Using Native and Synthetic Genes to Disrupt Inositol Pyrophosphates and Phosphate Accumulation in Plants.

Inositol pyrophosphates are eukaryotic signaling molecules that have been recently identified as key regulators of plant phosphate sensing and homeostasis. Given the importance of phosphate to current and future agronomic practices, we sought to design plants which could be used to sequester phosphate, as a step in a phytoremediation strategy. To achieve this, we expressed Diadenosine and Diphosphoinositol Polyphosphate Phosphohydrolase (DDP1), a yeast (Saccharomyces cerevisiae) enzyme demonstrated to hydrolyze inositol pyrophosphates, in Arabidopsis thaliana and pennycress (Thlaspi arvense), a spring annual cover crop with emerging importance as a biofuel crop. DDP1 expression in Arabidopsis decreased inositol pyrophosphates, activated Phosphate Starvation Response marker genes, and increased phosphate accumulation. These changes corresponded with alterations in plant growth and sensitivity to exogenously applied phosphate. Pennycress plants expressing DDP1 displayed increases in phosphate accumulation, suggesting that these plants could potentially serve to reclaim phosphate from phosphate-polluted soils. We also identified a native Arabidopsis gene, Nucleoside diphosphate-linked moiety X 13 (NUDIX13), which we show encodes an enzyme homologous to DDP1 with similar substrate specificity. Arabidopsis transgenics overexpressing NUDIX13 had lower inositol pyrophosphate levels and displayed phenotypes similar to DDP1-overexpressing transgenics, while nudix13-1 mutants had increased levels of inositol pyrophosphates. Taken together, our data demonstrates that DDP1 and NUDIX13 can be used in strategies to regulate plant inositol pyrophosphates and could serve as potential targets for engineering plants to reclaim phosphate from polluted environments.

Clinical applications of gene therapy for rare diseases: A review.

Rare diseases collectively exact a high toll on society due to their sheer number and overall prevalence. Their heterogeneity, diversity, and nature pose daunting clinical challenges for both management and treatment. In this review, we discuss recent advances in clinical applications of gene therapy for rare diseases, focusing on a variety of viral and non-viral strategies. The use of adeno-associated virus (AAV) vectors is discussed in the context of Luxturna, licenced for the treatment of RPE65 deficiency in the retinal epithelium. Imlygic, a herpes virus vector licenced for the treatment of refractory metastatic melanoma, will be an example of oncolytic vectors developed against rare cancers. Yescarta and Kymriah will showcase the use of retrovirus and lentivirus vectors in the autologous ex vivo production of chimeric antigen receptor T cells (CAR-T), licenced for the treatment of refractory leukaemias and lymphomas. Similar retroviral and lentiviral technology can be applied to autologous haematopoietic stem cells, exemplified by Strimvelis and Zynteglo, licenced treatments for adenosine deaminase-severe combined immunodeficiency (ADA-SCID) and ß-thalassaemia respectively. Antisense oligonucleotide technologies will be highlighted through Onpattro and Tegsedi, RNA interference drugs licenced for familial transthyretin (TTR) amyloidosis, and Spinraza, a splice-switching treatment for spinal muscular atrophy (SMA). An initial comparison of the effectiveness of AAV and oligonucleotide therapies in SMA is possible with Zolgensma, an AAV serotype 9 vector, and Spinraza. Through these examples of marketed gene therapies and gene cell therapies, we will discuss the expanding applications of such novel technologies to previously intractable rare diseases.

Urinary concentrations and determinants of glyphosate and glufosinate in pregnant Canadian participants in the MIREC study.

BACKGROUND: Glyphosate is the most widely applied herbicide in agriculture. Glufosinate is a broad spectrum herbicide used to manage glyphosate-resistant weeds. Despite the widespread use of these herbicides, biomonitoring data - which inform risk assessment and management - are sparse. OBJECTIVES: To identify determinants of urinary concentrations of these herbicides and their metabolites in pregnancy. METHODS: We measured urinary concentrations of glyphosate, glufosinate, and their primary metabolites aminomethylphosphonic acid (AMPA) and 3-methylphosphinicopropionic acid (3-MPPA) in a single spot urine specimen collected during the first trimester of pregnancy from the Maternal-Infant Research on Environmental Chemicals (MIREC) study. MIREC recruited about 2000 pregnant women from 10 Canadian cities between 2008 and 2011. We used UItra-Performance Liquid Chromatography coupled to tandem mass spectrometry (UPLC-MS/MS) with sensitive limits of detection to quantify analyte concentrations. We examined urinary concentrations according to maternal sociodemographics, sample collection characteristics, reported pesticide use, and consumption of fruits, vegetables, legumes, and grain products. We used ANOVA models with specific gravity-standardized chemical concentrations as the dependent variable to determine associations with maternal and sample determinants. RESULTS: Among women with biobanked urine samples (n = 1829-1854), 74% and 72% had detectable concentrations of glyphosate and AMPA, respectively. In contrast, one and six percent of women had detectable concentrations of glufosinate and 3-MPPA, respectively. The specific gravity-standardized geometric mean (95% CI) concentrations of glyphosate and AMPA were 0.112 (0.099-0.127) µg/L and 0.159 (0.147-0.172) µg/L, respectively. We observed a dose-response relationship between consumption of whole grain bread and higher urinary glyphosate concentrations. Season of urine collection and self-reported pesticide use were not associated with increased concentrations of any analyte. CONCLUSIONS: We detected glyphosate and AMPA in the majority of pregnant women from this predominantly urban Canadian cohort. Diet was a probable route of exposure.

Individual and mixture associations of perfluoroalkyl substances on liver function biomarkers in the Canadian Health Measures Survey.

BACKGROUND: Perfluoroalkyl substances can disrupt hepatic metabolism and may be associated with liver function biomarkers. We examined individual and mixture associations of PFAS on liver function biomarkers in a representative sample of Canadian adults. We explored the potential for effect modification by sex and body mass index, as well as by physical activity level which may attenuate the deleterious effect of PFAS on metabolic disorders. METHODS: We analyzed data from participants aged 20-74 from the Canadian Health Measures Survey. We used linear regression to examine associations between plasma concentrations of PFOA, PFOS, PFHxS, PFNA, PFDA, and PFUDA on serum concentrations of aspartate aminotransferase (AST), gamma-glutamyltransferase (GGT), alkaline phosphatase (ALP), alanine aminotransferase (ALT) and total bilirubin. We used quantile g-computation to estimate associations with a PFAS mixture for each simultaneous, one-quartile change in PFAS concentrations. RESULTS: Each doubling of PFOA, PFOS, PFHxS, or PFNA concentrations was associated with higher AST, GGT, and ALP concentrations. Each doubling of PFOA concentrations was associated with 16.5% (95%CI: 10.4, 23.0) higher GGT concentrations among adults not meeting Canada's physical activity guidelines vs. 6.6% (95%CI: -1.6, 15.5) among those meeting these guidelines. Sex and BMI also modified some associations, though to a lesser extent. We did not observe associations between ALT and PFOA (1.2% change; 95%CI: -2.5, 4.9), PFOS (2.2% change; 95%CI: -0.8, 5.3), or PFHxS (1.5% change; 95%CI: -0.4, 3.4). We also did not observe consistent associations for PFDA and PFUDA or with total bilirubin. In quantile g-computation models, each simultaneous one-quartile increase in the PFAS mixture was positively associated with AST (7.5% higher; 95%CI: 4.0, 10.4), GGT (9.7% higher; 95%CI: 1.7, 17.0), and ALP (2.8% higher; 95%CI: 0.5, 5.4). CONCLUSION: Higher plasma concentrations of PFOA, PFOS, PFHxS, and PFNA - both individually and as a mixture - were associated with higher serum concentrations of liver function biomarkers. These results contribute to emerging evidence suggesting that higher levels of physical activity appear to be protective against the hepatotoxic effects of PFOA. This work contributes to a growing body of evidence supporting the hepatotoxic effects of PFAS.

Efficacy of the Systane iLux Thermal Pulsation System for the Treatment of Meibomian Gland Dysfunction After 1 Week and 1 Month: A Prospective Study.

OBJECTIVES: To assess 1-week and 1-month efficacy of Systane iLux thermal pulsation treatment for meibomian gland dysfunction (MGD). METHODS: This prospective, nonrandomized, open-label, multicenter study enrolled 30 adult patients (60 eyes) who had a Standard Patient Evaluation of Eye Dryness (SPEED) questionnaire score greater than 6 and total meibomian gland secretion (MGS) score equal to or less than 12 in each eye. All participants received thermal pulsation treatment bilaterally. Primary efficacy measures included MGS score (sum of grades for 15 glands graded on a scale of 0-3; 0 [no secretion], 1 [inspissated], 2 [cloudy], and 3 [clear liquid]) and tear breakup time (TBUT). Secondary efficacy measures were SPEED and Ocular Surface Disease Index (OSDI) scores. RESULTS: The mean age of patients was 52.9±11.9 years. After 1 week, the mean MGS score improved significantly from 4.1±3.1 to 15.8±7.1 (right eye, OD) and 3.7±3.1 to 16.7±7.6 (left eye, OS); mean TBUT improved significantly from 4.9±4.1 to 8.4±3.6 (OD) and 5.2±4.2 to 8.9±3.9 (OS); and mean SPEED and OSDI scores improved significantly from 16.1±5.3 to 7.2±6.1 and 45.2±21.3 to 19.0±16.8, respectively (all P<0.001). After 1 month, the mean MGS score improved to 18.3±8.2 (OD) and 18.6±7.3 (OS); mean TBUT improved to 9.7±3.8 (OD) and 9.6±3.5 (OS); and mean SPEED and OSDI scores improved to 7.0±5.6 and 16.7±14.5, respectively (all P<0.001). No adverse events were reported. CONCLUSIONS: Systane iLux thermal pulsation treatment for MGD resulted in a statistically significant increase in meibomian gland secretion, improvement in tear film stability, and reduction in dry eye symptoms as early as both 1 week and 1 month.

Advanced Scanning Probe Nanolithography Using GaN Nanowires.

A fundamental understanding and advancement of nanopatterning and nanometrology are essential in the future development of nanotechnology, atomic scale manipulation, and quantum technology industries. Scanning probe-based patterning/imaging techniques have been attractive for many research groups to conduct their research in nanoscale device fabrication and nanotechnology mainly due to its cost-effective process; however, the current tip materials in these techniques suffer from poor durability, limited resolution, and relatively high fabrication costs. Here, we report on employing GaN nanowires as a robust semiconductor material in scanning probe lithography (SPL) and microscopy (SPM) with a relatively low-cost fabrication process and the capability to provide sub-10 nm lithography and atomic scale (<1 nm) patterning resolution in field-emission scanning probe lithography (FE-SPL) and scanning tunneling microscopy (STM), respectively. We demonstrate that GaN NWs are great candidates for advanced SPL and imaging that can provide atomic resolution imaging and sub-10 nm nanopatterning on different materials in both vacuum and ambient operations.

Decompensated cirrhosis: targeted training of acute medical teams to improve quality of care in first 24 hours.

BACKGROUND: A quality improvement project in a secondary care centre was initiated to investigate and evaluate the impact of staff education and the use of the British Society of Gastroenterology/British Association for the Study of the Liver cirrhosis care bundle in improving care of patients admitted to hospital with decompensated liver cirrhosis. METHOD: A staff training programme was implemented, involving around 30 health professionals consisting of consultants, junior doctors, physician associates and nurses from the acute medical unit. A review of electronic documentation and analysis of key clinical parameters, pre- and post-intervention, was carried out. RESULTS: The data show that the intervention has led to an improvement in patient management and clinical outcomes. CONCLUSION: This project illustrates that collaboration between hepatology and medical teams, with emphasis on education and training, benefits patients who present to hospital with decompensated liver cirrhosis.

Assessing undergraduate medical education through a generalist lens.

PROBLEM BEING ADDRESSED: Medical schools aim to integrate the values of generalism into their undergraduate programs. However, currently no program has been described to measure the degree to which formal curricular materials represent generalist principles. OBJECTIVE OF PROGRAM: To quantify the generalism principles present in undergraduate medical education learning materials and to provide recommendations to enhance generalism content. PROGRAM DESCRIPTION: A review of the literature and accreditation documents was conducted to identify key elements of medical generalism. An evidence-informed tool, the Toronto Generalism Assessment Tool, was developed and applied to the new preclerkship undergraduate cases at the University of Toronto in Ontario. The findings regarding the presence of generalism principles and recommendations to enhance generalism content were provided to case developers. The recommendations were valued and were incorporated into subsequent iterations of the cases. CONCLUSION: This is the first report of a successful evidence-informed program to assess the degree of generalism reflected in undergraduate medical education curricular documents. This program can be used by other institutions wishing to review their curricula through a generalist lens.

Pharmacist and student pharmacist views of professional and personal well-being and resilience.

OBJECTIVES: To describe the views of pharmacists and student pharmacists regarding (1) aspects of life and experiences that provide professional and personal satisfaction and fulfillment, (2) causes of stress, and (3) needs related to maintaining satisfaction and fulfillment. DESIGN: A generic qualitative research design was used for collecting data from 380 pharmacists and 332 student pharmacists who wrote responses to an online survey hosted by the American Pharmacists Association (APhA) from November 17 to December 2, 2018, using standard data collection procedures applied by that organization. APhA uses its member and affiliate data files as its sampling frame and limits the number of contacts per year for each person in those files. De-identified responses from those who volunteered to write comments were sent to the research team for analysis. A conventional content analysis approach was applied for analysis of the text. Analysts convened to discuss emergent themes and develop operational descriptions. Key segments of text that best represented each theme were identified. Personal presuppositions were disclosed and were useful for developing group consensus for theme identification and description. Rigor was supported through assessment of credibility, confirmability, intercoder checking, transferability, inductive thematic saturation, and authenticity. SETTING AND PARTICIPANTS: Participants are in the design since data already collected. OUTCOME MEASURES: Not applicable. RESULTS: Findings showed that pharmacists and student pharmacists are able to recognize and pursue achievement, recognition, responsibility, advancement, relationship, esteem, self-actualization, meaning, and accomplishment in both their professional and personal lives. However, external factors such as "workism" and individual factors such as "moral distress" were identified as areas of improvement that are needed for well-being and resilience. CONCLUSION: Pharmacists' basic human needs are being met, but to improve well-being and resilience for pharmacists in both their professional and personal lives, there is a need for addressing both the external factors and individual factors that they encounter.

The scope and variance of clinical nurse specialist job descriptions.

Specialist nurses have been part of the nursing workforce for decades but articulating the scope of such roles, educational requirements, professional expertise and levels of pay is still widely debated within the workplace. This article reports on a study that examined a sample of clinical nurse specialist (CNS) job descriptions from across the UK. One hundred job descriptions were sourced, originating from various healthcare settings, and audited to explore their scope and content. In conclusion, the job descriptions showed a high level of agreement of the scope domains of a CNS role but were less consistent when considering the experience and educational requirements of CNSs.

A new tumour suppressor enters the network of intestinal progenitor cell homeostasis.

In this issue of The EMBO Journal, Wilson et al (2012) elegantly discovered an important new axis for intestinal homeostasis and cancer, using an RNAi screen to enhance the RAS-induced multivulva (MUV) phenotype in Caenorhabditis elegans.

Developing a vision and strategic action plan for future community-based residency training.

OBJECTIVES: The Community Pharmacy Residency Program (CPRP) Planning Committee convened to develop a vision and a strategic action plan for the advancement of community pharmacy residency training. Aligned with the profession's efforts to achieve provider status and expand access to care, the Future Vision and Action Plan for Community-based Residency Training will provide guidance, direction, and a strategic action plan for community-based residency training to ensure that the future needs of community-based pharmacist practitioners are met. DATA SOURCES: National thought leaders, selected because of their leadership in pharmacy practice, academia, and residency training, served on the planning committee. The committee conducted a series of conference calls and an in-person strategic planning meeting held on January 13-14, 2015. Outcomes from the discussions were supplemented with related information from the literature. Results of a survey of CPRP directors and preceptors also informed the planning process. SUMMARY: The vision and strategic action plan for community-based residency training is intended to advance training to meet the emerging needs of patients in communities that are served by the pharmacy profession. The group anticipated the advanced skills required of pharmacists serving as community-based pharmacist practitioners and the likely education, training and competencies required by future residency graduates in order to deliver these services. The vision reflects a transformation of community residency training, from CPRPs to community-based residency training, and embodies the concept that residency training should be primarily focused on training the individual pharmacist practitioner based on the needs of patients served within the community, and not on the physical location where pharmacy services are provided. CONCLUSION: The development of a vision statement, core values statements, and strategic action plan will provide support, guidance, and direction to the profession of pharmacy to continue the advancement and expansion of community-based residency training.

Impact of the RxVaccinate program for pharmacy-based pneumococcal immunization: A cluster-randomized controlled trial.

OBJECTIVES: To evaluate the impact of the RxVaccinate program on the structure, process, and outcome measures and to assess team leaders' perceptions of the program. DESIGN: Cluster-randomized experimental design. SETTING: Community pharmacies. PARTICIPANTS: Community pharmacists. INTERVENTIONS: The RxVaccinate program consisted of (a) two self-directed training webinars and practice development and implementation tools and (b) expert and peer coaching sessions through an in-person 4-hour workshop and optional e-community and monthly teleconferences. One group received only the self-directed training (self-directed learning group), and the other group received both self-directed training and coaching sessions (coaching group). MAIN OUTCOME MEASURES: Both groups provided data on (a) completion of structure and process indicators at 3, 6, and 9 months after the in-person workshop, (b) number of pneumococcal vaccinations administered in pharmacy during the 12-month period preceding and following the in-person coaching workshop, and (c) team leaders' perceptions of the RxVaccinate program. RESULTS: Greater proportions of pharmacies in the coaching group completed structure and process indicators than pharmacies in the self-directed learning group. Both groups showed an increase in the number of pneumococcal vaccinations administered (P < 0.001). The increase was significantly greater among pharmacies in the coaching group than among pharmacies in the self-directed training (P = 0.032). Team leaders in both groups were generally satisfied with the RxVaccinate program. CONCLUSION: Although significant increases in the number of pharmacist-administered pneumococcal vaccinations were observed in both groups, the increase was greater in the group receiving both self-directed training and expert and peer coaching than the group without the coaching strategy. This could be because pharmacies in the coaching group were more likely to complete structure and process indicators than their counterparts. Future studies should examine key structure and process indicators affecting the success of pneumococcal vaccinations.

Exon skipping of hepatic APOB pre-mRNA with splice-switching oligonucleotides reduces LDL cholesterol in vivo.

Familial hypercholesterolemia (FH) is a genetic disorder characterized by extremely high levels of plasma low-density lipoprotein (LDL), due to defective LDL receptor-apolipoprotein B (APOB) binding. Current therapies such as statins or LDL apheresis for homozygous FH are insufficiently efficacious at lowering LDL cholesterol or are expensive. Treatments that target APOB100, the structural protein of LDL particles, are potential therapies for FH. We have developed a series of APOB-directed splice-switching oligonucleotides (SSOs) that cause the expression of APOB87, a truncated isoform of APOB100. APOB87, like similarly truncated isoforms expressed in patients with a different condition, familial hypobetalipoproteinemia, lowers LDL cholesterol by inhibiting very low-density lipoprotein (VLDL) assembly and increasing LDL clearance. We demonstrate that these "APO-skip " SSOs induce high levels of exon skipping and expression of the APOB87 isoform, but do not substantially inhibit APOB48 expression in cell lines. A single injection of an optimized APO-skip SSO into mice transgenic for human APOB resulted in abundant exon skipping that persists for >6 days. Weekly treatments generated a sustained reduction in LDL cholesterol levels of 34-51% in these mice, superior to pravastatin in a head-to-head comparison. These results validate APO-skip SSOs as a candidate therapy for FH.

Assessment of selected bioretention blends for nutrient retention using mesocosm experiments.

This study compares the performance of three bioretention media blends for N and P removal from simulated urban runoff in experimental mesocosms. TerraSolve, Biofilter, and "VT Mix" (Virginia Tech) were compared with and without vegetation at varying hydraulic residence times (HRTs). Adsorption isotherm experiments were also conducted. TerraSolve and VT Mix included water treatment residuals (WTRs), Biofilter and VT Mix included yard-waste compost (YWC), and TerraSolve included a mix of coir and peat. TerraSolve removed the highest amount of total P (>95%), which is attributed to the high quantity of WTRs. Results were similar for VT Mix, likely due to WTR content. Adsorption isotherms indicate a substantial difference due to this factor. Vegetative mesocosms were found to be less effective at P removal at an HRT of 6 to 12 h but not at an HRT of 24 h. VT Mix had the highest removal of total Kjeldahl nitrogen (TKN), significantly different than the other blends. Interactive effects with vegetation were observed, generally improving TKN removal at all HRTs, with the highest at 24 h. Substantial export of nutrients when using compost was not observed. The addition of YWC appeared to increase N removal, possibly by denitrification. It is recommended that bioretention media contain <10% fines, a source of amorphous Al for P adsorption, at least 3 to 5% total organic C in the form of a low P, relatively stable compost, and a minimum concentration of plant-available nutrients for establishment of vegetation. For systems that use HRT, optimum residence time is influenced by media composition.

Clinical behaviour and mortality in idiopathic vs secondary nonspecific interstitial pneumonia.

RATIONALE: Nonspecific interstitial pneumonia (NSIP) is a subtype of interstitial lung disease which can either be idiopathic or secondary to other conditions. Idiopathic NSIP is a relatively rare entity and diagnosis should be considered carefully as it is mainly a diagnosis of exclusion. The aim of this retrospective study was to evaluate a cohort of NSIP patients with a view to identifying any clinical and mortality differences between idiopathic and secondary varieties. METHODS: We screened 700 patients from our interstitial lung disease database and identified 44 cases of NSIP retrospectively. Statistical analysis was conducted to evaluate if there was a difference in demographics such as gender and ethnicity, physiological parameters including forced vital capacity, diffusing capacity, average oxygen saturations, and immunology profile between two groups. Furthermore, a difference in mortality was evaluated between idiopathic and secondary NSIP. RESULTS: The data analysis showed that 63.6% (28 of 44) of patients had idiopathic NSIP versus 36.4% (16 of 44) of patients had secondary NSIP. Majority of the secondary NSIP patients had an underlying connective tissue disease. In the idiopathic variety, there was a male preponderance (64.2%, P = .02) which was statistically different compared to relatively equal gender divide in secondary NSIP which was statistically insignificant (male vs. female: 43.8% vs. 56.3%, respectively, P = .42). The mean age of the idiopathic group was 74 years compared to 64 years in the secondary group which was statistically different (P = .01). In both groups (idiopathic and secondary NSIP), more than two-thirds (68%) were of White British ethnicity. Immunology profile was similar across both groups with no statistical difference in IgM, IgG, or IgA levels. At the time of analysis, there were 17.9% deaths (5 of 28) in the idiopathic NSIP group versus 6.3% (1 of 16) in the secondary NSIP group but this was not statistically significant (P = .14). Similarly, there was no statistically significant difference in the forced vital capacity (P = .59), diffusing capacity (P = .88), and resting oxygen saturations (P = .28) between idiopathic and secondary NSIP varieties. CONCLUSION: Our analysis showed that there was a statistically significant difference in gender (male preponderance in idiopathic NSIP only) and mean age difference among both varieties. There were no statistically significant differences in the clinical features and outcomes including mortality, physiological, and immunological parameters between idiopathic and secondary NSIP. Idiopathic NSIP was more common than secondary NSIP and secondary NSIP is mostly due to underlying connective tissue disease.

Modifying factors and temporal trends of adverse health effects of short-term exposure to PM2.5 in Canada (2001-2018).

Considerable evidence has been accumulated on serious acute health outcomes associated with short-term exposure to ambient fine particulate matter (PM2.5). Modifying factors of those associations, however, have been less explored and need further analyses. In this national study, we investigated whether short-term effects of PM2.5 are modified according to region, cause of mortality/hospitalization, season, age, and sex. PM2.5-related adverse health effects were estimated by an ecological time-series study, covering about 80 % of the Canadian population for 18 years (2001-2018). We estimated city-specific associations using daily averages of PM2.5 and temperature, and daily counts of hospitalizations and mortality (non-accidental all-cause, circulatory, and respiratory). National and regional associations were then estimated with a 2-stage model. We considered potential modifying factors of PM2.5-related adverse health effects, and examined linear trends in the annual associations. Nationally, PM2.5 exposure was associated with both hospitalizations and mortality, and there was evidence of differences by the modifying factors. Of the various causes, circulatory mortality and respiratory hospitalization were more attributable to PM2.5 exposure. We found regional differences for both all-cause hospitalization and all-cause mortality, and seasonal differences for respiratory hospitalization (warm season) and circulatory hospitalization (cold season). Circulatory mortality risk was significant for seniors and females. All-cause hospitalizations appeared to gradually decrease over time, but annual all-cause mortality remained constant at 0.6 % of the population. Adverse health effects of PM2.5 exposures may depend on not only PM2.5 concentration, but also other factors (region, cause, season, age, sex). National estimates for the baseline (age ≥ 1 year, both sexes) risk cannot be interpreted without consideration of the differences by modifying factors. Study findings can be used by seniors, women, and those who have pre-existing health conditions to make informed decisions regarding their health risks from daily exposure to ambient PM2.5.