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Decarbonisation of the transport sector is essential to mitigate anthropogenic climate change. Microbial metabolisms are already integral to the production of renewable, sustainable fuels and, building on that foundation, are being re-engineered to generate the advanced biofuels that will maintain mobility of people and goods during the energy transition. This review surveys the range of natural and engineered microbial systems for advanced biofuels production and summarises some of the techno-economic challenges associated with their implementation at industrial scales.

Infections after placement of cardiac implantable electronic devices (CIEDs) are associated with substantial morbidity and mortality. There is limited evidence on prophylactic strategies, other than the use of preoperative antibiotics, to prevent such infections.We conducted a randomized, controlled clinical trial to assess the safety and efficacy of an absorbable, antibiotic-eluting envelope in reducing the incidence of infection associated with CIED implantations. Patients who were undergoing a CIED pocket revision, generator replacement, or system upgrade or an initial implantation of a cardiac resynchronization therapy defibrillator were randomly assigned, in a 1:1 ratio, to receive the envelope or not. Standard-of-care strategies to prevent infection were used in all patients. The primary end point was infection resulting in system extraction or revision, long-term antibiotic therapy with infection recurrence, or death, within 12 months after the CIED implantation procedure. The secondary end point for safety was procedure-related or system-related complications within 12 months.A total of 6983 patients underwent randomization: 3495 to the envelope group and 3488 to the control group. The primary end point occurred in 25 patients in the envelope group and 42 patients in the control group (12-month Kaplan-Meier estimated event rate, 0.7% and 1.2%, respectively; hazard ratio, 0.60; 95% confidence interval [CI], 0.36 to 0.98; P = 0.04). The safety end point occurred in 201 patients in the envelope group and 236 patients in the control group (12-month Kaplan-Meier estimated event rate, 6.0% and 6.9%, respectively; hazard ratio, 0.87; 95% CI, 0.72 to 1.06; P0.001 for noninferiority). The mean (±SD) duration of follow-up was 20.7±8.5 months. Major CIED-related infections through the entire follow-up period occurred in 32 patients in the envelope group and 51 patients in the control group (hazard ratio, 0.63; 95% CI, 0.40 to 0.98).Adjunctive use of an antibacterial envelope resulted in a significantly lower incidence of major CIED infections than standard-of-care infection-prevention strategies alone, without a higher incidence of complications. (Funded by Medtronic; WRAP-IT ClinicalTrials.gov number, NCT02277990.).

Prevalence was reduced, and early evidence indicates herd immunity., In 2008, a national human papillomavirus (HPV) immunization program using a bivalent vaccine against HPV types 16 and 18 was implemented in Scotland along with a national surveillance program designed to determine the longitudinal effects of vaccination on HPV infection at the population level. Each year during 2009–2013, the surveillance program conducted HPV testing on a proportion of liquid-based cytology samples from women undergoing their first cervical screening test for precancerous cervical disease. By linking vaccination, cervical screening, and HPV testing data, over the study period we found a decline in HPV types 16 and 18, significant decreases in HPV types 31, 33, and 45 (suggesting cross-protection), and a nonsignificant increase in HPV 51. In addition, among nonvaccinated women, HPV types 16 and 18 infections were significantly lower in 2013 than in 2009. Our results preliminarily indicate herd immunity and sustained effectiveness of the bivalent vaccine on virologic outcomes at the population level.

Summary Designing improved vaccines against mutable viruses such as dengue and influenza would be helped by a better understanding of how the B‐cell memory compartment responds to variant antigens. Towards this we have recently shown, after secondary immunization of mice with a widely variant dengue virus envelope protein with only 63% amino acid identity, that IgM+ memory B cells with few mutations supported an efficient secondary germinal centre (GC) and serum response, superior to a primary response to the same protein. Here, further investigation of memory responses to variant proteins, using more closely related influenza virus haemagglutinins (HA) that were 82% identical, produced a variant‐induced boost response in the GC dominated by highly mutated B cells that failed, not efficiently improving serum avidity even in the presence of extra adjuvant, and that was worse than a primary response. This supports a hypothesis that over a certain level of antigenic differences, cross‐reactive memory B‐cell populations have reduced competency for affinity maturation. Combined with our previous observations, these findings also provide new parameters of success and failure in antibody memory responses.

Background: In Scotland, a national HPV immunisation programme began in 2008 for 12- to 13-year olds, with a catch-up campaign from 2008 to 2011 for those under the age of 18. To monitor the impact of HPV immunisation on cervical disease at the population level, a programme of national surveillance was established. Methods: We analysed colposcopy data from a cohort of women born between 1988 and 1992 who entered the Scottish Cervical Screening Programme (SCSP) and were aged 20–21 in 2008–2012. Results: By linking datasets from the SCSP and colposcopy services, we observed a significant reduction in diagnoses of cervical intraepithelial neoplasia 1 (CIN 1; RR 0.71, 95% CI 0.58 to 0.87; P=0.0008), CIN 2 (RR 0.5, 95% CI 0.4 to 0.63; P

1532-1827 Kavanagh, K Pollock, K G J Potts, A Love, J Cuschieri, K Cubie, H Robertson, C Donaghy, M Journal article Br J Cancer. 2014 Apr 15. doi: 10.1038/bjc.2014.198.; International audience; Background:In 2008, a national human papillomavirus (HPV) immunisation programme began in Scotland for 12-13 year old females with a three-year catch-up campaign for those under the age of 18. Since 2008, three-dose uptake of bivalent vaccine in the routine cohort aged 12-13 has exceeded 90% annually, while in the catch-up cohort overall uptake is 66%.Methods:To monitor the impact of HPV immunisation, a programme of national surveillance was established (pre and post introduction) which included yearly sampling and HPV genotyping of women attending for cervical screening at age 20. By linking individual vaccination, screening and HPV testing records, we aim to determine the impact of the immunisation programme on circulating type-specific HPV infection particularly for four outcomes: (i) the vaccine types HPV 16 or 18 (ii) types considered to be associated with cross-protection: HPV 31, 33 or 45; (iii) all other high-risk types and (iv) any HPV.Results:From a total of 4679 samples tested, we demonstrate that three doses (n=1100) of bivalent vaccine are associated with a significant reduction in prevalence of HPV 16 and 18 from 29.8% (95% confidence interval 28.3, 31.3%) to 13.6% (95% confidence interval 11.7, 15.8%). The data also suggest cross-protection against HPV 31, 33 and 45. HPV 51 and 56 emerged as the most prevalent (10.5% and 9.6%, respectively) non-vaccine high-risk types in those vaccinated, but at lower rates than HPV 16 (25.9%) in those unvaccinated.Conclusions:This data demonstrate the positive impact of bivalent vaccination on the prevalence of HPV 16, 18, 31, 33 and 45 in the target population and is encouraging for countries which have achieved high-vaccine uptake.British Journal of Cancer advance online publication, 15 April 2014; doi:10.1038/bjc.2014.198 www.bjcancer.com.

In addition to the large number of patients with isolated limb injuries, many patients with major blunt or penetrating trauma harbor extremity injuries as a component of their overall clinical picture. Extremity injuries range from gross deformities and amputations to more subtle injuries, potentially difficult to diagnose, or may escape detection in unconscious or intoxicated patients. However, many soft tissue and vascular injuries require time sensitive interventions to ensure salvage of the limb and the best outcome for the patient. This article reviews the acute management of vascular and soft tissue injuries in the emergency department.

Endometriosis is a debilitating disease estimated to affect 10% of reproductive-age women and characterized by the growth of endometrial tissue outside of the uterus. The present study char- acterizes a human endometrial explant culture model for studying the direct effects of TCDD exposure by assessing the expression of CYP1A1 and CYP1B1 mRNA (Northern blotting), protein (West- ern blotting), and activity (7-ethoxyresorufin-O-deethylase; EROD) in explants cultured with and without TCDD. Explants were obtained at laparoscopy or laparotomy from women under- going surgery for tubal ligation, endometriosis, or pelvic pain unrelated to endometriosis. The explants were cultured with 10 nM estradiol (E2 )o r 1n M E 2 plus 500 nM progesterone (P4) with or without TCDD (first 24 h). The expression of CYP1A1 and CYP1B1 mRNA was greatest with 10 nM TCDD and increased up to 72 h after initial exposure. EROD activity increased up to 120 h. Explants from a secretory phase biopsy became reorganized in culture and formed a new epithelial membrane, while maintaining basic endometrial morphology and viability for up to 120 h. At 24 h, TCDD significantly increased CYP1A1 and CYP1B1 mRNA, and at 72 h, TCDD significantly increased EROD activity and CYP1B1 protein compared to explants cultured without TCDD for similar times. CYP1B1 protein also exhibited substan- tial constitutive expression that was similar in uncultured biopsies, where CYP1B1 protein was immunolocalized in the cytoplasm of epithelial glands, with only occasional patches of protein in the surface epithelial membrane. In explants cultured with and with- out TCDD exposure, CYP1B1 protein was localized in the cyto- plasm of the new surface epithelial membrane and glands closest to the surface. CYP1A1 protein was not detected in uncultured biopsies or explants. Both younger age (age 30 and under) and proliferative phase were associated with higher TCDD-induced EROD activity in specimens treated with E2:P4. No significant endometriosis-related differences were observed for any of the biomarkers, but the detection of disease-specific change was lim- ited by small sample size and variability in tissue-cycle phase. The human endometrial explant culture model will be useful for future studies of the effects of dioxin-like compounds on human endo- metrium in relationship to cycle phase and hormonal exposure.

In September 2008, Scotland introduced a national human papillomavirus (HPV) immunisation programme with bivalent HPV vaccine, to prevent cervical cancer. This school-based programme routinely vaccinates girls aged between 12 and 13 years. A catch-up campaign, running over three years, also began at this time, offering vaccination to all girls aged 13 years to under 18 years old. The HPV immunisation campaign presented challenges due to this vaccine being targeted to girls in school and older girls who had left school. Following a long and comprehensive planning process, this campaign was successfully implemented across Scotland, delivering high vaccine uptake of 91.4% for three doses of vaccine in the first year (September 2008 to August 2009) for the routine cohort and 90.1% in the second year (September 2009 to August 2010) for the routine cohort. We describe the planning process, challenges and implementation strategies employed to achieve this high uptake.

Sinka, Katy Kavanagh, Kimberley Gordon, Ruth Love, John Potts, Alison Donaghy, Martin Robertson, Chris eng England 2013/08/30 06:00 J Epidemiol Community Health. 2014 Jan;68(1):57-63. doi: 10.1136/jech-2013-202620. Epub 2013 Aug 28.; International audience; BACKGROUND AND METHODS: The national immunisation records of over 220,000 girls offered vaccine in the routine or catch-up programme of the Human papillomavirus (HPV) programme in Scotland were analysed. Descriptive statistics and multilevel modelling were used to determine individual and organisational factors associated with uptake. Age, school year, school denomination, deprivation and, for school-leavers, mode of delivery were explored. Additional aggregate data were used to examine the effect of late uptake of missed doses in the routine vaccination programme. RESULTS: School-based delivery initially achieved over 80% uptake of complete courses in routine and catch-up age groups. Within this context of generally high coverage, there was an association between individual level deprivation and lower uptake, and a decline in in-year course completion over time. However, later uptake of missed doses in the following year substantially decreased these effects. There was no influence on uptake of the type of school (non-denominational/denominational). Vaccination of school-leavers in the catch-up campaign had lower coverage, with 50% starting and 30% completing the course in-year. There was no clear advantage of vaccination through general practice or through Board-run clinics in reaching this group. CONCLUSIONS: School-based vaccination can achieve high and equitable uptake of a multidose vaccine in a routine immunisation programme. Sustained high coverage with HPV vaccine across Scotland provides a stable platform for planning future strategies for cervical screening and understanding the impact of the vaccination at a population level.

As procalcitonin concentrations have been shown to be elevated in patients with septicemia and gram-negative infections in particular, we proceeded to investigate the effect of endotoxin, a product of gram-negative bacteria, on procalcitonin concentrations in normal human volunteers. Endotoxin from Escherichia coli 0113:H10:k, was injected i.v. at a dose of 4 mg/kg BW into these healthy volunteers. Blood samples were obtained before and 1, 2, 4, 6, 8, and 24 h after injection of the endotoxin. Each patient's cardiovascular and overall clinical status was monitored over this period. The patients developed chills and rigors, myalgia, and fever between 1-3 h. Tumor necrosis factor-alpha levels increased sharply at 1 h and peaked at 90 min, reaching the baseline concentration thereafter by 6 h. Interleukin-6 levels increased more gradually, peaking at 3 h and reaching the baseline concentration at 8 h. The procalcitonin concentration, which was undetectable (10 pg/mL) at 0, 1, and 2 h, was detectable at 4 h and peaked at 6 h, maintaining a plateau through 8 and 24 h (4 ng/mL). There was no elevation of calcitonin concentrations, which remained below 10 pg/mL, the lowest sensitivity of the assay. Procalcitonin was measured by a two-antibody immunoradiometric assay specific for this peptide, with no cross-reactivity with calcitonin, katacalcin, or calcitonin gene-related peptide. We conclude that endotoxin induces the release of procalcitonin systemically, that this increase is not associated with an increase in calcitonin, and that the increase in procalcitonin associated with septicemia in patients may be mediated through the effect of endotoxin described here. Whether procalcitonin participates in the mechanisms underlying inflammation remains to be investigated.

In 2013, Wales and England experienced large outbreaks of measles, a disease that has been targeted by the World Health Organisation for European elimination by 2015. Unfortunately, measles-mumps-rubella vaccine uptake declined to less than 80% in Wales and England after the Wakefield publicity and this resulted in increased population susceptibility to measles. In Scotland, measles-mumps-rubella vaccine uptake dropped to 87% in 2003. Scottish public health efforts in response to this decline aimed to maximise uptake of MMR1 by two years; ensure at least 95% uptake of one dose of measles-mumps-rubella before starting school at age five; and maximise uptake of the second dose of measles-mumps-rubella by age six. Although Scotland has not had any large outbreaks reported to date, transmission of measles from healthcare workers to patients has occurred and reiterates the importance of all healthcare workers accurately knowing their immune status and, when needed, to be fully immunised.

Existing fluoride concentration and consumption data were used to estimate fluoride intakes from the diet and toothpaste use, for New Zealand subpopulations, to identify any population groups at risk of high-fluoride intake.For each sub-population, two separate dietary intake estimates were made--one based on a non-fluoridated water supply (fluoride concentration of 0.1 mg/L), and the other based on a water supply fluoridated to a concentration of 1.0 mg/L. Fluoride concentration data were taken from historical surveys, while food consumption data were taken from national 24-hour dietary recall surveys or from simulated diets.Mean and 95th percentile estimations of dietary fluoride intake were well below the upper level of intake (UL), whether intakes were calculated on the basis of a non-fluoridated or fluoridated water supply. The use of fluoride-containing toothpastes provides additional fluoride intake. For many of the population groups considered, mean fluoride intakes were below the adequate intake (AI) level for caries protection, even after inclusion of the fluoride contribution from toothpaste. Intake of fluoride was driven by consumption of dietary staples (bread, potatoes),beverages (particularly tea, soft drinks, and beer), and the fluoride status of drinking water.Estimates of fluoride intake from the diet and toothpaste did not identify any groups at risk of exceeding the UL, with the exception of infants (6-12 months) living in areas with fluoridated water supplies and using high-fluoride toothpaste. In contrast, much of the adult population may be receiving insufficient fluoride for optimum caries protection from these sources, as represented by the AI.

To evaluate the impact of suppressing inositol 1,4,5-trisphosphate (InsP3) in plants, tobacco (Nicotiana tabacum) cells were transformed with the human type I inositol polyphosphate 5-phosphatase (InsP 5-ptase), an enzyme which specifically hydrolyzes InsP3. The transgenic cell lines showed a 12- to 25-fold increase in InsP 5-ptase activity in vitro and a 60% to 80% reduction in basal InsP3 compared with wild-type cells. Stimulation with Mas-7, a synthetic analog of the wasp venom peptide mastoparan, resulted in an approximately 2-fold increase in InsP3 in both wild-type and transgenic cells. However, even with stimulation, InsP3 levels in the transgenic cells did not reach wild-type basal values, suggesting that InsP3 signaling is compromised. Analysis of whole-cell lipids indicated that phosphatidylinositol 4,5-bisphosphate (PtdInsP2), the lipid precursor of InsP3, was greatly reduced in the transgenic cells. In vitro assays of enzymes involved in PtdInsP2 metabolism showed that the activity of the PtdInsP2-hydrolyzing enzyme phospholipase C was not significantly altered in the transgenic cells. In contrast, the activity of the plasma membrane PtdInsP 5 kinase was increased by approximately 3-fold in the transgenic cells. In vivo labeling studies revealed a greater incorporation of 32P into PtdInsP2 in the transgenic cells compared with the wild type, indicating that the rate of PtdInsP2 synthesis was increased. These studies show that the constitutive expression of the human type I InsP 5-ptase in tobacco cells leads to an up-regulation of the phosphoinositide pathway and highlight the importance of PtdInsP2 synthesis as a regulatory step in this system.

Rather than providing an encyclopedic review of extremity injuries, this article reviews selected serious injuries of the extremities that can be missed in the emergency department, either because they are relatively uncommon or because they are subtle in their clinical and radiographic presentation. They include injuries to the scapula, the shoulder, the forearm, the femur and hip, the knee, the tibia (which is the most common long bone fracture), and the ankle and foot. Their various causes include sports injuries, falls, and motor vehicle accidents. Several of these injuries can result in emergent complications or have time-dependent outcomes. Consequently, these injuries often must be managed by emergency physicians before specialist expertise becomes available.

The effect of sucralfate on the bioavailability of ciprofloxacin hydrochloride was assessed in 12 healthy male volunteers. The study was a four-period crossover design where subjects were randomized to one of four treatment sequences at entry. Treatments A, B, and C included sucralfate 2 g q 12h for five doses. For treatment A, the fifth dose of sucralfate was administered concurrently with ciprofloxacin 750 mg. For treatment B, 750 mg of ciprofloxacin was administered two hours before the fifth dose of sucralfate. Treatment C consisted of ciprofloxacin 750 mg six hours before the fifth dose of sucralfate. A 750-mg dose of ciprofloxacin was administered alone for treatment D. Blood and urine samples were collected at predetermined time intervals for 24 hours. Ciprofloxacin concentrations were determined by HPLC. The area under the concentration versus time curve from zero to infinity and the urinary recovery of ciprofloxacin were used for determining relative bioavailability. Concurrent administration of ciprofloxacin and sucralfate (treatment A) resulted in a significant decrease (p

Kavanagh, Kimberley Sinka, Katy Cuschieri, Kate Love, John Potts, Alison Pollock, Kevin G J Cubie, Heather Donaghy, Martin Robertson, Chris eng Research Support, Non-U.S. Gov't England 2013/11/06 06:00 BMC Infect Dis. 2013 Nov 5;13:519. doi: 10.1186/1471-2334-13-519.; International audience; BACKGROUND: Estimation of pre-immunisation prevalence of HPV and distribution of HPV types is fundamental to understanding the subsequent impact of HPV vaccination. We describe the type specific prevalence of HPV in females aged 20-21 in Scotland who attended or defaulted from cervical screening using three specimen types; from attenders liquid based cytology and from defaulters urine or self-taken swabs. METHODS: Residual liquid based cytology samples (n = 2148), collected from women aged 20-21 attending for their first smear were genotyped for HPV. A sample (n = 709) from women who had defaulted from screening was also made available for HPV testing through the use of postal testing kits (either urine samples (n = 378) or self-taken swabs (n = 331)). Estimates of prevalence weighted by deprivation, and for the postal testing kit, also by reminder status and specimen type were calculated for each HPV type. The distribution of HPV types were compared between specimen types and the occurrence of multiple high-risk infections examined. The influence of demographic factors on high-risk HPV positivity and multiple infections was examined via logistic regression. RESULTS: The prevalence of any HPV in young women aged 20-21 was 32.2% for urine, 39.5% for self-taken swab, and 49.4% for LBC specimens. Infection with vaccine specific types (HPV 16, 18) or those associated with cross-protection (HPV 31, 33, 45, 51) was common. Individuals were more likely to test positive for high-risk HPV if they resided in an area of high deprivation or in a rural area. The overall distribution of HPV types did not vary between defaulters and attenders. Multiple infections occurred in 48.1% of high-risk HPV positive individuals. Excluding vaccine types the most common pairing was HPV 56 and 66. CONCLUSIONS: Understanding of the pre-immunisation prevalence of HPV in young women puts Scotland in a prime position to assess the early effect of vaccination as the first highly vaccinated cohorts of individuals enter the screening programme. Differences in results with different specimen types must be taken into account when monitoring the impact of vaccination programmes.