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Probiotics may reduce necrotising enterocolitis and late-onset sepsis after preterm birth. However, there has been concern about the rigour and generalisability of some trials and there is no agreement about whether or not they should be used routinely. We aimed to test the effectiveness of the probiotic Bifidobacterium breve BBG-001 to reduce necrotising enterocolitis, late-onset sepsis, and death in preterm infants. In this multicentre, randomised controlled phase 3 study (the PiPS trial), we recruited infants born between 23 and 30 weeks' gestational age within 48 h of birth from 24 hospitals in southeast England. Infants were randomly assigned (1:1) to probiotic or placebo via a minimisation algorithm randomisation programme. The probiotic intervention was B breve BBG-001 suspended in dilute elemental infant formula given enterally in a daily dose of 8·2 to 9·2 log10 CFU; the placebo was dilute infant formula alone. Clinicians and families were masked to allocation. The primary outcomes were necrotising enterocolitis (Bell stage 2 or 3), blood culture positive sepsis more than 72 h after birth; and death before discharge from hospital. All primary analyses were by intention to treat. This trial is registered with ISRCTN, number 05511098 and EudraCT, number 2006-003445-17. Between July 1, 2010, and July 31, 2013, 1315 infants were recruited; of whom 654 were allocated to probiotic and 661 to placebo. Five infants had consent withdrawn after randomisation, thus 650 were analysed in the probiotic group and 660 in the placebo group. Rates of the primary outcomes did not differ significantly between the probiotic and placebo groups. 61 infants (9%) in the probiotic group had necrotising enterocolitis compared with 66 (10%) in the placebo group (adjusted risk ratio 0·93 (95% CI 0·68–1·27); 73 (11%) infants in the probiotics group had sepsis compared with 77 (12%) in the placebo group (0·97 (0·73–1·29); and 54 (8%) deaths occurred before discharge home in the probiotic group compared with 56 (9%) in the placebo group (0·93 [0·67–1·30]). No probiotic-associated adverse events were reported. There is no evidence of benefit for this intervention in this population; this result does not support the routine use of B breve BBG-001 for prevention of necrotising enterocolitis and late-onset sepis in very preterm infants. UK National Institute for Health Research Health Technology Assessment programme.

District heating uptake has grown with the increasing need for cleaner and more efficient energy supply. This has resulted in a rising number of new developments signing up to a district heating scheme, typically powered by Combined Heat and Power (CHP) boilers or biomass boilers with supplemental electrical or gas grid connections. These schemes have advanced rapidly in recent years, with much of the research focus targeting lower carbon technologies, improved load prediction and peak demand management. We assess the current status of District Heating Networks (DHNs) in the United Kingdom using published case studies and suggest next steps to improvement. Our findings show that the United Kingdom has good potential for uptake of district energy given the current political climate and government incentives, however significant improvements must be made to further penetrate the heating market.

Energy usage in buildings is coming increasingly under the spotlight as carbon policy focus shifts towards the utilization of thermal energy. In the UK, heating and hot water accounts for around 40% of energy consumption and 20% of greenhouse gas emissions. Heating is typically produced onsite, making widescale carbon or energetic improvements challenging. District heating networks (DHNs) can offer significant carbon reduction for many users but can only be implemented if the end user buildings have good thermal energy efficiency. This greatly limits the ability to implement advancing 4th and 5th generation DHNs, which are the most advanced systems available. We elucidate the current state of thermal efficiency in buildings in the UK and provide recommendations for necessary building requirements and modifications in order to accommodate 4th and 5th generation district heating. We conclude that key sectors must be addressed including creating a skilled workforce, producing relevant metrics and benchmarks, and providing financial support for early stage design exploration.

Domestic heating accounts for 64% of domestic energy usage in the UK, yet there are currently very few viable options for low carbon residential heating. The government’s carbon plan commits to improving the uptake of district heating connections in new build dwellings, but the greatest carbon saving can be made through targeting traditional housing stock. This paper aims to quantify the potential carbon and energy savings that can be made by connecting a traditional tenement building to a district heating scheme. The study uses a transient system simulation tool (TRNSYS) model to simulate the radiator system in a tenement block and shows that a significant benefit can be achieved by reducing the supply temperature; however, the minimum supply temperature is drastically limited by the building condition. Therefore, the study also critically compares the benefits of a lower supply temperature against minor refurbishments. It was found that improving building conditions alone could offer a 30% reduction in space heating energy consumption, while building improvements and integration of a river source heat pump could offer almost a 70% reduction. It is the recommendation of this study that a dwelling be improved as much as economically possible to achieve the greatest carbon and energetic savings.

Background Uncertainty remains about the role of probiotics to prevent necrotising enterocolitis (NEC) some of which arises from the variety of probiotic interventions used in different trials, many with no prior evidence of potential efficacy. Mechanistic studies of intestinal barrier function embedded in a large probiotic trial could provide evidence about which properties of probiotics might be important for NEC prevention thus facilitating identification of strains with therapeutic potential. Methods Intestinal permeability, stool microbiota, SCFAs and mucosal inflammation were assessed from the second postnatal week in babies enrolled to a randomised controlled trial of B. breve BBG-001 (the PiPS trial). Results were compared by allocation and by stool colonisation with the probiotic. Results Ninety-four preterm babies were recruited across six nested studies. B. breve BBG-001 content was higher by allocation and colonisation; Enterobacteriaceae and acetic acid levels were higher by colonisation. No measure of intestinal barrier function showed differences. The PiPS trial found no evidence of efficacy to reduce NEC. Conclusions That the negative results of the PiPS trial were associated with failure of this probiotic to modify intestinal barrier function supports the possibility that the tests described here have the potential to identify strains to progress to large clinical trials. Impact Uncertainty about the therapeutic role of probiotics to prevent necrotising enterocolitis is in part due to the wide range of bacterial strains with no previous evidence of efficacy used in clinical trials. We hypothesised that mechanistic studies embedded in a probiotic trial would provide evidence about which properties of probiotics might be important for NEC prevention. The finding that the probiotic strain tested, Bifidobacterium breve BBG-001, showed neither effects on intestinal barrier function nor clinical efficacy supports the possibility that these tests have the potential to identify strains to progress to large clinical trials.

Few quantifiable tissue biomarkers for the diagnosis and prognosis of prostate cancer exist. Using an unbiased, quantitative approach, this study evaluates the potential of three proteins of the 40S ribosomal protein complex as putative biomarkers of malignancy in prostate cancer. Prostate tissue arrays, constructed from 82 patient samples (245 tissue cores, stage pT3a or pT3b), were stained for antibodies against three ribosomal proteins, RPS19, RPS21 and RPS24. Semi-automated Ox-DAB signal quantification using ImageJ software revealed a significant change in expression of RPS19, RPS21 and RPS24 in malignant vs non-malignant tissue (p<0.0001). Receiver operating characteristics curves were calculated to evaluate the potential of each protein as a biomarker of malignancy in prostate cancer. Positive likelihood ratios for RPS19, RPS21 and RPS24 were calculated as 2.99, 4.21, and 2.56 respectively, indicating that the overexpression of the protein is correlated with the presence of disease. Triple-labelled, quantitative, immunofluorescence (with RPS19, RPS21 and RPS24) showed significant changes (p<0.01) in the global intersection coefficient, a measure of how often two fluorophore signals intersect, for RPS19 and RPS24 only. No change was observed in the co-localization of any other permutations of the three proteins. Our results show that RPS19, RPS21 or RPS24 are upregulated in malignant tissue and may serve as putative biomarkers for prostate cancer.

BackgroundIntestinal dysbiosis is implicated in the pathogenesis of necrotising enterocolitis and late-onset sepsis in preterm babies. The provision of non-invasive positive pressure ventilation is a common clinical intervention in preterm babies, and may be hypothesised to adversely affect intestinal bacterial growth, through increased aerophagia and induction of a hyperoxic intestinal environment; however this relationship has not been previously well characterised.MethodologyIn this prospectively recruited cohort study, high-throughput 16S rRNA gene sequencing was combined with contemporaneous clinical data collection, to assess within-subject changes in microbiome development around the time of transitioning from non-invasive positive pressure respiratory support to unsupported spontaneous breathing.ResultsIn a group of 14 preterm infants, bacterial diversity was seen to increase by 0.34 units/week (inverse Simpson index) at the point of transitioning off non-invasive positive pressure respiratory support. Correspondingly, a significant increase in anaerobic genera (Bifidobacteria spp, Veillonella spp), and a non-significant fall in Enterobacteriaceae was also seen at this time.ConclusionsProvision of non-invasive positive pressure ventilation is associated with suppression of both diversity accrual and obligate anaerobic growth in the preterm intestine. This has clinical implications in view of the widespread use of non-invasive positive pressure ventilation in preterm neonatal care (and wider adult use), and demonstrates the need for potential strategies (eg, probiotic support; reduced aerophagia) to support the development of a healthy gut microbiome during this time.

Background Mother-to-baby transmission of group B Streptococcus (GBS) is the main cause of early-onset infection. We evaluated whether, in women with clinical risk factors for early neonatal infection, the use of point-of-care rapid intrapartum test to detect maternal GBS colonisation reduces maternal antibiotic exposure compared with usual care, where antibiotics are administered due to those risk factors. We assessed the accuracy of the rapid test in diagnosing maternal GBS colonisation, against the reference standard of selective enrichment culture. Methods We undertook a parallel-group cluster randomised trial, with nested test accuracy study and microbiological sub-study. UK maternity units were randomised to a strategy of rapid test (GeneXpert GBS system, Cepheid) or usual care. Within units assigned to rapid testing, vaginal-rectal swabs were taken from women with risk factors for vertical GBS transmission in established term labour. The trial primary outcome was the proportion of women receiving intrapartum antibiotics to prevent neonatal early-onset GBS infection. The accuracy of the rapid test was compared against the standard of selective enrichment culture in diagnosing maternal GBS colonisation. Antibiotic resistance profiles were determined in paired maternal and infant samples. Results Twenty-two maternity units were randomised and 20 were recruited. A total of 722 mothers (749 babies) participated in rapid test units; 906 mothers (951 babies) were in usual care units. There was no evidence of a difference in the rates of intrapartum antibiotic prophylaxis (relative risk 1.16, 95% CI 0.83 to 1.64) between the rapid test (41%, 297/716) and usual care (36%, 328/906) units. No serious adverse events were reported. The sensitivity and specificity measures of the rapid test were 86% (95% CI 81 to 91%) and 89% (95% CI 85 to 92%), respectively. Babies born to mothers who carried antibiotic-resistant Escherichia coli were more likely to be colonised with antibiotic-resistant strains than those born to mothers with antibiotic-susceptible E. coli . Conclusion The use of intrapartum rapid test to diagnose maternal GBS colonisation did not reduce the rates of antibiotics administered for preventing neonatal early-onset GBS infection than usual care, although with considerable uncertainty. The accuracy of the rapid test is within acceptable limits. Trial registration ISRCTN74746075 . Prospectively registered on 16 April 2015

Prostate carcinoma is the most common cancer in men with few, quantifiable, biomarkers. Prostate cancer biomarker discovery has been hampered due to subjective analysis of protein expression in tissue sections. An unbiased, quantitative immunohistochemical approach provided here, for the diagnosis and stratification of prostate cancer could overcome this problem. Antibodies against four proteins BTF3, HINT1, NDRG1 and ODC1 were used in a prostate tissue array (> 500 individual tissue cores from 82 patients, 41 case pairs matched with one patient in each pair had biochemical recurrence). Protein expression, quantified in an unbiased manner using an automated analysis protocol in ImageJ software, was increased in malignant vs non-malignant prostate (by 2-2.5 fold, p<0.0001). Operating characteristics indicate sensitivity in the range of 0.68 to 0.74; combination of markers in a logistic regression model demonstrates further improvement in diagnostic power. Triple-labeled immunofluorescence (BTF3, HINT1 and NDRG1) in tissue array showed a significant (p<0.02) change in co-localization coefficients for BTF3 and NDRG1 co-expression in biochemical relapse vs non-relapse cancer epithelium. BTF3, HINT1, NDRG1 and ODC1 could be developed as epithelial specific biomarkers for tissue based diagnosis and stratification of prostate cancer.