Spatiotemporal microbial evolution on antibiotic landscapes

This is the author accepted manuscript. The final version is available from the American Association for the Advancement of Science via the DOI in thisA key aspect of bacterial survival is the ability to evolve while migrating across spatially varying environmental challenges. Laboratory experiments, however, often study evolution in well-mixed systems. Here, we introduce an experimental device, the microbial evolution and growth arena (MEGA)-plate, in which bacteria spread and evolved on a large antibiotic landscape (120 × 60 centimeters) that allowed visual observation of mutation and selection in a migrating bacterial front.While resistance increased consistently, multiple coexisting lineages diversified both phenotypically and genotypically. Analyzing mutants at and behind the propagating front,we found that evolution is not always led by the most resistant mutants; highly resistant mutants may be trapped behindmore sensitive lineages.TheMEGA-plate provides a versatile platformfor studying microbial adaption and directly visualizing evolutionary dynamics.National Defense Science and Engineering Graduate fellowshipNIHEuropean Union FP

Use of disease-modifying medications for rheumatoid arthritis by race and ethnicity in the National Ambulatory Medical Care Survey

Disease-modifying anti-rheumatic drugs (DMARDs) are recommended for virtually all patients with rheumatoid arthritis (RA). We investigated the use of DMARDs in patients with RA in a nationally representative sample of visits to US physicians in the National Ambulatory Care Medical Survey (NAMCS)

Cartography of Methicillin-Resistant S. aureus Transcripts: Detection, Orientation and Temporal Expression during Growth Phase and Stress Conditions

BACKGROUND: Staphylococcus aureus is a versatile bacterial opportunist responsible for a wide spectrum of infections. The severity of these infections is highly variable and depends on multiple parameters including the genome content of the bacterium as well as the condition of the infected host. Clinically and epidemiologically, S. aureus shows a particular capacity to survive and adapt to drastic environmental changes including the presence of numerous antimicrobial agents. Mechanisms triggering this adaptation remain largely unknown despite important research efforts. Most studies evaluating gene content have so far neglected to analyze the so-called intergenic regions as well as potential antisense RNA molecules. PRINCIPAL FINDINGS: Using high-throughput sequencing technology, we performed an inventory of the whole transcriptome of S. aureus strain N315. In addition to the annotated transcription units, we identified more than 195 small transcribed regions, in the chromosome and the plasmid of S. aureus strain N315. The coding strand of each transcript was identified and structural analysis enabled classification of all discovered transcripts. RNA purified at four time-points during the growth phase of the bacterium allowed us to define the temporal expression of such transcripts. A selection of 26 transcripts of interest dispersed along the intergenic regions was assessed for expression changes in the presence of various stress conditions including pH, temperature, oxidative shocks and growth in a stringent medium. Most of these transcripts showed expression patterns specific for the defined stress conditions that we tested. CONCLUSIONS: These RNA molecules potentially represent important effectors of S. aureus adaptation and more generally could support some of the epidemiological characteristics of the bacterium

Changes in Use of Disease‐Modifying Antirheumatic Drugs for Rheumatoid Arthritis in the United States During 1983–2009

ObjectiveUse of nonbiologic disease-modifying antirheumatic drugs (DMARDs) and/or biologic DMARDs is generally recommended to improve the prognosis of patients with rheumatoid arthritis (RA). The objective of this study was to describe the changing trends in DMARD use for RA over the past 2 decades.MethodsWe analyzed data from an open longitudinal cohort of RA patients recruited from rheumatologists' practices in northern California. We examined baseline demographic and clinical characteristics of the participants and their long-term DMARD use through annual comprehensive structured telephone interviews.ResultsA total of 1,507 established RA patients were recruited through 5 enrollment periods between 1983 and 2009. Between 1983 and 2009, the use of any DMARD increased from 71% of all patients to 83% (P for trend < 0.0001). In 2009, 43% received a biologic DMARD, 34% were on both nonbiologic and biologic DMARDs, and 40% were treated with only nonbiologic DMARDs. The 4 most commonly used nonbiologic DMARDs in 2009 were methotrexate (49%), hydroxychloroquine (30%), leflunomide (13%), and sulfasalazine (7%). Etanercept (20%) was the most commonly used biologic DMARD in 2009, followed by infliximab (10%), adalimumab (9%), and abatacept (6%). Use of oral steroids was common (40-50%) and remained similar throughout the study period.ConclusionThere has been a significant increase in the use of DMARDs for RA over the past 2 decades. However, 15% of the individuals with a clinical diagnosis of RA were not receiving DMARDs in 2009. Future research should focus on sociodemographic and clinical factors associated with DMARD use for RA

Longitudinal disease- and steroid-related damage among adults with childhood-onset systemic lupus erythematosus.

ObjectivesDetermine whether adults with childhood-onset systemic lupus erythematosus (cSLE) are at increased risk for disease- and steroid-related damage as compared to individuals with adult-onset SLE (aSLE), and whether they continue to accumulate disease damage in adulthood.MethodsData derive from the 2007-2015 cycles of the Lupus Outcomes Study, a longitudinal cohort of adults with confirmed SLE. The Brief Index of Lupus Damage (BILD), a validated, patient-reported measure, was used to assess SLE-associated damage. Participants with baseline BILD were included (N = 1035). Diagnosis at age < 18 years was defined as cSLE (N = 113). Outcome variables included BILD score at baseline and follow-up, clinically significant change in BILD score over follow-up period, and presence of steroid-related damage (cataracts, osteoporosis-related fracture, avascular necrosis or diabetes mellitus).ResultsMean time between baseline and follow up BILD assessment was 6.3 ± 1.7 years. In adjusted analyses, participants with cSLE and aSLE had similar levels of disease-related damage, and accumulated damage at similar rates. Participants with cSLE were more likely to report steroid-related damage (OR 1.7, 95% CI 1.1-2.8) in the adjusted analysis as compared to those with aSLE. Likelihood of steroid-related damage increased with disease duration for both groups, but was consistently higher among cSLE participants.ConclusionIn this longitudinal cohort of adults with SLE, participants continued to accumulate damage at similar rates over time, regardless of age at onset or disease duration. Childhood-onset predicted increased risk of steroid-related damage. Aggressive use of steroid-sparing treatment strategies during childhood may be important to prevent steroid-related damage in adulthood

Final adult height of patients with childhood-onset systemic lupus erythematosus: a cross sectional analysis

Abstract Background To compare final height to mid-parental target height among adults with childhood-onset systemic lupus erythematosus (cSLE) versus adult-onset SLE (aSLE), and to evaluate the impact of age at SLE onset on final height. Methods Data derived from the Lupus Outcomes Study, a longitudinal cohort of adults with SLE, was used for this cross-sectional analysis (N = 728). Participants aged 18–63 years with complete height data were included (N = 566) and were classified as cSLE if age at diagnosis was  2 SD below target height. Separate analyses were conducted for females and males to account for differences in timing of the pubertal growth spurt for each sex. Results Participants with cSLE were, on average, 2.4 cm shorter than their target height (95% CI -4, − 0.7). The adjusted odds ratio (OR) for substantially reduced final height was 3.9 (95% CI + 2.0, + 7.2, p < 0.001) as compared to participants with aSLE. Females diagnosed between 11 and 13 years were at greatest risk for substantially reduced final height, with adjusted OR of 11.2 (95% CI + 3.4, + 36.3) as compared to participants with aSLE (p < 0.001). Conclusions cSLE is associated with shorter-than-expected final height. Onset of SLE in the pubertal period, near the time of maximum linear growth, may have a particularly significant impact on final height

Final adult height of patients with childhood-onset systemic lupus erythematosus: a cross sectional analysis.

BACKGROUND:To compare final height to mid-parental target height among adults with childhood-onset systemic lupus erythematosus (cSLE) versus adult-onset SLE (aSLE), and to evaluate the impact of age at SLE onset on final height. METHODS:Data derived from the Lupus Outcomes Study, a longitudinal cohort of adults with SLE, was used for this cross-sectional analysis (N = 728). Participants aged 18-63&nbsp;years with complete height data were included (N&nbsp;= 566) and were classified as cSLE if age at diagnosis was &lt; 18&nbsp;years (N = 72). The Tanner formula was used to calculate mid-parental target height. Multivariate linear regression was used to determine mean difference between final height and target height. Multivariate logistic regression was used to compare odds of substantially reduced final height, defined as &gt; 2 SD below target height. Separate analyses were conducted for females and males to account for differences in timing of the pubertal growth spurt for each sex. RESULTS:Participants with cSLE were, on average, 2.4&nbsp;cm shorter than their target height (95% CI -4, - 0.7). The adjusted odds ratio (OR) for substantially reduced final height was 3.9 (95% CI + 2.0, + 7.2, p &lt; 0.001) as compared to participants with aSLE. Females diagnosed between 11 and 13&nbsp;years were at greatest risk for substantially reduced final height, with adjusted OR of 11.2 (95% CI + 3.4, + 36.3) as compared to participants with aSLE (p &lt; 0.001). CONCLUSIONS:cSLE is associated with shorter-than-expected final height. Onset of SLE in the pubertal period, near the time of maximum linear growth, may have a particularly significant impact on final height

Predictors of Stopping and Starting Disease‐Modifying Antirheumatic Drugs for Rheumatoid Arthritis

ObjectiveDisease-modifying antirheumatic drugs (DMARDs) are the standard of care for rheumatoid arthritis (RA); however, studies have found that many patients do not receive them. We examined predictors of starting and stopping DMARDs among a longitudinal cohort of patients with RA.MethodsStudy participants came from a cohort of RA patients recruited from a random sample of rheumatologists' practices in Northern California. We examined patterns and predictors of stopping and starting nonbiologic and biologic DMARDs during 1982-2009 based on annual questionnaires. Stopping was defined as stopping all DMARDs and starting was defined as transitioning from no DMARDs to any DMARDs across 2 consecutive years.ResultsThe analysis of starting DMARDs included 471 subjects with 1,974 pairs of years with no DMARD use in the first of 2 consecutive years. From this population, subjects started DMARD use by year 2 in 313 (15.9%) of the pairs. The analysis of stopping DMARDs included 1,026 subjects with 7,595 pairs of years with DMARD use in the first of 2 consecutive years; in 423 pairs (5.6%), subjects stopped DMARD use by year 2. In models that adjusted for RA-related factors, sociodemographics, and comorbidities, significant predictors of starting DMARDs included younger age, Hispanic ethnicity, shorter disease duration, and the use of oral glucocorticoids. In separate adjusted models, predictors of stopping DMARDs included Hispanic ethnicity and low income, while younger age was associated with a reduced risk of stopping.ConclusionEfforts to improve DMARD use should focus on patient age, ethnicity, and income and RA-related factors