A spermidine riboswitch class in bacteria exploits a close variant of an aptamer for the enzyme cofactor S-adenosylmethionine.

Natural polyamines such as spermidine and spermine cations have characteristics that make them highly likely to be sensed by riboswitches, such as their general affinity to polyanionic RNA and their broad contributions to cell physiology. Despite previous claims that polyamine riboswitches exist, evidence of their biological functions has remained unconvincing. Here, we report that rare variants of bacterial S-adenosylmethionine-I (SAM-I) riboswitches reject SAM and have adapted to selectively sense spermidine. These spermidine-sensing riboswitch variants are associated with genes whose protein products are directly involved in the production of spermidine and other polyamines. Biochemical and genetic assays demonstrate that representatives of this riboswitch class robustly function as genetic "off" switches, wherein spermidine binding causes premature transcription termination to suppress the expression of polyamine biosynthetic genes. These findings confirm the existence of natural spermidine-sensing riboswitches in bacteria and expand the list of variant riboswitch classes that have adapted to bind different ligands.

Histopathologic correlation of pancreatic fibrosis with pancreatic magnetic resonance imaging quantitative metrics and Cambridge classification.

PURPOSE: To determine the correlation of the T1-weighted signal intensity ratio (T1 SIR, or T1 Score) and arterial-to-delayed venous enhancement ratio (ADV ratio) of the pancreas with pancreatic fibrosis on histopathology. METHODS: Sixty consecutive adult CP patients who had an MRI/MRCP study prior to pancreatic surgery were analyzed. Three blinded observers measured T1 SIR of pancreas to spleen (T1 SIR p/s), pancreas-to-paraspinal muscle (T1 SIR p/m), ADV ratio, and Cambridge grade. Histopathologic grades were given by a gastrointestinal pathologist using Ammann's fibrosis score. Statistical analysis included Spearman's correlation coefficient of the T1 SIR, ADV ratio, Cambridge grade with the fibrosis score, and weighted kappa for interobserver agreement. RESULTS: The study population included 31 female and 29 male patients, with an average age of 52.1 (26-78 years). Correlations between fibrosis score and T1 SIR p/s, T1 SIR p/m, and ADV ratio were ρ = - 0.54 (p = 0.0001), ρ = - 0.19 (p = 0.19), and ρ = - 0.39 (p = 0.003), respectively. The correlation of Cambridge grade with fibrosis score was ρ = 0.26 (p = 0.07). There was substantial interobserver agreement (weighted kappa) for T1 SIR p/s (0.78), T1 SIR p/m (0.71), and ADV ratio (0.64). T1 SIR p/s of ≤ 1.20 provided a sensitivity of 74% and specificity of 50% (AUC: 0.74), while ADV ratio of ≤ 1.10 provided a sensitivity of 75% and specificity of 55% (AUC: 0.68) to detect a fibrosis score of ≥ 6. CONCLUSION: There is a moderate negative correlation between the T1 Score (SIR p/s) and ADV ratio with pancreatic fibrosis and a substantial interobserver agreement. These parenchymal metrics show a higher correlation than the Cambridge grade.

HPV Vaccination and the Risk of Invasive Cervical Cancer.

BACKGROUND: The efficacy and effectiveness of the quadrivalent human papillomavirus (HPV) vaccine in preventing high-grade cervical lesions have been shown. However, data to inform the relationship between quadrivalent HPV vaccination and the subsequent risk of invasive cervical cancer are lacking. METHODS: We used nationwide Swedish demographic and health registers to follow an open population of 1,672,983 girls and women who were 10 to 30 years of age from 2006 through 2017. We assessed the association between HPV vaccination and the risk of invasive cervical cancer, controlling for age at follow-up, calendar year, county of residence, and parental characteristics, including education, household income, mother's country of birth, and maternal disease history. RESULTS: During the study period, we evaluated girls and women for cervical cancer until their 31st birthday. Cervical cancer was diagnosed in 19 women who had received the quadrivalent HPV vaccine and in 538 women who had not received the vaccine. The cumulative incidence of cervical cancer was 47 cases per 100,000 persons among women who had been vaccinated and 94 cases per 100,000 persons among those who had not been vaccinated. After adjustment for age at follow-up, the incidence rate ratio for the comparison of the vaccinated population with the unvaccinated population was 0.51 (95% confidence interval [CI], 0.32 to 0.82). After additional adjustment for other covariates, the incidence rate ratio was 0.37 (95% CI, 0.21 to 0.57). After adjustment for all covariates, the incidence rate ratio was 0.12 (95% CI, 0.00 to 0.34) among women who had been vaccinated before the age of 17 years and 0.47 (95% CI, 0.27 to 0.75) among women who had been vaccinated at the age of 17 to 30 years. CONCLUSIONS: Among Swedish girls and women 10 to 30 years old, quadrivalent HPV vaccination was associated with a substantially reduced risk of invasive cervical cancer at the population level. (Funded by the Swedish Foundation for Strategic Research and others.).

Confidence in the National Immunization Program among parents in Sweden 2016 - A cross-sectional survey.

BACKGROUND: Vaccination coverage for infant vaccinations in the Swedish National Immunization Program (NIP) has been high for more than a decade, with approximately 97% of 2-year-old children fully immunized. Vaccination coverage against Human Papilloma Virus (HPV) has been around 80% since introduction for girls in 2012. This indicates high parental confidence in the NIP, but as seen in other European countries rapid shifts in confidence may occur. This study examined vaccine confidence and attitudes towards vaccinations among parents in the Swedish population. METHODS: A web-based survey was sent to 1046 parents with children aged 0-15 years, in a panel administrated by The Public Health Agency of Sweden. The survey included questions on vaccination awareness, safety and information channels. The response rate was 87%. Data were weighted to adjust for non-responders and for representativeness of the Swedish population. RESULTS: Parents were categorized as acceptors (79%), questioning acceptors (19%) or selective refusers (2%). When excluding responses for HPV vaccination, the proportion of acceptors increased to 91%. The main reasons for questioning or refusing a vaccine were worry over adverse events, negative or lack of information. Along a spectrum of beliefs, acceptors and questioning acceptors were more similar compared to selective refusers. Nurses at child health clinics constituted the most used vaccination information source for acceptors, whereas selective refusers to a greater extent searched information online and in social media. CONCLUSIONS: The study demonstrates that parents in Sweden have confidence in and are positive towards vaccinations given within the NIP. One in five parents question vaccines, particularly regarding the HPV vaccine, but still concur to the NIP. Information on vaccines online and at vaccination appointments, including vaccine safety, is important for maintaining confidence in vaccination. Conducting recurring studies is valuable for monitoring vaccine confidence and changes in attitudes towards vaccination.

Mode of HPV vaccination delivery and equity in vaccine uptake: A nationwide cohort study.

Ten years after its introduction, equity in human papillomavirus (HPV) vaccine uptake remains unattained, not least for the groups at highest risk of cervical cancer. In Sweden, three different delivery modes of the vaccine have been in effect since May 2007. We used this as a natural experiment to investigate girls' HPV vaccine uptake in relation to parental country of birth and socioeconomic characteristics, by mode of delivery. Our nationwide study cohort comprised 689,676 girls born between 1990 and 2003. Data on HPV vaccination of the girls and parental birth/socioeconomic characteristics were retrieved from national registers. We examined the association between girls' vaccine uptake and parental characteristics, stratified by mode of delivery. The cumulative uptake of at least one dose of HPV vaccine was 37%, 48% and 79% for subsidised opportunistic, free-of-charge catch-up outside-school and free-of-charge school-based vaccination, respectively. In the subsidised vaccination, having parents born outside of Sweden, with low education and low family income was strongly associated with lower uptake [HR (95% confidence interval (CI)) = 0.49 (0.48-0.50), 0.32 (0.31-0.33), 0.53 (0.52-0.54), respectively]. The associations were partially reduced in catch-up outside-school, and strongly reduced in school-based vaccination delivery [HR (95% CI) =0.82 (0.81-0.83), 0.92 (0.91-0.94), 0.87 (0.85-0.88), respectively]. Free-of-charge school-based HPV vaccination achieved the highest uptake and displayed the least disparity in country of birth and socioeconomic background of the parents. This appears to be the most effective and equitable delivery mode for reaching high population vaccination coverage, including high-risk groups for cervical cancer.

Cost-effectiveness of sex-neutral HPV-vaccination in Sweden, accounting for herd-immunity and sexual behaviour.

INTRODUCTION: The aim was to assess cost-effectiveness of expanding the Swedish HPV-vaccination program to include preadolescent boys, by comparing health-effects and costs of HPV-related disease, with a sex-neutral vaccination program versus only vaccinating girls. METHODS: We used a dynamic compartmental model to simulate the burden of HPV16/18-related disease in Sweden, accounting for indirect effects of vaccination through herd-immunity. The model accounted for sexual behaviour, such as age preferences and men who have sex with men. The main outcome was number of individuals with HPV-related cancers (cervical, genital, anal and oropharyngeal cancer) and cervical intraepithelial neoplasia (CIN). Costs included in the analysis were those incurred when treating HPV-related cancer and CIN, production losses during sick-leave, and acquisition and administration of vaccine. Health effects were measured as quality-adjusted life years (QALY). The time horizon was set to 100 years, and both effects and costs were discounted by 3% annually. Health effects and costs were accumulated over the time horizon and used to create an incremental cost-effectiveness ratio. RESULTS: A sex-neutral vaccination program would reduce HPV-related cancer and CIN, both due to direct effects among vaccinated as well as through herd-immunity, further decreasing HPV-related cancer burden annually by around 60 cases among men and women respectively in steady-state. The cost per gained QALY was estimated to 40,000 euro. Applying the procurement price of 2017, sex-neutral vaccination was dominant. CONCLUSION: Introducing a sex-neutral HPV-vaccination program would be good value for money also in Sweden where there this 80% coverage in the current HPV-vaccination program for preadolescent girls. The cost-effectiveness of a sex-neutral program is highly dependent on the price of the vaccine, the lower the price the more favourable it is to also vaccinate boys.

Improved autologous cortical bone harvest and viability with 2Flute otologic burs.

OBJECTIVES: To determine if 2Flute (Stryker Corporation, Kalamazoo, MI) otologic burs improve the size, cellular content, and bone healing of autologous cortical bone grafts harvested during canal wall reconstruction (CWR) tympanomastoidectomy with mastoid obliteration. STUDY DESIGN: Institutional review board-approved prospective cohort study. METHODS: Human autologous cortical bone chips were harvested using various burs (4 and 6 mm diameter; multiflute, and 2Flute [Stryker Corporation]) from patients undergoing CWR tympanomastoidectomy for the treatment of chronic otitis media with cholesteatoma. Bone chip size, cell counts, cellular gene expression, and new bone formation were quantified. RESULTS: Bone chips were significantly larger when harvested with 2Flute (Stryker Corporation) bur compared to multiflute burs at both 6 mm diameter (113 ± 14 µm2 vs. 66 ± 8 µm2 ; P < 0.05) and 4 mm diameter (70 ± 8 µm2 vs. 50 ± 3 µm2 ; P < 0.05). After 2 weeks in culture, cell numbers were significantly higher when harvested with 2Flute (Stryker Corporation) bur compared to multiflute burs at both 6 mm diameter (48.7 ± 3 vs. 31.8 ± 3 cells/µg bone; P < 0.05) and 4 mm diameter (27.6 ± 1.2 vs. 8.8 ± 1.2 cells/µg bone; P < 0.05). Bone-derived cells express osteoblast markers (alkaline phosphatase, osteocalcin). Cultured cells are able to form new bone in culture, and bone formation is facilitated by the presence of bone chips. CONCLUSION: Use of 2Flute (Stryker Corporation) otologic burs for human autologous cortical bone harvest results in more viable bone fragments, with larger bone chips and more osteoblasts. Future studies are needed to determine if this leads to improved bone healing. LEVEL OF EVIDENCE: NA. Laryngoscope, 128:E41-E46, 2018.

An epidemiological study to assess the true incidence and prevalence of rheumatic heart disease and acute rheumatic fever in New Caledonian school children.

AIM: To provide in New Caledonian school children (i) the prevalence of rheumatic heart disease (RHD) detected by annual screening program using new World Heart Federation diagnostic criteria; (ii) the point prevalence of acute rheumatic fever (ARF); and (iii) to investigate socio-demographic risk factors associated with RHD. METHODS: This study linked data from national ARF/RHD programs by combining ARF incidence data from the register with RHD prevalence data from echocardiographic screening data for a single age year of the population for overall point prevalence ARF/RHD rates. For the analysis, cases of echocardiographic detection of RHD are presumed to be synonymous with undiagnosed ARF. All results were weighted to minimise the bias introduced from absent pupils of each annual screening program. Incidence and prevalence were age-standardised to the WHO World Standard Population. Each 2013 cumulative prevalence of definite and borderline RHD was studied using a multivariate logistic regression adjusted for socio-demographic factors. RESULTS: The overall age-standardised incidence of clinical and undiagnosed ARF (i.e. echocardiographic-detected RHD) was combined as point prevalence and estimated to be 99/10 000 cases in 2012 and 114/10 000 cases in 2013. This included 40/10 000 prevalent cases of asymptomatic RHD detected by screening each year. Being Melanesian, OR 23.2 (95% CI: 3.4-157.3), or Polynesian, OR 21.5 (95% CI: 2.9-157.7), was associated with a higher prevalence of having definite RHD compared with being Caucasian. Being a girl was associated with a higher risk of having borderline RHD, OR 1.9 (95% CI: 1.03-3.3). CONCLUSION: Without echocardiographic screening, ARF/RHD burden is substantially underestimated.

Tobacco Smoking in Islands of the Pacific Region, 2001-2013.

We provide an overview of tobacco smoking patterns in Pacific island countries and territories to facilitate monitoring progress toward the goal of a Tobacco-Free Pacific by 2025. We examined data from 4 surveys conducted in the region between 2001 and 2013, including the STEPwise approach to surveillance for adults (25-64 years); the Global School-Based Student Health Survey and the Global Youth Tobacco Survey (students 13-15 years); and the Youth Risk Behavior Surveillance System (grade 9-12 students) in United States affiliated Pacific Islands (USAPIs). Adult smoking prevalence ranged from less than 5% of women in Vanuatu to almost 75% of men in Kiribati. Smoking prevalence among students (13-15 years) ranged between 5.6% and 52.1%. There were declines in smoking among youths in many USAPIs. To achieve the tobacco-free goal and reduce disease burden, accelerated action is needed to align national legislation with international agreements and build capacity for tobacco control at all levels.

Noncommunicable diseases and risk factors in adult populations of several Pacific Islands: results from the WHO STEPwise approach to surveillance.

OBJECTIVE: To provide an overview of the prevalence of noncommunicable diseases (NCDs) and their risk factors in several Pacific island countries and territories (PICTs), in accordance with global NCD targets. METHODS: For six risk factors, data for adults (aged 25-64 years) from published reports of the World Health Organization STEPwise approach to NCD surveillance, or methodologically similar surveys, were collated, age standardised and compared across fifteen PICTs. RESULTS: In the majority of PICT populations, more than half of male current drinkers drank heavily and more than 40% of men and 20% of women were current smokers. In 10 populations, about 50% or more of women were insufficiently physically active. Prevalence of hypertension and diabetes exceeded 20% and 25%, respectively, in several populations. Near or more than half of men and women in all populations were overweight; in most, more than one-third of both sexes were obese. CONCLUSIONS: The prevalence of NCDs and risk factors varies widely between PICTs and by sex. The evidence shows the high and alarming present and future burden of NCDs in the region. IMPLICATIONS: Strengthened political commitment and increased investment are urgently required to tackle the NCD crisis, successfully achieve targets and ensure continuing sustainable development in the Pacific islands.

Battling tuberculosis in an island context with a high burden of communicable and non-communicable diseases: epidemiology, progress, and lessons learned in Kiribati, 2000 to 2012.

OBJECTIVES: To examine the epidemiology of tuberculosis (TB) in Kiribati from 2000 to 2012, document lessons learned, and recommend ways to mitigate the burden of TB in Kiribati. METHODS: A descriptive study was performed using data on TB case notifications, prevalence, incidence, mortality, and treatment outcomes from global reports and data files. Progress towards meeting the Millennium Development Goal TB target (to reduce TB incidence by 2015) and the Regional Strategy to Stop Tuberculosis in the Western Pacific 2011-2015 targets (to reduce TB prevalence and mortality by half by 2015 relative to the level in 2000) was examined. RESULTS: TB case notifications and the estimated incidence and prevalence have increased in Kiribati since 2000. From 2000 to 2012, Kiribati reported a total of 3863 TB notifications; in 2012, the case notification rate was 343/100 000 population. The majority (89%) of TB patients complete treatment and/or are cured, and the estimated TB mortality rate has remained relatively stable at around 16/100 000 population. HIV testing of TB patients has increased over recent years from 8% of notifications tested in 2003 to 43% tested in 2012. Of all 818 tests, only four (0.5%) patients were confirmed HIV-positive. Drug-resistant TB has been detected in a small number of cases. CONCLUSIONS: TB rates continue to increase in Kiribati and the 2015 goals for TB control are unlikely to be met. This is probably due to the complex mix of risk factors present in Kiribati, including smoking, diabetes, alcohol use, crowded living, and poverty. A comprehensive approach to address these risk factors is needed to mitigate the burden of TB in Kiribati.

Increased incidence of invasive bacterial disease in chronic obstructive pulmonary disease compared to the general population--a population based cohort study.

BACKGROUND: Innate defence mechanisms of the airways are impaired in chronic obstructive pulmonary disease (COPD), predisposing patients to lower respiratory tract infections, but less is known about the association with other infections. In this population-based cohort study, we investigated the associations between COPD and invasive bacterial disease by comparing incidence rates of bacteraemia in COPD patients and randomly selected reference individuals from the general population. METHODS: In this population based cohort study all patients with COPD, ≥40 years of age, who were discharged from hospitals in southern Sweden between 1990 and 2003 were identified in the Swedish Inpatient Register (n = 15,403). Age and gender matched reference individuals were randomly selected from the general population. Records were cross-referenced to the microbiological databases covering the region, 1990-2010. The hazard ratios (HR) of bloodstream infections and hospitalisations for infections were estimated by Cox proportional hazards regression. RESULTS: We found that individuals with COPD had a 2.5-fold increased incidence of bacteraemia compared to the reference individuals from the general population adjusted for other co-morbidity and socio-economic status (hazard ratio: 2.5, 95% confidence interval: 2.2-2.7). The increased incidence of bacteraemia was paralleled by an increased incidence of hospitalisation for non-respiratory infections, i.e., skin infections, pyelonephritis, or septic arthritis. Despite higher absolute rates of bloodstream infections among COPD patients than among the general population, the distribution of different pathogens was similar. CONCLUSIONS: In summary this population-based study shows COPD is associated with an increased incidence of invasive bacterial infections compared to the general population, indicating a general frailty of acquiring severe infections in addition to the specific susceptibility to infections of respiratory origin. The underlying contributory factors (e.g. smoking, corticosteroid use, co-morbid diseases or a frailty inherent to COPD itself) need to be disentangled in further studies.

Risk of inflammatory bowel disease following Bacille Calmette-Guérin and smallpox vaccination: a population-based Danish case-cohort study.

BACKGROUND: Childhood immunology has been suggested to play a role in development of inflammatory bowel disease (IBD) based on the studies of childhood vaccinations, infections, and treatment with antibiotics. Bacille Calmette-Guérin (BCG) and smallpox vaccinations were gradually phased-out in Denmark for children born between 1965 and 1976, hence allowing the study of subsequent risk of Crohn's disease and ulcerative colitis in a unique prospective design. METHODS: The Copenhagen School Health Records Register contains detailed documentation of vaccination. Among the background cohort of individuals born between 1965 and 1976 (N = 47,622), cases with Crohn's disease (n = 218) and ulcerative colitis (n = 256) were identified through linkage to the Danish National Patient Registry. The vaccination status of the cases was compared with that of a subcohort (n = 5741) of the background cohort and analyzed in a case-cohort design. RESULTS: No difference in risk of IBD was observed between individuals vaccinated and unvaccinated with BCG (hazard ratio = 0.95; 95% confidence interval, 0.75-1.19) or smallpox vaccine (hazard ratio = 1.01; 95% confidence interval, 0.77-1.32). This was also the case for Crohn's disease and ulcerative colitis separately. However, BCG given before 4 months of age may decrease the risk of IBD (hazard ratio = 0.43; 95% confidence interval, 0.20-0.93). CONCLUSIONS: This prospective long-term case-cohort study shows that BCG and smallpox vaccination do not cause IBD later in life. These findings are important for the etiological understanding of IBD and of clinical importance because BCG is still one of the most commonly used childhood vaccinations, smallpox vaccine has been reintroduced in the U.S. military, and both vaccines may be used as vectors in new vaccines.

The immunological effect of revaccination with Bacille Calmette-Guérin vaccine at 19 months of age.

BACKGROUND: Bacille Calmette-Guérin (BCG) vaccination has important non-specific immune effects. In a randomized trial in Guinea-Bissau, BCG revaccination was associated with significantly increased survival in children who received diphtheria-tetanus-pertussis (DTP)-booster vaccine before enrolment and in children who did not receive micronutrient supplementation (MN). Within the trial we assessed the immunological effects of BCG revaccination. METHODS: Children were randomized to BCG or nothing. Blood was sampled 6-11 weeks after randomization (early sample group) or 5-9 months later (late sample group). In vitro cytokine responses (interferon (IFN)-γ, interleukin (IL)-13, tumor-necrosis-factor (TNF)-α, and IL-10) were assessed in whole blood cultures stimulated with lipopolysaccharide (LPS), purified protein derivative (PPD) or phytohaemagglutinin (PHA). Effect-modification by sex, DTP-booster vaccination and MN was studied. RESULTS: Cytokines were measured in 345 infants. BCG was associated with significantly increased IFN-γ (geometric mean ratio (GMR)=4.54 (95% confidence interval: 3.13-6.58)) and IL-13 (GMR=1.43 (1.00-2.05)) PPD responses, the effect being strongest in the early sample group. Across all three conditions BCG tended to increase IL-10 (LPS, PHA, PPD: GMR=1.20, 1.12, 1.20), most pronounced in the late sample group. BCG reduced the TNF-α/IL-10 ratio in boys with DTP-booster at bleeding and increased it in those without (interaction test: p=0.03). In children without MN, BCG was associated with reduced TNF-α response in the early sample group (p=0.006), and increased IL-10 in the late sample group (p=0.03). CONCLUSION: BCG revaccination resulted in a strong IFN-γ response to PPD, which waned slightly over time. BCG also affected the pro-/anti-inflammatory balance, with reduced TNF-α and increased IL-10 responses to LPS, PHA and PPD. This effect depended on sex, DTP-booster vaccination and micronutrient supplementation, being most pronounced in children who had received DTP-booster before enrolment and children who had not received MN, i.e. the group of children which also had lower mortality after BCG revaccination.

New families of human regulatory RNA structures identified by comparative analysis of vertebrate genomes.

Regulatory RNA structures are often members of families with multiple paralogous instances across the genome. Family members share functional and structural properties, which allow them to be studied as a whole, facilitating both bioinformatic and experimental characterization. We have developed a comparative method, EvoFam, for genome-wide identification of families of regulatory RNA structures, based on primary sequence and secondary structure similarity. We apply EvoFam to a 41-way genomic vertebrate alignment. Genome-wide, we identify 220 human, high-confidence families outside protein-coding regions comprising 725 individual structures, including 48 families with known structural RNA elements. Known families identified include both noncoding RNAs, e.g., miRNAs and the recently identified MALAT1/MEN ß lincRNA family; and cis-regulatory structures, e.g., iron-responsive elements. We also identify tens of new families supported by strong evolutionary evidence and other statistical evidence, such as GO term enrichments. For some of these, detailed analysis has led to the formulation of specific functional hypotheses. Examples include two hypothesized auto-regulatory feedback mechanisms: one involving six long hairpins in the 3'-UTR of MAT2A, a key metabolic gene that produces the primary human methyl donor S-adenosylmethionine; the other involving a tRNA-like structure in the intron of the tRNA maturation gene POP1. We experimentally validate the predicted MAT2A structures. Finally, we identify potential new regulatory networks, including large families of short hairpins enriched in immunity-related genes, e.g., TNF, FOS, and CTLA4, which include known transcript destabilizing elements. Our findings exemplify the diversity of post-transcriptional regulation and provide a resource for further characterization of new regulatory mechanisms and families of noncoding RNAs.

Risk of lymphoma and leukaemia after bacille Calmette-Guérin and smallpox vaccination: a Danish case-cohort study.

Vaccines may have non-specific effects as suggested mainly in mortality studies from low-income countries. The objective was to examine the effects of BCG and smallpox vaccinations on subsequent risk of lymphoma and leukaemia in a Danish population experiencing rapid out-phasing of these vaccines. In a background cohort (N=47,622) from the Copenhagen School Health Records Register, cases of leukaemia (N=20) and lymphoma (N=51) were identified through the Danish Cancer Registry. The vaccination status of the cases was compared with the vaccination status of a 5% random sample (N=2073) of the background cohort and analysed in a case-cohort design. BCG vaccination reduced the risk of lymphomas (HR=0.49 (95% CI: 0.26-0.93)), whereas smallpox vaccination did not (HR=1.32 (0.56-3.08)). With the small number of leukaemia cases, the analysis of leukaemia had limited power (BCG vaccination HR=0.81 (0.31-2.16); smallpox vaccination HR=1.32 (0.49-3.53)). The present study with very reliable vaccine history information indicates a beneficial effect of BCG vaccination on the risk of lymphomas.

Tandem riboswitch architectures exhibit complex gene control functions.

Riboswitches are structured RNAs typically located in the 5' untranslated regions of bacterial mRNAs that bind metabolites and control gene expression. Most riboswitches sense one metabolite and function as simple genetic switches. However, we found that the 5' region of the Bacillus clausii metE messenger RNA includes two riboswitches that respond to S-adenosylmethionine and coenzyme B12. This tandem arrangement yields a composite gene control system that functions as a two-input Boolean NOR logic gate. These findings and the discovery of additional tandem riboswitch architectures reveal how simple RNA elements can be assembled to make sophisticated genetic decisions without involving protein factors.

Health risks of smoking compared to Swedish snus.

Interest in tobacco harm reduction strategies has raised the question of the comparative health risks of cigarette smoking and use of other tobacco products. Although there appears to be a general belief that a unique smokeless tobacco product called Swedish snus has fewer health risks than cigarettes, no one has systematically reviewed the literature and compared the data on health risks in a quantitative manner. We reviewed the literature to identify all analytic epidemiologic studies that provided quantitative risk estimates associated with Swedish snus and cigarette smoking in a single population, using a common reference group. Seven studies were identified that addressed eight health outcomes. Although few in number, these seven studies do provide quantitative evidence that, for certain health outcomes, the health risks associated with snus are lower than those associated with smoking. Specifically, this is true for lung cancer (based on one study), for oral cancer (based on one study), for gastric cancer (based on one study), for cardiovascular disease (based on three of four studies), and for all-cause mortality (based on one study). This review has likely omitted many of the adverse effects of cigarettes, but probably few of the potential health effects of snus. Continued investigation of the reduced health risks of Swedish snus compared to cigarette smoking is warranted.

A common speed limit for RNA-cleaving ribozymes and deoxyribozymes.

It is widely believed that the reason proteins dominate biological catalysis is because polypeptides have greater chemical complexity compared with nucleic acids, and thus should have greater enzymatic power. Consistent with this hypothesis is the fact that protein enzymes typically exhibit chemical rate enhancements that are far more substantial than those achieved by natural and engineered ribozymes. To investigate the true catalytic power of nucleic acids, we determined the kinetic characteristics of 14 classes of engineered ribozymes and deoxyribozymes that accelerate RNA cleavage by internal phosphoester transfer. Half approach a maximum rate constant of approximately 1 min(-1), whereas ribonuclease A catalyzes the same reaction approximately 80,000-fold faster. Additional biochemical analyses indicate that this commonly encountered ribozyme "speed limit" coincides with the theoretical maximum rate enhancement for an enzyme that uses only two specific catalytic strategies. These results indicate that ribozymes using additional catalytic strategies could be made that promote RNA cleavage with rate enhancements that equal those of proteins.