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Recovery from pneumococcal (Spn) pneumonia induces development of tissue resident memory CD4+ TRM cells, BRM cells, and antibody secreting plasma cells in experienced lungs. These tissue resident lymphocytes confer protection against subsequent lethal challenge by serotype mismatched Spn (termed as heterotypic immunity). While traditional flow cytometry and gating strategies support premeditated identification of cells using a limited set of markers, discovery of novel tissue resident lymphocytes necessitates stable platforms that can handle larger sets of phenotypic markers and lends itself to unbiased clustering approaches. In this report, we leverage the power of full spectrum flow cytometry (FSFC) to develop a comprehensive panel of phenotypic markers that allows identification of multiple subsets of tissue resident lymphocytes in Spn-experienced murine lungs. Using Phenograph algorithm on this multidimensional data, we identify unforeseen heterogeneity in lung resident adaptive immune landscape which includes unexpected subsets of TRM and BRM cells. Further, using conventional gating strategy informed by our unsupervised clustering data, we confirm their presence exquisitely in Spn-experienced lungs as potentially relevant to heterotypic immunity and define CD73 as a highly expressed marker on TRM cells. Thus, our study emphasizes the utility of FSFC for confirmatory and discovery studies relating to tissue resident adaptive immunity.

Barrier tissues are populated by functionally plastic CD4+ resident memory T (TRM) cells. Whether the barrier epithelium regulates CD4+ TRM cell locations, plasticity and activities remains unclear. Here we report that lung epithelial cells, including distinct surfactant protein C (SPC)lowMHChigh epithelial cells, function as anatomically-segregated and temporally-dynamic antigen presenting cells. In vivo ablation of lung epithelial MHC-II results in altered localization of CD4+ TRM cells. Recurrent encounters with cognate antigen in the absence of epithelial MHC-II leads CD4+ TRM cells to co-express several classically antagonistic lineage-defining transcription factors, changes their cytokine profiles, and results in dysregulated barrier immunity. In addition, lung epithelial MHC-II is needed for surface expression of PD-L1, which engages its ligand PD-1 to constrain lung CD4+ TRM cell phenotypes. Thus, we establish epithelial antigen presentation as a critical regulator of CD4+ TRM cell function and identify epithelial-CD4+ TRM cell immune interactions as core elements of barrier immunity., The maintenance of T resident memory (TRM) cells within pulmonary tissues is incompletely understood. Here the authors show that antigen presentation by lung epithelial cells maintains function and phenotype of pulmonary TRM cells within specific locational niches.

Lung-resident memory B cells (BRM cells) are elicited after influenza infections of mice, but connections to other pathogens and hosts — as well as their functional significance — have yet to be determined. We postulate that BRM cells are core components of lung immunity. To test this, we examined whether lung BRM cells are elicited by the respiratory pathogen pneumococcus, are present in humans, and are important in pneumonia defense. Lungs of mice that had recovered from pneumococcal infections did not contain organized tertiary lymphoid organs, but did have plasma cells and noncirculating memory B cells. The latter expressed distinctive surface markers (including CD69, PD-L2, CD80, and CD73) and were poised to secrete antibodies upon stimulation. Human lungs also contained B cells with a resident memory phenotype. In mice recovered from pneumococcal pneumonia, depletion of PD-L2(+) B cells, including lung BRM cells, diminished bacterial clearance and the level of pneumococcus-reactive antibodies in the lung. These data define lung BRM cells as a common feature of pathogen-experienced lungs and provide direct evidence of a role for these cells in pulmonary antibacterial immunity.

Community-acquired pneumonia is a widespread disease with significant morbidity and mortality. Alveolar macrophages are tissue-resident lung cells that play a crucial role in innate immunity against bacteria that cause pneumonia. We hypothesized that alveolar macrophages display adaptive characteristics after resolution of bacterial pneumonia. We studied mice 1 to 6 months after self-limiting lung infections with Streptococcus pneumoniae, the most common cause of bacterial pneumonia. Alveolar macrophages, but not other myeloid cells, recovered from the lung showed long-term modifications of their surface marker phenotype. The remodeling of alveolar macrophages was (a) long-lasting (still observed 6 months after infection), (b) regionally localized (observed only in the affected lobe after lobar pneumonia), and (c) associated with macrophage-dependent enhanced protection against another pneumococcal serotype. Metabolomic and transcriptomic profiling revealed that alveolar macrophages of mice that recovered from pneumonia had new baseline activities and altered responses to infection that better resembled those of adult humans. The enhanced lung protection after mild and self-limiting bacterial respiratory infections includes a profound remodeling of the alveolar macrophage pool that is long-lasting; compartmentalized; and manifest across surface receptors, metabolites, and both resting and stimulated transcriptomes.

The role of cytochrome P450 drug metabolizing enzymes in the efficacy of tamoxifen treatment of breast cancer is subject to substantial interest and controversy. CYP2D6 have been intensively studied, but the role of CYP2C19 is less elucidated, and we studied the association of CYPC19 genotype and recurrence of breast cancer. We used outcome and genotyping data from the large publicly available International Tamoxifen Pharmacogenomics Consortium (ITPC) dataset. Cox regression was used to compute the hazard ratios (HRs) for recurrence. CYP2C19 genotype data was available for 2 423 patients and the final sample cohort comprised 2 102 patients. CYP2C19*2 or *19 alleles did not influence DFS. For the CYP2C19*2 allele, the HR was 1.05 (CI 0.78–1.42) and 0.79 (CI 0.32–1.94) for hetero- and homozygote carriers, respectively. The corresponding HR for hetero- and homozygote carriers of the CYP2C19*17 allele were 1.02 (CI 0.71–1.46) and 0.57 (CI 0.26–1.24), respectively. Accounting for CYP2D6 genotype status did not change these estimates. We found no evidence to support a clinically meaningful role of CYP2C19 polymorphisms and response to tamoxifen in breast cancer patients and, consequently, CYP2C19 genotype status should not be included in clinical decisions on tamoxifen treatment.

Background Community-acquired pneumonia (CAP) requires urgent and specific antimicrobial therapy. However, the causal pathogen is typically unknown at the point when anti-infective therapeutics must be initiated. Physicians synthesize information from diverse data streams to make appropriate decisions. Artificial intelligence (AI) excels at finding complex relationships in large volumes of data. We aimed to evaluate the abilities of experienced physicians and AI to answer this question at patient admission: is it a viral or a bacterial pneumonia? Methods We included patients hospitalized for CAP and recorded all data available in the first 3-h period of care (clinical, biological and radiological information). For this proof-of-concept investigation, we decided to study only CAP caused by a singular and identified pathogen. We built a machine learning model prediction using all collected data. Finally, an independent validation set of samples was used to test the pathogen prediction performance of: (i) a panel of three experts and (ii) the AI algorithm. Both were blinded regarding the final microbial diagnosis. Positive likelihood ratio (LR) values > 10 and negative LR values Results We included 153 patients with CAP (70.6% men; 62 [51–73] years old; mean SAPSII, 37 [27–47]), 37% had viral pneumonia, 24% had bacterial pneumonia, 20% had a co-infection and 19% had no identified respiratory pathogen. We performed the analysis on 93 patients as co-pathogen and no-pathogen cases were excluded. The discriminant abilities of the AI approach were low to moderate (LR+ = 2.12 for viral and 6.29 for bacterial pneumonia), and the discriminant abilities of the experts were very low to low (LR+ = 3.81 for viral and 1.89 for bacterial pneumonia). Conclusion Neither experts nor an AI algorithm can predict the microbial etiology of CAP within the first hours of hospitalization when there is an urgent need to define the anti-infective therapeutic strategy.

Barrier tissues are sentinelled by CD4+ TRM cells with potent anti-microbial activities and considerable lineage plasticity. We hypothesized that local antigen presentation by lung epithelial cells (LECs) instruct CD4+ TRM cell activities. Pneumococcal infections in transgenic mice, flow- and spectral-cytometry, computational biology, and immunofluorescence were used to study this biology. All LECs including a novel alveolar surfactant protein C (SPC)low LEC were adept at antigen presentation. Temporal analysis of LECs for MHC-II and costimulatory/coinhibitory molecules revealed that airway club cells were T-cell stimulatory via CD40 while alveolar LECs expressed T-cell inhibitory PD-L1. This anatomical segregation of LEC antigen presentation correlated with deposition of CD4+ TRM cells around airways such that ablation of LEC MHC-II disrupted CD4+ TRM niches and blockade of CD40 signals prevented accumulation of CD4+ TRM cells. Recurrent memory recalls in absence of LEC MHC-II led to expansion of unconventional CD4+ TRM cells co-expressing classically incompatible lineage-defining transcription factors, changing their cytokine repertoire and leading to dysregulated immunity that phenocopied clinical features of checkpoint blockade therapy. Consequently, a tight correlation between MHC-II and PD-L1 was confirmed in mouse and human LECs. We discovered that LEC MHC-II functions in post-translational trafficking lockstep with PD-L1 to exert its restraints on TRM cell activities. Our results identify epithelial antigen presentation as critical instructors of CD4+ TRM cell locations, phenotypes and activities and establish epithelial-CD4+ TRM cell immunological synapses as key components of barrier immunity.

Resident memory B cells (BRM) in influenza-recovered mouse lungs were recently described, but whether other types of infections elicit these cells is unknown. The relevance of BRM in human lungs and to lung immune defenses also remains unexplored. Using flow cytometry and immunofluorescence, we found that respiratory pneumococcal exposures in mice elicited lung BRM without concurrent tertiary lymphoid structure formation. Additionally, flow cytometry analysis of normal human lung tissue showed that human lungs are enriched compared to human blood for B cells bearing a resident memory phenotype. These findings indicate that lung BRM are a common feature of antigen-experienced lungs. Multiple mouse models were used to address the contributions of B cell immunity to anti-pneumococcal lung defenses. Mice exposed to a low virulence pneumococcal strain 4 weeks previously were well-protected from a serotype-mismatched pneumococcal challenge. When previously exposed mice were depleted of circulating B cells (but not lung B cells) with anti-CD20 treatment before the challenge infection, there was no effect on the acquired lung immunity. However, a genetically engineered mouse strain allowed effective depletion of lung B cells bearing PD-L2 (a mouse memory B cell marker) from previously exposed mice, and doing so before the virulent pneumococcal challenge resulted in substantial defects in bacterial clearance compared to mice with lung B cells intact. These results provide the first direct evidence of a role for lung BRM in anti-bacterial lung immunity. Notably, this defense was pneumococcal serotype-independent, distinguishing it from the serotype-specific immunity elicited by current pneumococcal vaccines.

Legionellosis is an important public health problem in the United States and other countries, and residents of long-term care facilities (LTCFs) are at higher risk for Legionnaires' disease than the general population. In this study, we reviewed published US and international guidelines for the primary prevention of legionellosis in LTCFs, including nursing homes, skilled nursing facilities, assisted living facilities, and aged care facilities. The results of this review indicate that most guidelines emphasize adequate design and maintenance of water systems and water temperatures; however, guidance regarding routine preventative environmental testing for Legionella bacteria is not uniform among various jurisdictions, and facilities are generally left without clear guidance on this issue. In the United States, the Centers for Disease Control and Prevention does not recommend such testing in LTCFs, in contrast to the Veterans Health Administration and Environmental Protection Agency. Internationally, the World Health Organization recommends routine environmental testing, as do Ireland; France; The Netherlands; South Africa; Vienna, Austria; and Queensland, Australia. Among domestic and international guidelines in favor of environmental testing, recommendations on the frequency of testing for Legionella in water systems vary. Further research to inform recommendations on the usefulness of routine environmental testing and other measures for the primary prevention of legionellosis in this setting is needed.

As a single polypeptide, cytochrome P450 BM3 fuses oxidase and reductase domains and couples each domain's function to perform catalysis with exceptional activity upon binding of substrate for hydroxylation. Mutations introduced into the enzyme to change its substrate specificity often decrease coupling efficiency between the two domains, resulting in unproductive consumption of cofactors and formation of water and/or reactive species. This phenomenon can correlate with leakage, in which P450 BM3 uses electrons from NADPH to reduce oxygen to water and/or reactive species even without bound substrate. The physical basis for leakage is not yet well understood in this particular member of the cytochrome P450 family. To clarify the relationship between leakage and coupling, we used simulations to illustrate how different combinations of kinetic parameters related to substrate-free consumption of NADPH and substrate hydroxylation can lead to either minimal effects on coupling or a dramatic decrease in coupling as a result of leakage. We explored leakage in P450 BM3 by introducing leakage-enhancing mutations and combining these mutations to assess whether doing so increases leakage further. The variants in this study provide evidence that while a transition to high spin may be vital for coupled hydroxylation, it is not required for enhanced leakage; substrate binding and the consequent shift in spin state are not necessary as a redox switch for catalytic oxidation of NADPH. Additionally, the variants in this study suggest a tradeoff between leakage and stability and thus evolvability, as the mutations we investigated were far more deleterious than other mutations that have been used to change substrate specificity.

Recent work has shown that resident memory B cells (BRM) are generated in the lung after flu infection. However, it is unclear whether the existence of lung BRM is unique to influenza, which often elicits iBALT, or alternatively if these cells represent a common feature of the lung immune landscape. We aimed to determine whether bacterial lung exposures experienced by nearly all human children might also elicit lung BRM. To model this scenario, we gave young mice repeated respiratory exposures to low virulence pneumococci. After at least 4 weeks, we then analyzed lung B cells using flow cytometry and an intravital CD45 stain to exclude intravascular leukocytes. Pneumococcus-exposed mice had many more extravascular IgD- lung B cells than controls, and these B cells remained in the lung at least 12 weeks after the last exposure. Although unorganized aggregates of B and T cells were observed in previously exposed lungs, no iBALT structures were generated. Most of the IgD-B cells expressed the memory markers PD-L2, CD80, and CD73; a majority of the B cells expressed two or more of these markers, indicating they are poised to become antibody secreting upon rechallenge. Notably, the hallmark lung TRM phenotype (CD11abrightCD69+CD44brightCD62Llow) was also observed on lung B cells; these markers may represent a common resident memory lymphocyte phenotype. Although all lung B cells were CD20+, they were not affected by αCD20 antibody treatment, which requires circulation of bound cells for depletion to occur. BRM appear to be a common feature of the adaptive immune cell repertoire of experienced lungs. These cells do not require iBALT for their maintenance and represent a previously unrecognized pool of B cells resistant to depletion with αCD20 therapy.

To the editor: Multiple myeloma (MM) is the second most common hematologic malignancy in the United States (US), representing 1.4% of all new cancers,[1][1] and is twice as common among African Americans as it is among other racial or ethnic groups.[2][2] Although the absolute burden (or number) of

When an adverse event occurs in an overdose patient, it may be difficult to determine whether the event was caused by the ingested drug or by medical therapy. Naranjo et al. developed a probability scale, the Naranjo Adverse Drug Reaction Probability Scale (Naranjo Scale), to assess the probability that a drug administered in therapeutic doses caused an adverse event thereby classifying the event as an adverse drug reaction (ADR). Although Naranjo et al. specifically excluded the application of this scale to adverse events in overdose patients, case reports demonstrate that authors continue to apply the Naranjo Scale to events in these patients.The World Health Organization defines an ADR as occurring only when drugs are administered in therapeutic doses. Yet ADRs continue to be reported in overdose patients. We sought to examine the use of the Naranjo scale in case reports of overdose patients to assess the potential consequences of that application.A Medline search via PubMed without language limits, through September 2012, using the search terms "Naranjo" and "overdose" or "poisoning" yielded 146 publications. Additional searches were performed to find articles with keywords of the Naranjo Scale development, current applications and validity of application in specific populations such as critically ill and overdose patients.From the 146 publications, we identified 17 case reports or case series of overdose patients in which the Naranjo Scale was applied to a clinical complication to support a causal relationship between an administered drug and the clinical complication and thereby classify the clinical complication as an ADR. We also identified a recent publication in which the Naranjo Scale was applied to a new treatment modality (lipid emulsion) that is currently administered to overdose patients. Original publication of the Naranjo Scale and studies evaluating its use in critically ill patients or those with drug-induced disease were also retrieved.Adverse events that occur in overdose patients are excluded from the definition of ADR. Yet in case reports or series of overdose patients, the Naranjo Scale has been applied to assess the probability an event was caused by the ingested drug or therapeutic modality. This application of the Naranjo Scale is not scientifically valid and may lead to erroneous conclusions. There is no evidence to support the application of the Naranjo scale to any events that occur in overdose patients.

PURPOSE: Previous research and reporting has focused on the incidence and prevention of medication errors in the hospital setting; however, no previous study has reported the frequencies, characteristics and outcomes of out-of-hospital medication (OHME) errors. METHOD: Data from the National Poison Data System (NPDS) was collected for 2000-2005 and information regarding out-of-hospital medication errors reported to Poison Control Centers (PCC) was collected by a trained investigator. RESULTS: From 2000-2005 there were 1,166,116 OHME reported to PCC. Of these patients, 88,451 (7.5%) received medical evaluation by a healthcare provided and 229 (0.01%) deaths reported. The most common drug classes involved included cough/cold medications, analgesics, cardiovascular agents, antihistamines, antidepressants and antimicrobial agents. The most common error reported in both children and adults was taking or giving medication twice. CONCLUSIONS: OHME occur frequently and the NPDS may be a useful resource for data collection and evaluation in this previously overlooked population. The majority of OHME reported did not result in any significant morbidity or mortality and were managed at home without need for healthcare referrral. Further study of OHME is needed, and in particular whether healthcare professionals can target educational instruction to patients so as to effectively reduce the frequency of the most common or injurious errors. Language: en

Background No study has predicted the future incidence rate and annual burden (number) of new cases in the United States of invasive and in situ female breast cancers stratified by the estrogen receptor (ER) status. Methods We constructed forecasts for women age 30 to 84 years in 2011 through 2030 using cancer incidence data from the Surveillance, Epidemiology, and End Results Program, novel age-period-cohort forecasting models, and population projections from the US Census Bureau. Results The total number of new tumors (invasive plus in situ) is expected to rise from 283 000 in 2011 to 441 000 in 2030 (plausible range 353 500 to 466 700 cases). The proportion of all new case patients age 70 to 84 years is expected to increase from 24.3% to 34.8%, while the proportion ages 50 to 69 years is expected to decrease from 54.7% to 43.6%. The proportion of ER-positive invasive cancers is expected to remain nearly the same at 62.6%, whereas the proportion of ER-positive in situ cancers is expected to increase from 19.1% to 28.9%. The proportion of ER-negative cancers (invasive and in situ) is expected to decrease from 16.8% to 8.6%. Conclusions Breast cancer overall will rise in the United States through 2030, especially for ER-positive in situ tumors among women age 70 to 84 years. In contrast, ER-negative invasive and in situ tumors will fall, for reasons that are not fully understood. These results highlight a need to optimize case management among older women, characterize the natural history of in situ cancers, and identify those factors responsible for declining ER-negative incidence.

Genetically encoded, fluorescent biosensors have been developed to probe the activities of various signaling molecules inside cells ranging from changes in intracellular ion concentrations to dynamics of lipid second messengers. HyPer is a member of this class of biosensors and is the first to dynamically respond to hydrogen peroxide (H[subscript 2]O[subscript 2]), a reactive oxygen species that functions as a signaling molecule. However, detailed characterization of HyPer's signal is not currently available within the context of bacteria exposed to external oxidative stress, which occurs in the immunological response of higher organisms against invasive pathogenic bacteria. Here, we performed this characterization, specifically in Escherichia coli exposed to external H[subscript 2]O[subscript 2]. We found that the temporal behavior of the signal does not correspond exactly to peroxide concentration in the system as a function of time and expression of the sensor decreases the peroxide scavenging activity of the cell. We also determined the effects of cell number, both before and after normalization of externally added H[subscript 2]O[subscript 2] to the number of cells. Finally, we report quantitative characteristics of HyPer's signal in this context, including the dynamic range of the signal, the signal-to-noise ratio, and the half saturation constant. These parameters show statistically meaningful differences in signal between two commonly used strains of E. coli, demonstrating how signal can vary with strain. Taken together, our results establish a systematic, quantitative framework for researchers seeking to better understand the role of H[subscript 2]O[subscript 2] in the immunological response against bacteria, and for understanding potential differences in the details of HyPer's quantitative performance across studies., Massachusetts Institute of Technology. James H. Ferry Fund for Innovation in Research Education, National Science Foundation (U.S.) (NSF Graduate Research Fellowship), Massachusetts Institute of Technology (Joseph R. Mares endowed chair in chemical engineering), Burroughs Wellcome Fund (Career Award at the Scientific Interface)

Previous research and reporting has focused on the incidence and prevention of medication errors in the hospital setting; however, no previous study has reported the frequencies, characteristics and outcomes of out-of-hospital medication (OHME) errors.Data from the National Poison Data System (NPDS) was collected for 2000-2005 and information regarding out-of-hospital medication errors reported to Poison Control Centers (PCC) was collected by a trained investigator.From 2000-2005 there were 1,166,116 OHME reported to PCC. Of these patients, 88,451 (7.5%) received medical evaluation by a healthcare provided and 229 (0.01%) deaths reported. The most common drug classes involved included cough/cold medications, analgesics, cardiovascular agents, antihistamines, antidepressants and antimicrobial agents. The most common error reported in both children and adults was taking or giving medication twice.OHME occur frequently and the NPDS may be a useful resource for data collection and evaluation in this previously overlooked population. The majority of OHME reported did not result in any significant morbidity or mortality and were managed at home without need for healthcare referrral. Further study of OHME is needed, and in particular whether healthcare professionals can target educational instruction to patients so as to effectively reduce the frequency of the most common or injurious errors.

BACKGROUND: During the next several decades, 40 million American women born between 1946 through 1964 will face very high absolute risks of post-menopausal breast cancer, and 56 million women currently in their 20s and 30s will face substantial risks of pre-menopausal breast cancer. No study to date has predicted the future annual incidence rate and burden (number) of new cases in the United States (US) of both invasive and in-situ female breast cancers stratified by the estrogen receptor (ER) status of the tumor. However, such forecasts could help the oncology community develop a proactive roadmap to optimize prevention and treatment strategies. METHODS: We constructed forecasts for women ages 30 through 84 in 2011 through 2030 using cancer incidence data from the Surveillance Epidemiology and End Results Program, novel age-period-cohort (APC) forecasting models, and population projections from the US Census Bureau. We modelled 16 subsets of breast tumors defined by positive versus negative ER status (a correlate of tumor biology and standard clinical predictive marker), invasive versus in-situ behavior, and four age group (two pre-menopausal groups 30 - 39 and 40 - 49, and two post-menopausal groups 50 - 69 and 70 - 84). Screening mammography is recommended for women ages 50 - 74 by the US Preventive Services Task Force and starting at age 40 by the American Cancer Society; the age-group-specific models allowed the APC model parameters to implicitly reflect screening effects in the population. For each subset we applied a second-generation APC forecasting model incorporating JoinPoint regression of breast cancer birth cohort effects. RESULTS: The incidence of both invasive and in-situ ER+ tumors is expected to increase significantly during our forecast period. In contrast, the incidence of both invasive and in-situ ER- tumors is expected to decrease significantly. The total number of new tumors (invasive plus in-situ) is expected to rise more than 50% from 283,000 in 2011 to 441,000 in 2030 (plausible range from 353,000 to 466,700 cases). The proportion of new cases ages 70 - 84 is expected to increase from 24% to 35%, while the proportion ages 50 - 69 is expected to decrease from 55% to 44%. The proportion of ER+ invasive cancers is expected to remain the same near 63%, whereas the proportion of ER+ in-situ cancers is expected to increase from 19% to 29%. The proportion of ER- cancers (invasive and in-situ) is expected to decrease from 17% to 9%. CONCLUSIONS: Breast cancer will continue to rise in the US through 2030, especially for ER+ in-situ tumors among older women. In contrast, ER- invasive and in-situ tumors will continue to fall. These results highlight a need to optimize case management among older women, and to better understand etiological factors responsible for declining ER- incidence rates. Citation Format: Philip S. Rosenberg, Kimberly A. Barker, William F. Anderson. Estrogen receptor status and the future burden of invasive and in-situ breast cancers in the United States. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3699. doi:10.1158/1538-7445.AM2015-3699

BACKGROUND: Multiple myeloma (MM) is the second most common hematological malignancy in the United States (US), representing 1.4% of all new cancers. MM incidence increases rapidly with age, is twice as common among African Americans versus other groups, and is a top ten cause of cancer deaths among African Americans. Although the absolute number of new MM cases per year, or MM burden, is expected to be higher in future years because of predictable changes in the demographic profile of the US, to date no study has made detailed forecasts of future MM incidence or burden by age, race/ethnicity, and sex. In this study we construct such forecasts for the period 2011 through 2034 using cancer incidence data from the National Cancer Institute’s Surveillance Epidemiology and End Results (SEER) Program, a novel age-period-cohort (APC) forecasting model, and official projections of population sizes produced by the US Bureau of the Census. METHODS: We obtained MM case and population data from the SEER 13 Registries Database for 1993 – 2010 for all men and women, and for non-Hispanic whites, Hispanics, Blacks, and Asian and Pacific Islanders (API). To obtain stable APC estimates for each population, we aggregated single-year data into sixteen 3-year age groups (37 – 39 through 82 – 84) and six 3-year periods (1993 – 1995 through 2008 – 2010) spanning 21 partially overlapping 6-year birth cohorts centered on birth-years 1911, 1914, through 1971. Cohort effects in our APC models enabled us to make incidence forecasts allowing for different time trends in different age groups and to extrapolate incidence trends to future birth cohorts. We estimated future numbers of new cases for each sex by race/ethnic group by multiplying APC incidence rate forecasts from SEER 13 (which covers 14% of the US) by US Census population projections for the entire US for each sex and race/ethnic group. RESULTS: APC-based age incidence curves estimated from SEER13 data for incorporation into national projections reflected the contemporary epidemiology of MM: age incidence was higher among men than women in every race/ethnic group especially at ages 64 – 84 years, was highest in Blacks and lowest in API, and was similar in non-Hispanic Whites and Hispanics. In APC analyses, observed MM incidence from 1993 – 2010 was stable among men ages 37 – 63, increasing by around 0.5 percent per year among men ages 64 – 84, and stable among women in all age groups. Projected incidence for 2011 – 2034 was stable or slightly increasing in every age group. Projected MM burdens (numbers of new cases per year) were stable or slightly increasing for men and women ages 37 – 63. In contrast, large increases in the numbers of Americans ages 64 – 84 are expected to result in substantial increases in MM burden in this age group. In 2011-2013 we estimate a total of 11,200 new MM cases in men and 8,500 new cases in women. For 2032-2034 we forecast a total of 18,500 new cases in men and 13,700 new cases in women (65% and 61% increases, respectively). Among older persons ages 64 – 84, corresponding estimates are 7,300 male and 5,400 female cases in 2011 – 2013 approximately doubling to 14,100 male and 10,300 female cases in 2032-2034. Among older black men, who have the highest MM incidence and whose population is expected to increase by 4.3% per year, the projected increase in burden is 152% (from 1,210 to 3,050 cases per year). Among older Hispanic men (stable MM incidence, population increasing by 5.5% per year) the burden is expected to triple (from 460 to 1,370 cases per year). Among all older men, increases in MM burden above population growth reflect a modest increase in MM incidence. Increases in MM burden in other groups are in line with corresponding increases in population. DISCUSSION: MM incidence has been relatively stable in the US during 1993 – 2010. Our forecast is that MM incidence will continue to be quite stable during 2011 – 2032. Nonetheless, because of predictable demographic shifts in the US, the number of new MM cases per year is expected to increase by 65% in men and 61% in women between 2011-2013 and 2032-2034. Almost all of these increases will occur among older Americans ages 64 – 84. In this age group, the number of new cases overall will double, and more than double among Black and Hispanic men and women. IMPACT: Detailed forecasts quantify increasing demands for health services personnel and resources, and highlight the need for more effective MM therapies, especially for patients ages 64 – 84. Disclosures No relevant conflicts of interest to declare.

To the Editor:The safety of energy drinks is currently debated in the US. Seifert et al. stated that they performed “analysis of energy drink toxicity in The National Poison Data Systems (NPDS)”.1 ...