Airway inflammation accelerates pulmonary exacerbations in cystic fibrosis.

Airway inflammation underlies cystic fibrosis (CF) pulmonary exacerbations. In a prospective multicenter study of randomly selected, clinically stable adolescents and adults, we assessed relationships between 24 inflammation-associated molecules and the future occurrence of CF pulmonary exacerbation using proportional hazards models. We explored relationships for potential confounding or mediation by clinical factors and assessed sensitivities to treatments including CF transmembrane regulator (CFTR) protein synthesis modulators. Results from 114 participants, including seven on ivacaftor or lumacaftor-ivacaftor, representative of the US CF population during the study period, identified 10 biomarkers associated with future exacerbations mediated by percent predicted forced expiratory volume in 1 s. The findings were not sensitive to anti-inflammatory, antibiotic, and CFTR modulator treatments. The analyses suggest that combination treatments addressing RAGE-axis inflammation, protease-mediated injury, and oxidative stress might prevent pulmonary exacerbations. Our work may apply to other airway inflammatory diseases such as bronchiectasis and the acute respiratory distress syndrome.

Revising primary and secondary school curricula in the Caribbean to enhance education on the risks for noncommunicable diseases.

In the English-speaking Caribbean, an estimated 46% of men and 61% of women are currently overweight or obese, and 8% of children younger than 5 years are also overweight. To combat this worsening epidemic, driven by unhealthy dietary patterns, the Heads of Government of the Caribbean Community (CARICOM) issued the 2007 Port-of-Spain Declaration, which included mandates on the provision of healthy school meals, promotion of healthy dietary patterns, and reintroduction of physical education in schools. These mandates are aligned with evidence-based approaches used in childhood obesity prevention programs. School-based interventions, including curriculum revisions, are part of a multipronged approach to improve nutrition in children and are designed to complement and reinforce other interventions in schools. However, formal evaluation of the Port-of-Spain Declaration showed that most CARICOM member countries had difficulty implementing the mandates related to schools and diet. The Improving Household Nutrition Security and Public Health in the CARICOM project, in collaboration with regional institutions, the CARICOM Secretariat, and the Caribbean Examinations Council, sought to enhance nutrition education through revision of region-wide primary and secondary school curricula to increase the focus on prevention of noncommunicable diseases. This paper describes the process of revising the Caribbean Examinations Council's Human and Social Biology syllabus for secondary schools and the CARICOM Health and Family Life Education Regional Curriculum Framework for primary schools, which was achieved through multisectoral collaboration. We used the Framework for Reporting Adaptations and Modifications-Enhanced model to describe the process through which the modifications were made.

Se calcula que, en el Caribe de habla inglesa, el 46% de los hombres y el 61% de las mujeres tienen sobrepeso o son obesos, así como el 8% de los menores de 5 años. Para combatir esta epidemia creciente, debida a los hábitos de alimentación poco saludables, los Jefes de Gobierno de la Comunidad del Caribe (CARICOM) emitieron en el 2007 la Declaración de Puerto España, que incluía mandatos relativos al suministro de comidas escolares saludables, la promoción de hábitos de alimentación saludables y la reintroducción de la educación física en las escuelas. Estos mandatos están en consonancia con los enfoques basados en la evidencia que se aplican en los programas de prevención de la obesidad infantil. Las intervenciones en los centros escolares, entre ellas la revisión de los planes de estudios, forman parte de una estrategia multidimensional dirigida a mejorar la nutrición infantil, y tienen la finalidad de complementar y reforzar otras intervenciones en las escuelas. Sin embargo, los resultados de la evaluación formal de la Declaración de Puerto España mostraron que la mayoría de los países miembros de la CARICOM tuvieron dificultades para poner en práctica los mandatos relativos a las escuelas y la alimentación. El proyecto "Mejorar la seguridad nutricional de los hogares y la salud pública en la Comunidad del Caribe", en colaboración con instituciones regionales, la Secretaría de la CARICOM y el Caribbean Examinations Council, se propuso mejorar la educación nutricional por medio de la revisión de los planes de estudio de las escuelas primarias y secundarias de toda la región, para prestar mayor atención a la prevención de las enfermedades no transmisibles. En este artículo se describe el proceso de revisión del temario del Caribbean Examinations Council en materia de Biología Humana y Social para las escuelas secundarias, así como del marco curricular regional de educación para la salud y la vida familiar de la CARICOM para las escuelas primarias, que se llevó a cabo mediante una colaboración multisectorial. Para describir el proceso por el cual se realizaron las modificaciones, los autores usaron el modelo ampliado del marco para informar las adaptaciones y modificaciones (FRAME, por su sigla en inglés).

No Caribe anglófono, estima-se que atualmente 46% dos homens e 61% das mulheres estejam com sobrepeso ou obesidade e que 8% das crianças menores de 5 anos também estejam com sobrepeso. Para combater essa epidemia que se agrava, impulsionada por padrões alimentares pouco saudáveis, os chefes de governo da Comunidade do Caribe (CARICOM) emitiram a Declaração de Port-of-Spain de 2007, que incluía mandatos sobre o fornecimento de refeições saudáveis nas escolas, a promoção de padrões alimentares saudáveis e a reintrodução da educação física nas escolas. Esses mandatos são consistentes com abordagens baseadas em evidências usadas em programas de prevenção da obesidade infantil. Intervenções realizadas nas escolas, incluindo revisões curriculares, fazem parte de uma abordagem multifacetada para melhorar a nutrição das crianças, com o objetivo de complementar e reforçar outras intervenções nas escolas. Entretanto, a avaliação formal da Declaração de Port-of-Spain mostrou que a maioria dos países membros da CARICOM teve dificuldade em implementar os mandatos relacionados às escolas e à dieta. O projeto Melhorando a Segurança Nutricional das Famílias e a Saúde Pública na CARICOM, em colaboração com instituições regionais, a Secretaria da CARICOM e o Conselho de Exames do Caribe, buscou aprimorar a educação nutricional por meio da revisão dos currículos do ensino fundamental e médio em toda a região para aumentar o foco na prevenção de doenças não transmissíveis. Este artigo descreve o processo de revisão do programa de Biologia Humana e Social do Conselho de Exames do Caribe (para escolas do ensino médio) e da Estrutura Curricular Regional de Educação em Saúde e Vida Familiar da CARICOM (para escolas do ensino fundamental), que foi alcançado por meio de colaboração multissetorial. Usamos o modelo avançado da Estrutura para Informar Adaptações e Modificações (FRAME) para descrever o processo utilizado para fazer as modificações.

Revising primary and secondary school curricula in the Caribbean to enhance education on the risks for noncommunicable diseases / Revisión de los planes de estudio de las escuelas primarias y secundarias del Caribe para mejorar la educación sobre los riesgos de las enfermedades no transmisibles / Revisão dos currículos do ensino fundamental e médio no Caribe para melhorar a educação sobre os riscos de doenças não transmissíveis

ABSTRACT In the English-speaking Caribbean, an estimated 46% of men and 61% of women are currently overweight or obese, and 8% of children younger than 5 years are also overweight. To combat this worsening epidemic, driven by unhealthy dietary patterns, the Heads of Government of the Caribbean Community (CARICOM) issued the 2007 Port-of-Spain Declaration, which included mandates on the provision of healthy school meals, promotion of healthy dietary patterns, and reintroduction of physical education in schools. These mandates are aligned with evidence-based approaches used in childhood obesity prevention programs. School-based interventions, including curriculum revisions, are part of a multipronged approach to improve nutrition in children and are designed to complement and reinforce other interventions in schools. However, formal evaluation of the Port-of-Spain Declaration showed that most CARICOM member countries had difficulty implementing the mandates related to schools and diet. The Improving Household Nutrition Security and Public Health in the CARICOM project, in collaboration with regional institutions, the CARICOM Secretariat, and the Caribbean Examinations Council, sought to enhance nutrition education through revision of region-wide primary and secondary school curricula to increase the focus on prevention of noncommunicable diseases. This paper describes the process of revising the Caribbean Examinations Council's Human and Social Biology syllabus for secondary schools and the CARICOM Health and Family Life Education Regional Curriculum Framework for primary schools, which was achieved through multisectoral collaboration. We used the Framework for Reporting Adaptations and Modifications-Enhanced model to describe the process through which the modifications were made.

RESUMEN Se calcula que, en el Caribe de habla inglesa, el 46% de los hombres y el 61% de las mujeres tienen sobrepeso o son obesos, así como el 8% de los menores de 5 años. Para combatir esta epidemia creciente, debida a los hábitos de alimentación poco saludables, los Jefes de Gobierno de la Comunidad del Caribe (CARICOM) emitieron en el 2007 la Declaración de Puerto España, que incluía mandatos relativos al suministro de comidas escolares saludables, la promoción de hábitos de alimentación saludables y la reintroducción de la educación física en las escuelas. Estos mandatos están en consonancia con los enfoques basados en la evidencia que se aplican en los programas de prevención de la obesidad infantil. Las intervenciones en los centros escolares, entre ellas la revisión de los planes de estudios, forman parte de una estrategia multidimensional dirigida a mejorar la nutrición infantil, y tienen la finalidad de complementar y reforzar otras intervenciones en las escuelas. Sin embargo, los resultados de la evaluación formal de la Declaración de Puerto España mostraron que la mayoría de los países miembros de la CARICOM tuvieron dificultades para poner en práctica los mandatos relativos a las escuelas y la alimentación. El proyecto "Mejorar la seguridad nutricional de los hogares y la salud pública en la Comunidad del Caribe", en colaboración con instituciones regionales, la Secretaría de la CARICOM y el Caribbean Examinations Council, se propuso mejorar la educación nutricional por medio de la revisión de los planes de estudio de las escuelas primarias y secundarias de toda la región, para prestar mayor atención a la prevención de las enfermedades no transmisibles. En este artículo se describe el proceso de revisión del temario del Caribbean Examinations Council en materia de Biología Humana y Social para las escuelas secundarias, así como del marco curricular regional de educación para la salud y la vida familiar de la CARICOM para las escuelas primarias, que se llevó a cabo mediante una colaboración multisectorial. Para describir el proceso por el cual se realizaron las modificaciones, los autores usaron el modelo ampliado del marco para informar las adaptaciones y modificaciones (FRAME, por su sigla en inglés).

RESUMO No Caribe anglófono, estima-se que atualmente 46% dos homens e 61% das mulheres estejam com sobrepeso ou obesidade e que 8% das crianças menores de 5 anos também estejam com sobrepeso. Para combater essa epidemia que se agrava, impulsionada por padrões alimentares pouco saudáveis, os chefes de governo da Comunidade do Caribe (CARICOM) emitiram a Declaração de Port-of-Spain de 2007, que incluía mandatos sobre o fornecimento de refeições saudáveis nas escolas, a promoção de padrões alimentares saudáveis e a reintrodução da educação física nas escolas. Esses mandatos são consistentes com abordagens baseadas em evidências usadas em programas de prevenção da obesidade infantil. Intervenções realizadas nas escolas, incluindo revisões curriculares, fazem parte de uma abordagem multifacetada para melhorar a nutrição das crianças, com o objetivo de complementar e reforçar outras intervenções nas escolas. Entretanto, a avaliação formal da Declaração de Port-of-Spain mostrou que a maioria dos países membros da CARICOM teve dificuldade em implementar os mandatos relacionados às escolas e à dieta. O projeto Melhorando a Segurança Nutricional das Famílias e a Saúde Pública na CARICOM, em colaboração com instituições regionais, a Secretaria da CARICOM e o Conselho de Exames do Caribe, buscou aprimorar a educação nutricional por meio da revisão dos currículos do ensino fundamental e médio em toda a região para aumentar o foco na prevenção de doenças não transmissíveis. Este artigo descreve o processo de revisão do programa de Biologia Humana e Social do Conselho de Exames do Caribe (para escolas do ensino médio) e da Estrutura Curricular Regional de Educação em Saúde e Vida Familiar da CARICOM (para escolas do ensino fundamental), que foi alcançado por meio de colaboração multissetorial. Usamos o modelo avançado da Estrutura para Informar Adaptações e Modificações (FRAME) para descrever o processo utilizado para fazer as modificações.

Prospective multicenter randomized patient recruitment and sample collection to enable future measurements of sputum biomarkers of inflammation in an observational study of cystic fibrosis.

BACKGROUND: Biomarkers of inflammation predictive of cystic fibrosis (CF) disease outcomes would increase the power of clinical trials and contribute to better personalization of clinical assessments. A representative patient cohort would improve searching for believable, generalizable, reproducible and accurate biomarkers. METHODS: We recruited patients from Mountain West CF Consortium (MWCFC) care centers for prospective observational study of sputum biomarkers of inflammation. After informed consent, centers enrolled randomly selected patients with CF who were clinically stable sputum producers, 12 years of age and older, without previous organ transplantation. RESULTS: From December 8, 2014 through January 16, 2016, we enrolled 114 patients (53 male) with CF with continuing data collection. Baseline characteristics included mean age 27 years (SD = 12), 80% predicted forced expiratory volume in 1 s (SD = 23%), 1.0 prior year pulmonary exacerbations (SD = 1.2), home elevation 328 m (SD = 112) above sea level. Compared with other patients in the US CF Foundation Patient Registry (CFFPR) in 2014, MWCFC patients had similar distribution of sex, age, lung function, weight and rates of exacerbations, diabetes, pancreatic insufficiency, CF-related arthropathy and airway infections including methicillin-sensitive or -resistant Staphylococcus aureus, Pseudomonas aeruginosa, Burkholderia cepacia complex, fungal and non-tuberculous Mycobacteria infections. They received CF-specific treatments at similar frequencies. CONCLUSIONS: Randomly-selected, sputum-producing patients within the MWCFC represent sputum-producing patients in the CFFPR. They have similar characteristics, lung function and frequencies of pulmonary exacerbations, microbial infections and use of CF-specific treatments. These findings will plausibly make future interpretations of quantitative measurements of inflammatory biomarkers generalizable to sputum-producing patients in the CFFPR.

Evaluation of Food Insecurity in Adults and Children With Cystic Fibrosis: Community Case Study.

Advances in the care and treatment of cystic fibrosis (CF) have led to improved mortality rates; therefore, considerably more individuals with CF are living into adulthood. With an increased number of CF patients advancing into adulthood, there is the need for more research that surrounds the aging adult CF patient. It is important to conduct research and collect results on the aging CF population to help better prepare the CF patient, who is dealing with the heavy treatment and financial burden of their disease, build autonomy and increase their quality of life. Of note, research has found that social, behavioral, and physical factors influence the ability of those with CF to follow dietary recommendations. A primary treatment goal in CF is a high calorie, high protein, and high fat diet. A socio-economic factor that has not been adequately investigated with regards to dietary compliance of individuals with CF is food insecurity. The aim of this community case study was to document the experiences and estimate the prevalence of food insecurity among CF patients residing in Idaho. The correlation between food insecurity and health outcomes (lung function and body mass index) was also examined. Participants included adult patients and parents of pediatric patients with CF. Food insecurity rates among CF patients of all ages were found to be significantly higher than that seen in the overall community; however, no specific correlation between food insecurity and body mass index (BMI) or lung function emerged. This case study highlights the need for continued research around food access issues in this patient population. The data resulting from this study shows the value of CF advocacy organizations promoting efforts to build resources and provide education around food insecurity issues.

Absorption and Safety With Sustained Use of RELiZORB Evaluation (ASSURE) Study in Patients With Cystic Fibrosis Receiving Enteral Feeding.

OBJECTIVES: Pancreatic insufficiency (PI) and malabsorption of fats lead to reduced caloric intake, inability to maintain weight, and increased gastrointestinal symptoms. Thus, enteral nutrition (EN) is used in patients with cystic fibrosis (CF) and poor nutritional status. The current study evaluated safety, tolerability, and improvement of fatty acid (FA) status in red blood cell (RBC) membranes, a marker of long-term FA absorption, with an in-line digestive cartridge (RELiZORB) that hydrolyzes fat in enteral formula. METHODS: Patients with CF receiving EN participated in a multicenter, 90-day open-label study during which RELiZORB was used with overnight EN. The primary endpoint was change over time in RBC uptake of docosahexaenoic acid (DHA)+ eicosapentaenoic acid (EPA). Gastrointestinal symptoms were collected to evaluate safety and tolerability. Several clinical and anthropometric parameters were also assessed throughout the study. RESULTS: A total of 36 subjects completed the study with a mean age of 13.8 years, body mass index of 17.7 and 6.2 years mean use of overnight EN. Fat absorption significantly improved as shown by increased RBC levels of DHA+EPA, improved ω-6/ω-3 ratio, and increased plasma levels of DHA+EPA. RELiZORB use was not associated with any unanticipated adverse events. CONCLUSIONS: RELiZORB use was found to be safe, well tolerated, and resulted in increased levels of FAs in RBCs and plasma. This is the first prospective study to show EN can improve FA abnormalities in CF. Because improvement in omega-3 levels has been shown to help pulmonary and inflammatory status as well as anthropometric parameters in CF, RELiZORB may have important long-term therapeutic benefits in patients with CF.

Azithromycin for Early Pseudomonas Infection in Cystic Fibrosis. The OPTIMIZE Randomized Trial.

RATIONALE: New isolation of Pseudomonas aeruginosa (Pa) is generally treated with inhaled antipseudomonal antibiotics such as tobramycin inhalation solution (TIS). A therapeutic approach that complements traditional antimicrobial therapy by reducing the risk of pulmonary exacerbation and inflammation may ultimately prolong the time to Pa recurrence. OBJECTIVES: To test the hypothesis that the addition of azithromycin to TIS in children with cystic fibrosis and early Pa decreases the risk of pulmonary exacerbation and prolongs the time to Pa recurrence. METHODS: The OPTIMIZE (Optimizing Treatment for Early Pseudomonas aeruginosa Infection in Cystic Fibrosis) trial was a multicenter, double-blind, randomized, placebo-controlled, 18-month trial in children with CF, 6 months to 18 years of age, with early Pa. Azithromycin or placebo was given 3× weekly with standardized TIS. MEASUREMENTS AND MAIN RESULTS: The primary endpoint was the time to pulmonary exacerbation requiring antibiotics and the secondary endpoint was the time to Pa recurrence, in addition to other clinical and safety outcomes. A total of 221 participants (111 placebo, 110 azithromycin) out of a planned 274 were enrolled. Enrollment was stopped early by the NHLBI because the trial had reached the prespecified interim boundary for efficacy. The risk of pulmonary exacerbation was reduced by 44% in the azithromycin group as compared with the placebo group (hazard ratio, 0.56; 95% confidence interval, 0.37-0.83; P = 0.004). Weight increased by 1.27 kg in the azithromycin group compared with the placebo group (95% confidence interval, 0.01-2.52; P = 0.046). No significant differences were seen in microbiological or other clinical or safety endpoints. CONCLUSIONS: Azithromycin was associated with a significant reduction in the risk of pulmonary exacerbation and a sustained improvement in weight, but had no impact on microbiological outcomes in children with early Pa. Clinical trial registered with clinicaltrials.gov (NCT02054156).

Increased Fat Absorption From Enteral Formula Through an In-line Digestive Cartridge in Patients With Cystic Fibrosis.

OBJECTIVES: Supplemental enteral nutrition (EN) is used by approximately 12% of people with cystic fibrosis (CF). The objective of this study was to evaluate the safety, tolerability, and fat absorption of a new in-line digestive cartridge (Relizorb) that hydrolyzes fat in enteral formula provided to patients with CF. METHODS: Patients with CF receiving EN participated in a multicenter, randomized, double-blind, crossover trial with an open-label safety evaluation period. Plasma omega-3 fatty acid (FA) concentrations were measured and used as markers of fat absorption. Gastrointestinal symptoms were recorded to evaluate safety and tolerability. Information regarding the effect of EN on appetite and breakfast consumption was also collected. RESULTS: Before study entry, participants had received EN for a mean of 6.6 years at a mean volume of approximately 800 mL, yet had a mean body mass index of only 17.5 kg/m and omega-3 FA plasma concentrations were only 60% of levels found in normal healthy subjects. Compared with placebo, cartridge use resulted in a statistically significant 2.8-fold increase in plasma omega-3 FA concentrations. There were no adverse experiences associated with cartridge use, and a decrease in the frequency and severity of most symptoms of malabsorption was observed with cartridge use. Participants reported increased preservation of appetite and breakfast consumption with cartridge use compared with their pre-study regimen. CONCLUSIONS: Use of this in-line digestive cartridge was safe and well tolerated, and resulted in significantly increased levels of plasma omega-3 FA used with enteral formula, suggesting an overall increased fat absorption.

Directly sampling the lung of a young child with cystic fibrosis reveals diverse microbiota.

RATIONALE: The airways of people with cystic fibrosis (CF) are chronically infected with a variety of bacterial species. Although routine culture methods are usually used to diagnose these infections, culture-independent, DNA-based methods have identified many bacterial species in CF respiratory secretions that are not routinely cultured. Many prior culture-independent studies focused either on microbiota in explanted CF lungs, reflecting end-stage disease, or those in oropharyngeal swabs, which likely sample areas in addition to the lower airways. Therefore, it was unknown whether the lower airways of children with CF, well before end-stage but with symptomatic lung disease, truly contained diverse microbiota. OBJECTIVES: To define the microbiota in the diseased lung tissue of a child who underwent lobectomy for severe, localized CF lung disease. METHODS: After pathologic examination verified that this child's lung tissue reflected CF lung disease, we used bacterial ribosomal RNA gene pyrosequencing and computational phylogenetic analysis to identify the microbiota in serial sections of the tissue. MEASUREMENTS AND MAIN RESULTS: This analysis identified diverse, and anatomically heterogeneous, bacterial populations in the lung tissue that contained both culturable and nonculturable species, including abundant Haemophilus, Ralstonia, and Propionibacterium species. Routine clinical cultures identified only Staphylococcus aureus, which represented only a small fraction of the microbiota found by sequencing. Microbiota analysis of an intraoperative oropharyngeal swab identified predominantly Streptococcus species. The oropharyngeal findings therefore represented the lung tissue microbiota poorly, in agreement with findings from earlier studies of oropharyngeal swabs in end-stage disease. CONCLUSIONS: These results support the concept that diverse and spatially heterogeneous microbiota, not necessarily dominated by "traditional CF pathogens," are present in the airways of young, symptomatic children with early CF lung disease.

Social and Environmental Risk Factors for Hypertension in African Americans.

This study tests the hypothesis that disparities of hypertension risk in African Americans is related to lead exposure, perceptions of racism, and stress, among urban (Roxbury, MA) and rural (Gadsden, FL) communities. Analysis of preliminary data from Phase I reveal 60% in Gadsden and 39% in Roxbury respondents self-reported having hypertension. In Gadsden 80% people did not know if their residence contained lead paint, compared to 45% in Roxbury. In Gadsden County, 58% of respondents reported experiencing racial discrimination in different settings compared with 72% in Roxbury. In regression analyses high cholesterol emerged as a significant predictors of hypertension in Gadsden County (OR=8.29, CI=1.4-49.3), whereas monthly household income (OR=0.15, CI=0.04-0.7) and diabetes (OR=6.06, CI=1.4-26.17) were significant predictors of hypertension in Roxbury after adjusting for other covariates. These preliminary findings set the stage for initiating Phase II (Phase I continues recruitment), that entail biological marker measurements to rigorously test main hypothesis.

Mutational analysis of the flagellar protein FliG: sites of interaction with FliM and implications for organization of the switch complex.

The switch complex at the base of the bacterial flagellum is essential for flagellar assembly, rotation, and switching. In Escherichia coli and Salmonella, the complex contains about 26 copies of FliG, 34 copies of FliM, and more then 100 copies of FliN, together forming the basal body C ring. FliG is involved most directly in motor rotation and is located in the upper (membrane-proximal) part of the C ring. A crystal structure of the middle and C-terminal parts of FliG shows two globular domains connected by an alpha-helix and a short extended segment. The middle domain of FliG has a conserved surface patch formed by the residues EHPQ(125-128) and R(160) (the EHPQR motif), and the C-terminal domain has a conserved surface hydrophobic patch. To examine the functional importance of these and other surface features of FliG, we made mutations in residues distributed over the protein surface and measured the effects on flagellar assembly and function. Mutations preventing flagellar assembly occurred mainly in the vicinity of the EHPQR motif and the hydrophobic patch. Mutations causing aberrant clockwise or counterclockwise motor bias occurred in these same regions and in the waist between the upper and lower parts of the C-terminal domain. Pull-down assays with glutathione S-transferase-FliM showed that FliG interacts with FliM through both the EHPQR motif and the hydrophobic patch. We propose a model for the organization of FliG and FliM subunits that accounts for the FliG-FliM interactions identified here and for the different copy numbers of FliG and FliM in the flagellum.

Clinical inquiries: What are safe sleeping arrangements for infants?

Non-supine sleep position and parental tobacco use are known risk factors for sudden infant death syndrome (SIDS). Recent studies show that co-sleeping (bed sharing) slightly increases the overall risk of SIDS (strength of recommendation [SOR]: B) and is greatest for infants less than 11 weeks old (SOR: B). The relationship between bed sharing and SIDS is strongest for infants whose parents use tobacco (SOR: B). Infants who sleep in a room separate from their caregivers or on a couch or an armchair are at increased risk for SIDS (SOR: B). Using bedding accessories such as duvets or pillows may increase an infant's risk of SIDS (SOR: B).

Crystal structure of the flagellar rotor protein FliN from Thermotoga maritima.

FliN is a component of the bacterial flagellum that is present at levels of more than 100 copies and forms the bulk of the C ring, a drum-shaped structure at the inner end of the basal body. FliN interacts with FliG and FliM to form the rotor-mounted switch complex that controls clockwise-counterclockwise switching of the motor. In addition to its functions in motor rotation and switching, FliN is thought to have a role in the export of proteins that form the exterior structures of the flagellum (the rod, hook, and filament). Here, we describe the crystal structure of most of the FliN protein of Thermotoga maritima. FliN is a tightly intertwined dimer composed mostly of beta sheet. Several well-conserved hydrophobic residues form a nonpolar patch on the surface of the molecule. A mutation in the hydrophobic patch affected both flagellar assembly and switching, showing that this surface feature is important for FliN function. The association state of FliN in solution was studied by analytical ultracentrifugation, which provided clues to the higher-level organization of the protein. T. maritima FliN is primarily a dimer in solution, and T. maritima FliN and FliM together form a stable FliM(1)-FliN(4) complex. Escherichia coli FliN forms a stable tetramer in solution. The arrangement of FliN subunits in the tetramer was modeled by reference to the crystal structure of tetrameric HrcQB(C), a related protein that functions in virulence factor secretion in Pseudomonas syringae. The modeled tetramer is elongated, with approximate dimensions of 110 by 40 by 35 Angstroms, and it has a large hydrophobic cleft formed from the hydrophobic patches on the dimers. On the basis of the present data and available electron microscopic images, we propose a model for the organization of FliN subunits in the C ring.

Crystal structure of the middle and C-terminal domains of the flagellar rotor protein FliG.

The FliG protein is essential for assembly, rotation and clockwise/counter-clockwise (CW/CCW) switching of the bacterial flagellum. About 25 copies of FliG are present in a large rotor-mounted assembly termed the 'switch complex', which also contains the proteins FliM and FliN. Mutational studies have identified the segments of FliG most crucial for flagellar assembly, rotation and switching. The structure of the C-terminal domain, which functions specifically in rotation, was reported previously. Here, we describe the crystal structure of a larger fragment of the FliG protein from Thermotoga maritima, which encompasses the middle and C-terminal parts of the protein (termed FliG-MC). The FliG-MC molecule consists of two compact globular domains, linked by an alpha-helix and an extended segment that contains a well-conserved Gly-Gly motif. Mutational studies indicate that FliM binds to both of the globular domains, and given the flexibility of the linking segment, FliM is likely to determine the relative orientation of the domains in the flagellum. We propose a model for the organization of FliG-MC molecules in the flagellum, and suggest that CW/CCW switching might occur by movement of the C-terminal domain relative to other parts of FliG, under the control of FliM.