertainty surrounding individual patient factors such as age, ethnicity and BMI. WHAT IS NEW AND CONCLUSIONS: Current practice amongst UK anticoagulation clinics largely follows current national guidelines but better guidance on dosing, taking into account factors that determine interindividual variability in daily warfarin dose requirements would improve and standardize oral anticoagulation with warfarin.

A prolonged outbreak of invasive meningococcal disease in an extended Irish Traveller family across three Health Service Executive (HSE) areas in Ireland, 2010 to 2013.

Between March 2010 and November 2013 eight laboratory-confirmed cases of serogroup B, invasive meningococcal disease (IMD) were identified in an extended Irish Traveller family across three Health Service Executive (HSE) areas of Ireland. Cases were aged between 5 and 46 months, and were either a cousin or sibling of another case. All eight cases survived. Chemoprophylaxis was given to relevant nuclear family members and close contacts on each occasion, but failed to prevent further cases. Neisseria meningitidis isolates from six cases were highly related, belonging to the ST-41/44 clonal complex, and shared the porA designation 7­2,4. In November 2013, the outbreak control team recommended that directly observed ciprofloxacin chemoprophylaxis be administered simultaneously to the extended family, and that the four component meningococcal B (4CMenB) vaccine be administered to family members aged 2 months to 23 years inclusive and relevant close contacts of the eighth case. Subsequently these recommendations were implemented at three regional clinics. Additionally pharyngeal swabs (n=112) were collected to assess carriage rates of N. meningitidis in this extended family. Pharyngeal carriage of N. meningitidis was detected in 15 (13%) family members. From the epidemiological investigation and carriage study overcrowding was the most likely risk factor identified in this outbreak. To date, the combination of directly observed ciprofloxacin chemoprophylaxis and use of 4CMenB vaccine have controlled the outbreak with no further cases diagnosed.

Development of an Ultra-Pure, Carrier-Free (209)Po Solution Standard.

Ultra-pure, carrier-free (209)Po solution standards have been prepared and standardized for their massic alpha-particle emission rate. The standards, which will be disseminated by the National Institute of Standards and Technology (NIST) as Standard Reference Material SRM 4326a, have a mean mass of (5.169 ± 0.003) g of a solution of polonium in nominal 2.0 mol▪L(-1) HCl (having a solution density of (1.032 ± 0.002) g▪ mL(-1) at 20 °C) that are contained in 5 mL, flame-sealed, borosilicate glass ampoules. They are certified to contain a (209)Po massic alpha-particle emission rate of (39.01 ± 0.18) s(-1)▪g(-1) as of a reference time of 1200 EST, 01 December 2013. This new standard series replaces SRM 4326 that was issued by NIST in 1994. The standardization was based on 4πα liquid scintillation (LS) spectrometry with two different LS counting systems and under wide variations in measurement and counting source conditions. The methodology for the standardization, with corrections for detection of the low-energy conversion electrons from the delayed 2 keV isomeric state in (205)Pb and for the radiations accompanying the small 0.45 % electron-capture branch to (209)Bi, involves a unique spectral analysis procedure that is specific for the case of (209)Po decay. The entire measurement protocol is similar, but revised and improved from that used for SRM 4326. Spectroscopic impurity analyses revealed that no photon-emitting or alpha-emitting radionuclidic impurities were detected. The most common impurity associated with (209)Po is (208)Po and the activity ratio of (208)Po/(209)Po was < 10(-7).

Revision of the NIST Standard for (223)Ra: New Measurements and Review of 2008 Data.

After discovering a discrepancy in the transfer standard currently being disseminated by the National Institute of Standards and Technology (NIST), we have performed a new primary standardization of the alpha-emitter (223)Ra using Live-timed Anticoincidence Counting (LTAC) and the Triple-to-Double Coincidence Ratio Method (TDCR). Additional confirmatory measurements were made with the CIEMAT-NIST efficiency tracing method (CNET) of liquid scintillation counting, integral γ-ray counting using a NaI(Tl) well counter, and several High Purity Germanium (HPGe) detectors in an attempt to understand the origin of the discrepancy and to provide a correction. The results indicate that a -9.5 % difference exists between activity values obtained using the former transfer standard relative to the new primary standardization. During one of the experiments, a 2 % difference in activity was observed between dilutions of the (223)Ra master solution prepared using the composition used in the original standardization and those prepared using 1 mol·L(-1) HCl. This effect appeared to be dependent on the number of dilutions or the total dilution factor to the master solution, but the magnitude was not reproducible. A new calibration factor ("K-value") has been determined for the NIST Secondary Standard Ionization Chamber (IC "A"), thereby correcting the discrepancy between the primary and secondary standards.