Comparing healthcare needs by language: interpreted Arabic and Somali telehealth calls in two regions of Sweden, 2014-18.

BACKGROUND: Limited language fluency can impede healthcare system navigation. In Sweden, the national telehealth line (Healthcare Guide 1177) offers interpretation in Arabic and Somali. We compared calls by language to identify differences in healthcare use for immigrant populations, focusing on three contact causes: pregnancy; vomiting or nausea in children; and worry/anxiety. METHODS: We conducted a cross-sectional analysis of 3.9 million (n = 18 351 Arabic, n = 7199 Somali) telehealth calls (2014-18). Using multivariable logistic regression, we investigated associations between language of the call (Arabic, Somali, non-interpreted) and each contact cause. Potential confounders (age, region, year, and additionally for vomiting or nausea, month) and an interaction between age and language were considered. RESULTS: Compared with non-interpreted calls, interpreted calls were associated with increased odds of being for pregnancy, especially for 19 to 29-year-olds [adjusted odds ratio (aOR) (95% CI) = 4.04 (3.66-4.46) and 4.60 (4.05-5.23), for Arabic and Somali calls, respectively]. Vomiting or nausea showed similar results, with aOR increasing with age: from 0.90 (0.75-1.07) (Arabic, <1 year) to 3.79 (2.86-5.01) (Somali, 5-9 years). In contrast, in unadjusted analyses, Arabic and Somali calls were associated with decreased odds of being for worry/anxiety [OR = 0.47 (0.38-0.58) and 0.34 (0.21-0.50)], respectively, compared with non-interpreted calls. CONCLUSION: Our results suggest callers to the interpreted lines may need additional assistance navigating the healthcare system for pregnancy and for vomiting or nausea among children. These findings can inform healthcare services planning for immigrants to Sweden and highlight a novel use of telehealth data as a way to uncover disparities in healthcare use within a multi-linguistic population.

Predictors of Serum Per- and Polyfluoroalkyl Substances Concentrations among U.S. Couples Attending a Fertility Clinic.

Previous studies have examined the predictors of PFAS concentrations among pregnant women and children. However, no study has explored the predictors of preconception PFAS concentrations among couples in the United States. This study included 572 females and 279 males (249 couples) who attended a U.S. fertility clinic between 2005 and 2019. Questionnaire information on demographics, reproductive history, and lifestyles and serum samples quantified for PFAS concentrations were collected at study enrollment. We examined the PFAS distribution and correlation within couples. We used Ridge regressions to predict the serum concentration of each PFAS in females and males using data of (1) socio-demographic and reproductive history, (2) diet, (3) behavioral factors, and (4) all factors included in (1) to (3) after accounting for temporal exposure trends. We used general linear models for univariate association of each factor with the PFAS concentration. We found moderate to high correlations for PFAS concentrations within couples. Among all examined factors, diet explained more of the variation in PFAS concentrations (1-48%), while behavioral factors explained the least (0-4%). Individuals reporting White race, with a higher body mass index, and nulliparous women had higher PFAS concentrations than others. Fish and shellfish consumption was positively associated with PFAS concentrations among both females and males, while intake of beans (females), peas (male), kale (females), and tortilla (both) was inversely associated with PFAS concentrations. Our findings provide important data for identifying sources of couples' PFAS exposure and informing interventions to reduce PFAS exposure in the preconception period.

Association between per- and polyfluoroalkyl substances exposure and thyroid function biomarkers among females attending a fertility clinic.

Per- and polyfluoroalkyl substances (PFAS) exposure was associated with changes in thyroid function in pregnant mothers and the general population. Limited such evidence exists in other susceptible populations such as females with fertility problems. This cross-sectional study included 287 females seeking medically assisted reproduction at a fertility clinic in Massachusetts, United States, between 2005 and 2019. Six long-alkyl chain PFAS, thyroid hormones, and autoimmune antibodies were quantified in baseline serum samples. We used generalized linear models and quantile g-computation to evaluate associations of individual PFAS and their total mixture with thyroid biomarkers. Most females were White individuals (82.7%), had graduate degrees (57.8%), and nearly half had unexplained subfertility (45.9%). Serum concentrations of all examined PFAS and their mixture were significantly associated with 2.6%-5.6% lower total triiodothyronine (TT3) concentrations. Serum concentrations of perfluorononanoate (PFNA), perfluorodecanoate (PFDA), and perfluoroundecanoate (PFUnDA), and of the total mixture were associated with higher ratios of free thyroxine (FT4) to free triiodothyronine (FT3). No associations were found for PFAS and TSH or autoimmune antibodies. Our findings support the thyroid-disrupting effect of long alkyl-chain PFAS among a vulnerable population of subfertile females.

Mendelian randomization reveals apolipoprotein B shortens healthspan and possibly increases risk for Alzheimer's disease.

Apolipoprotein B-100 (APOB) is a component of fat- and cholesterol-transporting molecules in the bloodstream. It is the main lipoprotein in low-density lipoprotein cholesterol (LDL) and has been implicated in conditions that end healthspan (the interval between birth and onset of chronic disease). However, APOB's direct relationship with healthspan remains uncertain. With Mendelian randomization, we show that higher levels of APOB and LDL shorten healthspan in humans. Multivariable Mendelian randomization of APOB and LDL on healthspan suggests that the predominant trait accounting for the relationship is APOB. In addition, we provide preliminary evidence that APOB increases risk for Alzheimer's disease, a condition that ends healthspan. If these relationships are causal, they suggest that interventions to improve healthspan in aging populations could include strategies targeting APOB. Ultimately, given that more than 44 million people currently suffer from Alzheimer's disease worldwide, such interventions are needed.

Maternal and Paternal Preconception Serum Concentrations of Per and Polyfluoroalkyl Substances in Relation to Birth Outcomes.

Prenatal per and polyfluoroalkyl substances (PFAS) exposure is associated with adverse birth outcomes. There is an absence of evidence on the relationship between maternal and paternal preconception PFAS exposure and birth outcomes. This study included 312 mothers and 145 fathers with a singleton live birth from a preconception cohort of subfertile couples seeking fertility treatment at a U.S. clinic. PFAS were quantified in serum samples collected before conception. Gestational age (GA) and birthweight (BW) were abstracted from delivery records. We also assessed low birthweight (BW < 2500 g) and preterm birth (GA < 37 completed weeks). We utilized multivariable linear regression, logistic regression, and quantile-based g computation to examine maternal or paternal serum concentrations of individual PFAS and mixture with birth outcomes. Maternal serum concentrations of perfluorooctanesulfonate (PFOS), perfluorohexanesulfonate (PFHxS), and the total PFAS mixture were inversely associated with birthweight. Maternal PFOS concentration was associated with a higher risk of low birthweight. Conversely, paternal PFOS and PFHxS concentrations were imprecisely associated with higher birthweight. No associations were found for gestational age or preterm birth. The findings have important implications for preconception care. Future research with larger sample sizes would assist in validating these findings.

Estimated number of reported vaccine-preventable disease cases averted following the introduction of routine vaccination programs in Sweden, 1910-2019.

BACKGROUND: Routine childhood vaccination programs have had enormous positive public health impacts worldwide. However, in some areas, these benefits may be impeded by vaccine hesitancy and undervaccination. We estimated the number of reported cases of measles, pertussis, mumps and poliomyelitis averted in Sweden after the introduction of routine childhood vaccination programs. METHODS: We used annual national data on population size and the number of reported cases of measles (1911-2019), pertussis (1911-2019), mumps (1914-2019) and poliomyelitis (1910-2019) for Sweden. For each disease, we calculated the median and 95% confidence interval of the annual pre-vaccination incidence to estimate the number of counterfactual cases; that is, the estimated number of cases that would have been observed in the post-vaccination period had no vaccine been introduced (median incidence × average annual population). For the post-vaccination periods, we calculated reported cases averted and assumed all decreases were due to vaccines. RESULTS: In total, for all four diseases combined, over 2.1 million cases were reported over the respective surveillance periods. Since the introduction of vaccinations, we estimate that over 1.5 million reported cases of these four diseases combined have been averted: measles (633 091), pertussis (608 670), mumps (262 951) and poliomyelitis (58 240). However, due to underreporting, especially during pre-vaccination years, these are likely underestimates. CONCLUSIONS: Since the introduction of these routine childhood vaccination programs in Sweden, a substantial number of reported cases of vaccine-preventable diseases have been averted. Vigilance against both failure to vaccinate and undervaccination is necessary to prevent future increases of these vaccine-preventable diseases.

Non-chemotherapy adjuvant agents in TP53 mutant Ewing sarcoma.

Ewing sarcoma (EWS) is a malignant tumor arising in bone or soft tissue that occurs in adolescent and young adult patients as well as adults later in life. Although non-metastatic EWS is typically responsive to treatment when newly diagnosed, relapsed cases have an unmet need for which no standard treatment approach exists. Recent phase III clinical trials for EWS comparing 7 vs 5 chemotherapy drugs have failed to improve survival. To extend the durability of remission for EWS, we investigated 3 non-chemotherapy adjuvant therapy drug candidates to be combined with chemotherapy. The efficacy of these adjuvant drugs was investigated via anchorage-dependent growth assays, anchorage-independent soft-agar colony formation assays and EWS xenograft mouse models. Enoxacin and entinostat were the most effective adjuvant drug in both long-term in vitro and in vivo adjuvant studies. In the context that enoxacin is an FDA-approved antibiotic, and that entinostat is an investigational agent not yet FDA-approved, we propose enoxacin as an adjuvant drug for further preclinical and clinical investigation in EWS patients.

Association of Early Pregnancy Perfluoroalkyl and Polyfluoroalkyl Substance Exposure With Birth Outcomes.

Importance: Prenatal perfluoroalkyl and polyfluoroalkyl substances (PFAS) have been linked to adverse birth outcomes. Previous research showed that higher folate concentrations are associated with lower blood PFAS concentrations in adolescents and adults. Further studies are needed to explore whether prenatal folate status mitigates PFAS-related adverse birth outcomes. Objective: To examine whether prenatal folate status modifies the negative associations between pregnancy PFAS concentrations, birth weight, and gestational age previously observed in a US cohort. Design, Setting, and Participants: In a prospective design, a prebirth cohort of mothers or pregnant women was recruited between April 1999 and November 2002, in Project Viva, a study conducted in eastern Massachusetts. Statistical analyses were performed from May 24 and October 25, 2022. Exposure: Plasma concentrations of 6 PFAS compounds were measured in early pregnancy (median gestational week, 9.6). Folate status was assessed through a food frequency questionnaire and measured in plasma samples collected in early pregnancy. Main Outcomes and Measures: Birth weight and gestational age, abstracted from delivery records; birth weight z score, standardized by gestational age and infant sex; low birth weight, defined as birth weight less than 2500 g; and preterm birth, defined as birth at less than 37 completed gestational weeks. Results: The cohort included a total of 1400 mother-singleton pairs. The mean (SD) age of the mothers was 32.21 (4.89) years. Most of the mothers were White (73.2%) and had a college degree or higher (69.1%). Early pregnancy plasma perfluorooctanoic acid concentration was associated with lower birth weight and birth weight z score only among mothers whose dietary folate intake (birth weight: ß, -89.13 g; 95% CI, -166.84 to -11.42 g; birth weight z score: -0.13; 95% CI, -0.26 to -0.003) or plasma folate concentration (birth weight: -87.03 g; 95% CI, -180.11 to 6.05 g; birth weight z score: -0.14; 95% CI, -0.30 to 0.02) were below the 25th percentile (dietary: 660 µg/d, plasma: 14 ng/mL). No associations were found among mothers in the higher folate level groups, although the tests for heterogeneity did not reject the null. Associations between plasma perfluorooctane sulfonic acid and perfluorononanoate (PFNA) concentrations and lower birth weight, and between PFNA and earlier gestational age were noted only among mothers whose prenatal dietary folate intake or plasma folate concentration was in the lowest quartile range. No associations were found among mothers in higher folate status quartile groups. Conclusions and Relevance: In this large, US prebirth cohort, early pregnancy exposure to select PFAS compounds was associated with adverse birth outcomes only among mothers below the 25th percentile of prenatal dietary or plasma folate levels.

Trauma and female reproductive health across the lifecourse: motivating a research agenda for the future of women's health.

The aetiology behind many female reproductive disorders is poorly studied and incompletely understood despite the prevalence of such conditions and substantial burden they impose on women's lives. In light of evidence demonstrating a higher incidence of trauma exposure in women with many such disorders, we present a set of interlinked working hypotheses proposing relationships between traumatic events and reproductive and mental health that can define a research agenda to better understand reproductive outcomes from a trauma-informed perspective across the lifecourse. Additionally, we note the potential for racism to act as a traumatic experience, highlight the importance of considering the interaction between mental and reproductive health concerns, and propose several neuroendocrinological mechanisms by which traumatic experiences might increase the risk of adverse health outcomes in these domains. Finally, we emphasize the need for future primary research investigating the proposed pathways between traumatic experiences and adverse female reproductive outcomes.

Lifestyle interventions to reduce endocrine-disrupting phthalate and phenol exposures among reproductive age men and women: A review and future steps.

Non-persistent endocrine-disrupting chemicals (EDCs), including phthalates and phenols, are ubiquitous in both the environment and human body. A growing body of epidemiologic studies have identified concerning links between EDCs and adverse reproductive and developmental health effects. Despite consistent evidence, risk assessments and policy interventions often arrive late. This presents an urgent need to identify evidence-based interventions for implementation at both clinical and community levels to reduce EDC exposure, especially in susceptible populations. The reproductive life cycle (menarche to menopause for females and after pubertal onset for males) includes some of the most vulnerable periods to environmental exposures, such as the preconception and perinatal stages, representing a key window of opportunity to intervene and prevent unfavorable health outcomes. This review aims to synthesize and assess behavioral, dietary, and residential EDC-driven interventions to develop recommendations for subsequent, larger-scale studies that address knowledge-gaps in current interventions during the reproductive life cycle. We selected 21 primary interventions for evaluation, in addition to four supplemental interventions. Among these, accessible (web-based) educational resources, targeted replacement of (known) toxic products, and personalization of the intervention through meetings and support groups, were the most promising strategies for reducing EDC concentrations. However, we document a paucity of interventions to prevent phthalate and phenol exposures during the reproductive years, especially among men. Accordingly, we recommend additional, larger clinical and community-based intervention studies to reduce EDC exposure. Specifically, future intervention studies should focus on short-term, mid-, and long-term exposure reduction to phthalates and phenols. The latter, especially, is required for the development of clinical and public health guidelines to promote reproductive and developmental health globally.

Reproductive medicine in the face of climate change: a call for prevention through leadership.

Climate change has led to a multitude of ecological disruptions and downstream reproductive health consequences that impair our reproductive capacity and, in turn, harm the health and survival of future generations. Atmospheric changes, driven by anthropogenic emissions, expose global populations to droughts, heat waves, rising sea levels, and extreme weather events-posing major threats to public health and exacerbating environmental health disparities. Existing evidence demonstrates the potential for climate-driven events to impact reproductive health outcomes, yet very few studies have explored this relationship. Recently, the American Society for Reproductive Medicine, the American College of Obstetricians and Gynecologists, and the International Federation of Gynecology and Obstetrics released position statements regarding reproductive health and environmental exposures. Unfortunately, such initiatives have yielded little action within the health care system. To address this stagnation, health care workers must meld research findings into actionable preventive medicine strategies and transition to a more action-oriented approach to address the climate crisis. The objective of this article is to elucidate the urgency of the climate crisis in relation to reproductive health and push the health care workers to recognize their intrinsic opportunity as leaders in climate action at local, state, national, and international levels. We call on health care organizations and health care workers to leverage their inherent positions as climate action leaders to increase climate resilience and mitigate climate-related adverse reproductive health outcomes.

Sensitization of osteosarcoma to irradiation by targeting nuclear FGFR1.

Over the past 25 years, chemotherapy regimens for osteosarcoma have failed to improve the 65-70% long-term survival rate. Radiation therapy is generally ineffective except for palliative care. We here investigated whether osteosarcoma can be sensitized to radiation therapy targeting specific molecules in osteosarcoma. Large-scale RNA sequencing analysis in osteosarcoma tissues and cell lines revealed that FGFR1 is the most frequently expressed receptor tyrosine kinase in osteosarcoma. Nuclear FGFR1 (nFGFR1) was observed by subcellular localization assays. The functional studies using a FGFR1IIIb antibody or small molecule FGFR1 inhibitors showed that nFGFR1, but not membrane-bound FGFR1, induces G2 cell-cycle checkpoint adaptation, cell survival and polyploidy following irradiation in osteosarcoma cells. Further, the activation of nFGFR1 induces Histone H3 phosphorylation at Ser 10 and c-jun/c-fos expression to contribute cell survival rendering radiation resistance. Furthermore, an in vivo mouse study revealed that radiation resistance can be reversed by the inhibition of nFGFR1. Our findings provide insights into the potential role of nFGFR1 to radiation resistance. Thus, we propose nFGFR1 could be a potential therapeutic target or a biomarker to determine which patients might benefit from radiation therapy.

Interaction of prenatal bisphenols, maternal nutrients, and toxic metal exposures on neurodevelopment of 2-year-olds in the APrON cohort.

BACKGROUND: Epidemiological studies suggest that Bisphenol-A (BPA) is a developmental neurotoxicant, but the modifying effects of maternal nutrient status or neurotoxicant metal co-exposures have not been reported. Bisphenol-S (BPS) is being used as a BPA-alternative, but few epidemiological studies have evaluated its effects. OBJECTIVES: To examine if prenatal maternal BPA or BPS exposure are associated with children's neurodevelopment at two years of age while adjusting for effect-measure modification by sex, maternal nutrients, and co-exposure to neurotoxic metals. METHODS: Total BPA and BPS concentrations were analyzed in spot maternal urine from the second trimester; metals and maternal nutrient status were analyzed in blood. Child neurodevelopment was evaluated with the Bayley Scales of Infant Development-III (Bayley-III) at age 2 (394 maternal-child pairs) and linear regression was used to investigate associations. RESULTS: Among nutrients and neurotoxic metals, selenium (Se) and cadmium (Cd) were the most significant predictors of Bayley-III scale scores. Higher maternal Cd was significantly correlated with poorer motor performance (p < 0.01), and higher levels of maternal Se were significantly associated with poorer performance on the cognitive, motor, and adaptive behavior scales (p < 0.05). While maternal Cd did not modify relationships between bisphenol exposures and Bayley-III scores, both maternal Se and child sex were significant effect-measure modifiers. Associations between BPA exposure and social emotional scores were negative for boys (p = 0.056) but positive for girls (p = 0.046). Higher exposure to bisphenols was associated with lower motor scores among children with lower levels of maternal Se. CONCLUSION: Higher maternal Cd was associated with poorer motor development, but it was not an effect-measure modifier of bisphenols' effects on motor development. Maternal Se may be protective against adverse effects of bisphenols, and additional nutrient-bisphenol interaction studies examining sex-specific effects of BPA and BPS on child development are warranted.

Design considerations of an IL13Rα2 antibody-drug conjugate for diffuse intrinsic pontine glioma.

Diffuse intrinsic pontine glioma (DIPG), a rare pediatric brain tumor, afflicts approximately 350 new patients each year in the United States. DIPG is noted for its lethality, as fewer than 1% of patients survive to five years. Multiple clinical trials involving chemotherapy, radiotherapy, and/or targeted therapy have all failed to improve clinical outcomes. Recently, high-throughput sequencing of a cohort of DIPG samples identified potential therapeutic targets, including interleukin 13 receptor subunit alpha 2 (IL13Rα2) which was expressed in multiple tumor samples and comparably absent in normal brain tissue, identifying IL13Rα2 as a potential therapeutic target in DIPG. In this work, we investigated the role of IL13Rα2 signaling in progression and invasion of DIPG and viability of IL13Rα2 as a therapeutic target through the use of immunoconjugate agents. We discovered that IL13Rα2 stimulation via canonical ligands demonstrates minimal impact on both the cellular proliferation and cellular invasion of DIPG cells, suggesting IL13Rα2 signaling is non-essential for DIPG progression in vitro. However, exposure to an anti-IL13Rα2 antibody-drug conjugate demonstrated potent pharmacological response in DIPG cell models both in vitro and ex ovo in a manner strongly associated with IL13Rα2 expression, supporting the potential use of targeting IL13Rα2 as a DIPG therapy. However, the tested ADC was effective in most but not all cell models, thus selection of the optimal payload will be essential for clinical translation of an anti-IL13Rα2 ADC for DIPG.

Investigating novel approaches to tick-borne encephalitis surveillance in Sweden, 2010-2017.

Tick-borne encephalitis (TBE) is a vaccine-preventable, high-priority disease in Sweden, with increasing incidence. However, surveillance is limited to case reports. We investigated relationships between reported TBE incidence and syndromic surveillance data to determine if these novel data sources could provide earlier indications of disease activity. We retrospectively compared national, weekly (2010-2017) reported TBE incidence to the percentage of TBE-related a) searches on the main Swedish healthcare information website and b) calls to its telehealth service using Spearman's ρ to determine the most strongly correlated lags. We conducted a sub-analysis (2012-2017) of TBE-related Google Trends queries and compared the number of TBE-related media stories to each novel surveillance dataset. Healthcare website searches for "tbe" and "vaccine" combined, "tbe", "tick", and "tick bite" led case data by 12, 8, 7, and 6 weeks, respectively (ρ = 0.87-0.89); telehealth calls led by 4 weeks (ρ = 0.92; all p < 0.001). Correlations and lags for Google Trends and healthcare website searches were fairly similar to each other. In comparison, correlation between the different syndromic surveillance datasets and the number of media stories was lower (ρ = 0.25-0.56). We observed volume discrepancies between TBE incidence and the novel surveillance datasets during some years, particularly for web searches. Syndromic surveillance data were strongly correlated with and preceded case data by 4-12 weeks. Syndromic data may provide advanced awareness and earlier indications of TBE activity, which can improve timing and specificity of public health communications. The use of these data as supplements to notifiable disease data for national planning and preparedness in real-time should be investigated.

Dynamic modeling of hepatitis C transmission among people who inject drugs.

To reach the WHO goal of hepatitis C elimination, it is essential to identify the number of people unaware of their hepatitis C virus (HCV) infection and to investigate the effect of interventions on the disease transmission dynamics. In many high-income countries, one of the primary routes of HCV transmission is via contaminated needles shared by people who inject drugs (PWIDs). However, substantial underreporting combined with high uncertainty regarding the size of this difficult to reach population, makes it challenging to estimate the core indicators recommended by the WHO. To support progress toward the elimination goal, we present a novel multi-layered dynamic transmission model for HCV transmission within a PWID population. The model explicitly accounts for disease stage (acute and chronic), injection drug use status (active and former PWIDs), status of diagnosis (diagnosed and undiagnosed) and country of disease acquisition (domestic or abroad). First, based on this model, and using routine surveillance data, we estimate the number of undiagnosed PWIDs, the true incidence, the average time until diagnosis, the reproduction numbers and associated uncertainties. Second, we examine the impact of two interventions on disease dynamics: (1) direct-acting antiviral drug treatment, and (2) needle exchange programs. As a proof of concept, we illustrate our results for a specific data set. In addition, we develop a web application to allow our model to be explored interactively and with different parameter values.

Influenza-like illness-related emergency department visits: Christmas and New Year holiday peaks and relationships with laboratory-confirmed respiratory virus detections, Edmonton, Alberta, 2004-2014.

BACKGROUND: Emergency department (ED) visit volumes can be especially high during the Christmas-New Year holidays, a period occurring during the influenza season in Canada. METHODS: Using daily data, we examined the relationship between ED visits for the chief complaint "cough" (for Edmonton, Alberta residents) and laboratory detections for influenza A and respiratory syncytial virus (RSV) (for Edmonton and surrounding areas), lagged 0-5 days ahead, for non-pandemic years (2004-2008 and 2010-2014) using multivariable linear regression adjusting for temporal variables. We defined these cough-related visits as influenza-like illness (ILI)-related ED visits and, for 2004-2014, compared Christmas-New Year holiday (December 24-January 3) and non-holiday volumes during the influenza season (October-April). RESULTS: Adjusting for temporal variables, ILI-related ED visits were significantly associated with laboratory detections for influenza A and RSV. During non-pandemic years, the highest peak in ILI-related visit volumes always occurred during the holidays. The median number of holiday ILI-related visits/day (42.5) was almost twice the non-holiday median (24) and was even higher in 2012-2013 (80) and 2013-2014 (86). Holiday ILI-related ED visit volumes/100 000 population ranged from 56.0 (2010-2011) to 117.4 (2012-2013). In contrast, lower visit volumes occurred during the holidays of pandemic-affected years (2008-2010). CONCLUSIONS: During non-pandemic years, ILI-related ED visit volumes were associated with variations in detections for influenza A and RSV and always peaked during the Christmas-New Year holidays. This predictability should be used to prepare for, and possibly prevent, this increase in healthcare use; however, interventions beyond disease prevention strategies are likely needed.

Estimating the burden of recurrent events in the presence of competing risks: the method of mean cumulative count.

Cumulative incidence has been widely used to estimate the cumulative probability of developing an event of interest by a given time, in the presence of competing risks. When it is of interest to measure the total burden of recurrent events in a population, however, the cumulative incidence method is not appropriate because it considers only the first occurrence of the event of interest for each individual in the analysis: Subsequent occurrences are not included. Here, we discuss a straightforward and intuitive method termed "mean cumulative count," which reflects a summarization of all events that occur in the population by a given time, not just the first event for each subject. We explore the mathematical relationship between mean cumulative count and cumulative incidence. Detailed calculation of mean cumulative count is described by using a simple hypothetical example, and the computation code with an illustrative example is provided. Using follow-up data from January 1975 to August 2009 collected in the Childhood Cancer Survivor Study, we show applications of mean cumulative count and cumulative incidence for the outcome of subsequent neoplasms to demonstrate different but complementary information obtained from the 2 approaches and the specific utility of the former.