Planetary health indicators for the local level: opportunities and challenges in applying the happy planet index in Victoria, Australia.

The United Nations Sustainable Development Goals, New Urban Agenda and Paris Agreement on Climate Change are blueprints for health promotion action that mandate human health is linked inextricably to the health of the environment. In the Anthropocene, new indicators are required to promote community engagement with, and measurement of, healthy and sustainable wellbeing for people and planet. This study explored the need for a metric such as the Happy Planet Index that explicitly links human health to health of the environment for a local level scale in Australia. The project arose from an international coalition of health promoters advocating for 'planetary health' approaches. Qualitative description methods guided the study design involving key informant interviews (n = 17) and four focus groups (n = 27 participants) with health and/or sustainability academics, practitioners and policy-makers. Document analysis of health and environment indices and policy mandates augmented the analysis. Qualitative content analysis techniques were used to analyse the findings. There was strong interest for a local level composite indicator, such as a rescaled Happy Planet Index (life expectancy × life satisfaction × equity adjustment/ecological footprint) for use at a local level. The value of a composite index was: its ability to promote community engagement with planetary health thinking; an advocacy tool for joint health and sustainability policy; to justify programs on health and environmental co-benefits; and to provide a mechanism for correlative comparisons between local governments and national comparisons. However, disciplinary silos currently limit partnerships for health promotion and planetary health and a local composite index could help bridge these divides.

Circulating mature granzyme B+ T cells distinguish Crohn's disease-associated axial spondyloarthritis from axial spondyloarthritis and Crohn's disease.

BACKGROUND: Axial spondyloarthritis (axSpA) has strong connections with intestinal inflammation as occurs in Crohn's disease (CD). However, the immunologic mechanisms that distinguish axSpA, CD, and those with features of both diseases (CD-axSpA) are unknown. This study aimed to address this question by initial unbiased single cell RNA-sequencing (scRNAseq) on a pilot cohort followed by validating findings using flow cytometry and ELISA in a larger cohort. METHODS: Two individuals each with CD, axSpA, CD-axSpA, and healthy controls (HC) were recruited for a pilot discovery scRNAseq cohort, and the validation cohort consisted of 18 axSpA, 24 CD, 13 CD-axSpA, and 17 HC that was evaluated by flow cytometry on PBMCs and ELISAs for plasma cytokines. RESULTS: Uniquely, PBMCs from subjects with CD-axSpA demonstrated a significant increase in granzyme B+ T cells of both CD4+ and CD8+ lineages by both scRNAseq and flow cytometry. T cell maturation was also greater in those with CD-axSpA, particularly the CD4+ granzyme B+ population. Pathway analysis suggested increased interferon response genes in all immune cell populations within CD-axSpA. Although IFN-γ was elevated in the plasma of a subset of subjects with CD-axSpA, IL-6 was also significantly elevated. CONCLUSIONS: Our findings support the presence of a chronic interferonopathy in subjects with CD-axSpA characterized by interferon signaling by pathway analysis and an expansion of mature, cytotoxic T cells. These data indicate fundamental immunological differences between CD-axSpA and both of the putative "parent" conditions, suggesting that it is a distinct disease with unique natural history and treatment needs.

Multi 'Omics Analysis of Intestinal Tissue in Ankylosing Spondylitis Identifies Alterations in the Tryptophan Metabolism Pathway.

Intestinal microbial dysbiosis, intestinal inflammation, and Th17 immunity are all linked to the pathophysiology of spondyloarthritis (SpA); however, the mechanisms linking them remain unknown. One potential hypothesis suggests that the dysbiotic gut microbiome as a whole produces metabolites that influence human immune cells. To identify potential disease-relevant, microbiome-produced metabolites, we performed metabolomics screening and shotgun metagenomics on paired colon biopsies and fecal samples, respectively, from subjects with axial SpA (axSpA, N=21), Crohn's disease (CD, N=27), and Crohn's-axSpA overlap (CD-axSpA, N=12), as well as controls (HC, N=24). Using LC-MS based metabolomics of 4 non-inflamed pinch biopsies of the distal colon from subjects, we identified significant alterations in tryptophan pathway metabolites, including an expansion of indole-3-acetate (IAA) in axSpA and CD-axSpA compared to HC and CD and indole-3-acetaldehyde (I3Ald) in axSpA and CD-axSpA but not CD compared to HC, suggesting possible specificity to the development of axSpA. We then performed shotgun metagenomics of fecal samples to characterize gut microbial dysbiosis across these disease states. In spite of no significant differences in alpha-diversity among the 4 groups, our results confirmed differences in gene abundances of numerous enzymes involved in tryptophan metabolism. Specifically, gene abundance of indolepyruvate decarboxylase, which generates IAA and I3Ald, was significantly elevated in individuals with axSpA while gene abundances in HC demonstrated a propensity towards tryptophan synthesis. Such genetic changes were not observed in CD, again suggesting disease specificity for axSpA. Given the emerging role of tryptophan and its metabolites in immune function, altogether these data indicate that tryptophan metabolism into I3Ald and then IAA is one mechanism by which the gut microbiome potentially influences the development of axSpA.

Promoting Self-Advocacy Among Older Adults: Lessons From Boston's Senior Civic Academy.

Fostering ways for older residents to be civically engaged is one dimension of an age-friendly community. While research on civic engagement among older adults often focuses on volunteering, this study focuses on advocacy and political involvement as another important form. The Age-Friendly Boston Initiative developed the Senior Civic Academy (SCA) program as a self-advocacy course that simultaneously educates older residents about policy-making processes and engages them in advocacy training to incorporate their voices in local policy and planning. This study details the formative evaluation of the SCA, and utilizes mixed methods to evaluate the program's impact on the participants (N = 49). Lessons learned from the SCA serve as a guide for other communities to develop programs that encourage civic engagement and advocacy among older adults.

Restoration of short chain fatty acid and bile acid metabolism following fecal microbiota transplantation in patients with recurrent Clostridium difficile infection.

A significant proportion of individuals develop recurrent Clostridium difficile infection (CDI) following initial disease. Fecal microbiota transplantation (FMT), a highly effective treatment method for recurrent CDI, has been demonstrated to induce microbiota recovery. One of the proposed functions associated with restoration of colonization resistance against C. difficile has been recovery of bile acid metabolism. In this study, we aimed to assess recovery of short chain fatty acids (SCFAs) in addition to bile acids alongside microbial community structure in six patients with recurrent CDI following treatment with FMT over time. Using 16S rRNA gene-based sequencing, we observed marked similarity of the microbiota between recipients following FMT (n = 6, sampling up to 6 months post-FMT) and their respective donors. Sustained increases in the levels of the SCFAs butyrate, acetate, and propionate were observed post-FMT, and variable recovery over time was observed in the secondary bile acids deoxycholate and lithocholate. To correlate these changes with specific microbial taxa at an individual level, we applied a generalized estimating equation approach to model metabolite concentrations with the presence of specific members of the microbiota. Metabolites that increased following FMT were associated with bacteria classified within the Lachnospiraceae, Ruminococcaceae, and unclassified Clostridiales families. In contrast, members of these taxa were inversely associated with primary bile acids. The longitudinal aspect of this study allowed us to characterize individualized patterns of recovery, revealing variability between and within patients following FMT.

Fecal Incontinence and Pelvic Floor Dysfunction in Women: A Review.

Pelvic floor dysfunction and fecal incontinence is a common and debilitating condition in women, particularly as women age, and often goes under-reported to health care providers. It is important for providers to ask patients about possible symptoms. An algorithm for evaluation and treatment is presented. Current and future therapies are described and discussed.

National and state prevalence of smoke-free rules in homes with and without children and smokers: Two decades of progress.

OBJECTIVE: The home is the primary source of secondhand smoke (SHS) exposure for children. We assessed national and state progress in smoke-free home (SFH) rule adoption in homes with and without children and adult smokers. METHODS: Data came from the 1992-1993 and 2010-2011 Tobacco Use Supplements to the Current Population Survey, a U.S. national probability household survey. Households were defined as having a SFH rule if all household respondents aged ≥18 indicated no one was allowed to smoke inside the home at any time. Households with children were those with occupants aged <18. Smokers were those who smoked ≥100 lifetime cigarettes and now smoked "everyday" or "some days". RESULTS: From 1992-1993 to 2010-2011, SFH rule prevalence increased from 43.0% to 83.0% (p<.05). Among households with children, SFH rules increased overall (44.9% to 88.6%), in households without smokers (59.7% to 95.0%), and households with ≥1 smokers (9.7% to 61.0%) (p<.05). Among households without children, SFH rules increased overall (40.8% to 81.1%), in households without smokers (53.4% to 90.1%), and households with ≥1 smokers (6.3% to 40.9%) (p<.05). Prevalence increased in all states, irrespective of smoker or child occupancy (p<.05). In 2010-2011, among homes with smokers and children, SFH rule prevalence ranged from 36.5% (West Virginia) to 86.8% (California). CONCLUSIONS: Considerable progress has been made adopting SFH rules, but many U.S. children continue to be exposed to SHS because their homes are not smoke-free. Further efforts to promote adoption of SFH rules are essential to protect all children from this health risk.

Effects of a reduced dose schedule and intramuscular administration of anthrax vaccine adsorbed on immunogenicity and safety at 7 months: a randomized trial.

CONTEXT: In 1999, the US Congress directed the Centers for Disease Control and Prevention to conduct a pivotal safety and efficacy study of anthrax vaccine adsorbed (AVA). OBJECTIVE: To determine the effects on serological responses and injection site adverse events (AEs) resulting from changing the route of administration of AVA from subcutaneous (s.q.) to intramuscular (i.m.) and omitting the week 2 dose from the licensed schedule. DESIGN, SETTING, AND PARTICIPANTS: Assessment of the first 1005 enrollees in a multisite, randomized, double-blind, noninferiority, phase 4 human clinical trial (ongoing from May 2002). INTERVENTION: Healthy adults received AVA by the s.q. (reference group) or i.m. route at 0, 2, and 4 weeks and 6 months (4-SQ or 4-IM; n = 165-170 per group) or at a reduced 3-dose schedule (3-IM; n = 501). A control group (n = 169) received saline injections at the same time intervals. MAIN OUTCOME MEASURES: Noninferiority at week 8 and month 7 of anti-protective antigen IgG geometric mean concentration (GMC), geometric mean titer (GMT), and proportion of responders with a 4-fold rise in titer (%4 x R). Reactogenicity outcomes were proportions of injection site and systemic AEs. RESULTS: At week 8, the 4-IM group (GMC, 90.8 microg/mL; GMT, 1114.8; %4 x R, 97.7) was noninferior to the 4-SQ group (GMC, 105.1 microg/mL; GMT, 1315.4; %4 x R, 98.8) for all 3 primary end points. The 3-IM group was noninferior for only the %4 x R (GMC, 52.2 microg/mL; GMT, 650.6; %4 x R, 94.4). At month 7, all groups were noninferior to the licensed regimen for all end points. Solicited injection site AEs assessed during examinations occurred at lower proportions in the 4-IM group compared with 4-SQ. The odds ratio for ordinal end point pain reported immediately after injection was reduced by 50% for the 4-IM vs 4-SQ groups (P < .001). Route of administration did not significantly influence the occurrence of systemic AEs. CONCLUSIONS: The 4-IM and 3-IM regimens of AVA provided noninferior immunological priming by month 7 when compared with the 4-SQ licensed regimen. Intramuscular administration significantly reduced the occurrence of injection site AEs. Trial Registration clinicaltrials.gov Identifier: NCT00119067.

Standardized, mathematical model-based and validated in vitro analysis of anthrax lethal toxin neutralization.

Quantification of anthrax lethal toxin (LTx) neutralization activity (TNA) is pivotal in assessing protective antibody responses to anthrax vaccines and for evaluation of immunotherapies for anthrax. We have adapted and redesigned the TNA assay to establish a unifying, standardized, quantitative and validated technology platform for LTx neutralization in the J774A.1 murine cell line. Critical design features of this platform are 1) the application of a free-form or constrained 4 parameter logistic (4-PL) function to model neutralization responses within and between boundary limits of 100% cell survival and 95% cell lysis and 2) to exploit innovative assay curve recognition algorithms for interpretive endpoints. The assay was validated using human serum ED50 (dilution of serum effecting 50% neutralization) as the primary reportable value (RV). Intra-operator and intermediate precision, expressed as the coefficient of variation (%CV), were high at 10.5-15.5%CV and 13.5-14.5%CV respectively. TNA assay dilutional linearity was demonstrated for human sera using linear regression analysis of log(10) transformed data with slope=0.99, intercept=-0.03 and r(2)=0.985. Assay accuracy, inferred from the precision and linearity data and using a spike-recovery approach, was high with a percent error (%E) range of only 3.4-20.5%E. The lower limit of detection (LLOD) was ED50=12 and the lower limit of quantification (LLOQ) was ED50=36. The cell-based assay was robust, tolerating incubation temperatures from 35 to 39 degrees C, CO(2) concentrations from 3% to 7% and reporter substrate (MTT) concentrations of 2.5-7.5 mg/ml. Strict assay quality control parameters were met for up to 25 cell culture passages. The long term (50 month) assay stability, determined using human reference standards AVR414 and AVR801, indicated high precision, consistent accuracy and no detectable assay drift. A customized software program provided two additional assay metrics, Quantification Titer (QT) and Threshold Titer (TT), both of which demonstrate acceptable accuracy, precision and dilutional linearity. The TT was also used to establish the assay reactivity threshold (RT). The application of the assay to sera from humans, Rhesus macaques and rabbits was demonstrated separately and by aggregate dilutional linearity analysis of the ED50 (slope=0.98, intercept=0.003, r(2)=0.989). We propose this TNA assay format with a qualified standard reference serum and customized interpretive software as a unifying platform technology for determination of functional serologic responses to anthrax vaccines and for evaluation of anthrax immunotherapeutics.

Clonal groups and the spread of resistance to trimethoprim-sulfamethoxazole in uropathogenic Escherichia coli.

BACKGROUND: Antibiotic resistance is increasingly complicating the management of urinary tract infection. We investigated the extent to which a group of Escherichia coli called clonal group A (CGA), which is associated with resistance to trimethoprim-sulfamethoxazole (TMP-SMZ), accounted for TMP-SMZ resistance among a prospectively collected set of uropathogenic and rectal E. coli isolates from a university population in Michigan. METHODS: Resistant and susceptible uropathogenic E. coli isolates (45 each) and 79 randomly selected rectal E. coli isolates were evaluated for CGA status by use of 2 definitions of this group-- the enterobacterial repetitive intergenic consensus sequence 2 (ERIC2)-polymerase chain reaction (PCR) pattern A fingerprint and the C288T single nucleotide polymorphism (SNP) in the fumC gene. We compared virulence gene profiles and molecular mechanisms of resistance to TMP-SMZ between isolates classified as CGA by both approaches to better characterize the relationship between isolates. RESULTS: Of the 45 isolates that exhibited ERIC2-PCR pattern A, one-half (23 of 45) were resistant to TMP-SMZ, and 16 contained the C288T SNP. The pattern A isolates were diverse, exhibiting multiple mechanisms of resistance to TMP-SMZ and various combinations of virulence factors. C288T SNP isolates showed less variation, with 15 of 16 resistant to TMP-SMZ and a 1.8-kb class I integron bearing the dfrA17 gene present in 14 of 15 resistant isolates. Twelve of 16 exhibited the same combination of virulence genes. Pulsed-field gel electrophoresis patterns for these 12 isolates were unique. CONCLUSION: CGA, as defined by the fumC C288T SNP, appears to be distantly clonal but is not an outbreak-related group. The widespread group has likely evolved through lateral transfer of genes conferring virulence and antibiotic resistance.

Immune responses to Bacillus anthracis protective antigen in patients with bioterrorism-related cutaneous or inhalation anthrax.

Anti-protective antigen (PA) immunoglobulin (Ig) G, toxin neutralization, and PA-specific IgG memory B cell responses were studied in patients with bioterrorism-related cutaneous or inhalation anthrax and in a patient with laboratory-acquired cutaneous anthrax. Responses were determined for >1 year after the onset of symptoms. Eleven days after the onset of symptoms (15 days after likely exposure), anti-PA IgG was detected in 16 of 17 patients with confirmed or suspected clinical anthrax who were tested. Anti-PA IgG remained detectable 8-16 months after the onset of symptoms in all 6 survivors of inhalation anthrax and in 7 of 11 survivors of cutaneous anthrax who were tested. Anti-PA IgG levels and serum toxin neutralizing activity were strongly associated (R2=0.83). PA-specific IgG memory B cells were detectable in all 6 survivors of inhalation anthrax but in only 2 of 7 patients with cutaneous anthrax who were tested. Anti-PA IgG is an important diagnostic marker of anthrax, a predictor of serum anti-toxin activity, and a marker of immunological memory against anthrax.

Comparison of a multiplexed fluorescent covalent microsphere immunoassay and an enzyme-linked immunosorbent assay for measurement of human immunoglobulin G antibodies to anthrax toxins.

Recently, the Centers for Disease Control and Prevention reported an accurate, sensitive, specific, reproducible, and quantitative enzyme-linked immunosorbent assay (ELISA) for immunoglobulin G (IgG) antibodies to Bacillus anthracis protective antigen (PA) in human serum (C. P. Quinn, V. A. Semenova, C. M. Elie et al., Emerg. Infect. Dis. 8:1103-1110, 2002). The ELISA had a minimum detectable concentration (MDC) of 0.06 microgram/ml, which, when dilution adjusted, yielded a whole-serum MDC of 3.0 micro g of anti-PA IgG per ml. The reliable detection limit (RDL) was 0.09 microgram/ml, while the dynamic range was 0.06 to 1.7 microgram/ml. The diagnostic sensitivity of the assay was 97.6% and the diagnostic specificity was 94.2% for clinically verified cases of anthrax. A competitive inhibition anti-PA IgG ELISA was also developed to enhance the diagnostic specificity to 100%. We report a newly developed fluorescence covalent microbead immunosorbent assay (FCMIA) for B. anthracis PA which was Luminex xMap technology. The FCMIA MDC was 0.006 microgram of anti-PA IgG per ml, the RDL was 0.016 microgram/ml, and the whole-serum equivalent MDC was 1.5 micrograms/ml. The dynamic range was 0.006 to 6.8 microgram/ml. Using this system, we analyzed 20 serum samples for anti-PA IgG and compared our results to those measured by ELISA in a double-masked analysis. The two methods had a high positive correlation (r2 = 0.852; P < 0.001). The FCMIA appears to have benefits over the ELISA for the measurement of anti-PA IgG, including greater sensitivity and speed, enhanced dynamic range and reagent stability, the use of smaller sample volumes, and the ability to be multiplexed (measurement of more than one analyte simultaneously), as evidenced by the multiplexed measurement in the present report of anti-PA and anti-lethal factor IgG in serum from a confirmed clinical anthrax infection.

Specific, sensitive, and quantitative enzyme-linked immunosorbent assay for human immunoglobulin G antibodies to anthrax toxin protective antigen.

The bioterrorism-associated human anthrax epidemic in the fall of 2001 highlighted the need for a sensitive, reproducible, and specific laboratory test for the confirmatory diagnosis of human anthrax. The Centers for Disease Control and Prevention developed, optimized, and rapidly qualified an enzyme-linked immunosorbent assay (ELISA) for immunoglobulin G (IgG) antibodies to Bacillus anthracis protective antigen (PA) in human serum. The qualified ELISA had a minimum detection limit of 0.06 micro g/mL, a reliable lower limit of detection of 0.09 micro g/mL, and a lower limit of quantification in undiluted serum specimens of 3.0 micro g/mL anti-PA IgG. The diagnostic sensitivity of the assay was 97.8%, and the diagnostic specificity was 97.6%. A competitive inhibition anti-PA IgG ELISA was also developed to enhance diagnostic specificity to 100%. The anti-PA ELISAs proved valuable for the confirmation of cases of cutaneous and inhalational anthrax and evaluation of patients in whom the diagnosis of anthrax was being considered.

Prevalence and predictors of trimethoprim-sulfamethoxazole resistance among uropathogenic Escherichia coli isolates in Michigan.

Resistance among uropathogenic Escherichia coli to trimethoprim-sulfamethoxazole (TMP-SMX) has increased. Risk factors for resistance and the impact on clinical failure have been poorly described. We performed a retrospective cohort study of women with acute uncomplicated cystitis seen at a university health center and at primary care clinics in southeastern Michigan from 1992 to 1999. The prevalence of TMP-SMX resistance increased from 8.1% to 15.8% (P=.01). Women who had taken TMP-SMX recently were >16 times as likely as women who had not taken antibiotics recently to be infected with an isolate resistant to this agent; those who had taken any other antibiotic were more than twice as likely to be infected with a resistant isolate. Women infected with a TMP-SMX-resistant isolate who were treated with TMP-SMX were >17 times as likely to have treatment failure. Recent antibiotic use is a risk factor for infection with a TMP-SMX-resistant isolate; patients who are infected with a TMP-SMX-resistant isolate and who are treated with this agent are at a higher risk for clinical failure.