Performance of empirical and model-based classifiers for detecting sucrase-isomaltase inhibition using the 13 C-sucrose breath test.

Background: Environmental enteric dysfunction (EED) is a syndrome characterized by epithelial damage including blunting of the small intestinal villi and altered digestive and absorptive capacity which may negatively impact linear growth in children. The 13 C-sucrose breath test ( 13 C-SBT) has been proposed to estimate sucrase-isomaltase (SIM) activity, which is thought to be reduced in EED. We previously showed how various summary measures of the 13 C-SBT breath curve reflect SIM inhibition. However, it is uncertain how the performance of these classifiers is affected by test duration. Methods: We leveraged SBT data from a cross-over study in 16 adults who received 0, 100, and 750 mg of Reducose, a natural SIM inhibitor. We evaluated the performance of a pharmacokinetic-model-based classifier, ρ , and three empirical classifiers (cumulative percent dose recovered at 90 minutes (cPDR90), time to 50% dose recovered, and time to peak dose recovery rate), as a function of test duration using receiver operating characteristic curves. We also assessed the sensitivity, specificity, and accuracy of consensus classifiers. Results: Test durations of less than 2 hours generally failed to accurately predict later breath curve dynamics. The cPDR90 classifier had the highest area-under-the-curve and, by design, was robust to shorter test durations. For detecting mild SIM inhibition, ρ had a higher sensitivity. Conclusions: We recommend SBT tests run for at least a 2-hour duration. Although cPDR90 was the classifier with highest accuracy and robustness to test duration in this application, concerns remain about its sensitivity to misspecification of CO 2 production rate. More research is needed to assess these classifiers in target populations.

Time-varying associations of patient and tumor characteristics with cancer survival: an analysis of SEER data across 14 cancer sites, 2004-2017.

PURPOSE: Surveillance, Epidemiology, and End Results (SEER) cancer registries provides information about survival duration and cause of death for cancer patients. Baseline demographic and tumor characteristics such as age, sex, race, year of diagnosis, and tumor stage can inform the expected survival time of patients, but their associations with survival may not be constant over the post-diagnosis period. METHODS: Using SEER data, we examined if there were time-varying associations of patient and tumor characteristics on survival, and we assessed how these relationships differed across 14 cancer sites. Standard Cox proportional hazards models were extended to allow for time-varying associations and incorporated into a competing-risks framework, separately modeling cancer-specific and other-cause deaths. For each cancer site and for each of the five factors, we estimated the relative hazard ratio and absolute hazard over time in the presence of competing risks. RESULTS: Our comprehensive consideration of patient and tumor characteristics when estimating time-varying hazards showed that the associations of age, tumor stage at diagnosis, and race/ethnicity with risk of death (cancer-specific and other-cause) change over time for many cancers; characteristics of sex and year of diagnosis exhibit some time-varying patterns as well. Stage at diagnosis had the largest associations with survival. CONCLUSION: These findings suggest that proportional hazards assumptions are often violated when examining patient characteristics on cancer survival post-diagnosis. We discuss several interesting results where the relative hazards are time-varying and suggest possible interpretations. Based on the time-varying associations of several important covariates on survival after cancer diagnosis using a pan-cancer approach, the likelihood of the proportional hazards assumption being met or corresponding interpretation should be considered in survival analyses, as flawed inference may have implications for cancer care and policy.

Cervicovaginal and Anal Self-Sampling for Human Papillomavirus Testing in a Transgender and Gender Diverse Population Assigned Female at Birth: Comfort, Difficulty, and Willingness to Use.

Purpose: Transgender and gender diverse (TGD) people assigned female at birth (AFAB) face numerous barriers to preventive care, including for cervical cancer screening. At-home human papillomavirus (HPV) testing may expand access to cervical cancer screening for TGD people AFAB. This study assessed the perceptions of TGD individuals AFAB who self-collected cervicovaginal and anal samples. Methods: We recruited TGD individuals AFAB to collect cervicovaginal and anal specimens at home using self-sampling for HPV testing, and individuals reported their perceptions of self-sampling. Associations between demographic and health characteristics and each of comfort of use, ease of use, and willingness to use self-sampling were estimated using robust Poisson regression. Results: Of 137 consenting participants, 101 completed the sample collection and the surveys. The majority of participants reported that the cervicovaginal self-swab was not uncomfortable (68.3%) and not difficult to use (86.1%), and nearly all (96.0%) were willing to use the swab in the future. Fewer participants found the anal swab to not be uncomfortable (47.5%), but most participants still found the anal swab to not be difficult to use (70.2%) and were willing to use the swab in the future (89.1%). Participants were more willing to use either swab if they had not seen a medical professional in the past year. Conclusions: TGD individuals AFAB were willing to use and preferred self-sampling methods for cervicovaginal and anal HPV testing. Developing clinically approved self-sampling options for HPV testing could expand access to cancer screening for TGD populations.

Prevalence and Determinants of Cervicovaginal, Oral, and Anal Human Papillomavirus Infection in a Population of Transgender and Gender Diverse People Assigned Female at Birth.

Purpose: The human papillomavirus (HPV) causes cervicovaginal, oral, and anogenital cancer, and cervical cancer screening options include HPV testing of a clinician-collected sample. Transgender and gender diverse (TGD) people assigned female at birth (AFAB) face many barriers to preventive care, including cancer screening. Self-sampling options may increase access and participation in HPV testing and cancer screening. This study estimated the prevalence of HPV in self-collected cervicovaginal, oral, and anal samples from Midwestern TGD individuals AFAB. Methods: We recruited TGD individuals AFAB for an observational study, mailing them materials to self-collect cervicovaginal, oral, and anal samples at home. We tested samples for high-risk (HR; 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59) and other HPV genotypes (6, 11, 66, 68, 73, 90) using a polymerase chain reaction mass array test. Prevalence ratios for HPV infection at each site as a function of participant characteristics were estimated in log-binomial models. Results: Out of 137 consenting participants, 102 completed sample collection. Among those with valid tests, 8.8% (HR = 6.6%; HPV 16/18 = 3.3%) were positive for oral HPV, 30.5% (HR = 26.8%; HPV 16/18 = 9.7%) for cervicovaginal HPV, and 39.6% (HR = 33.3%; HPV 16/18 = 8.3%) for anal HPV. A larger fraction of oral (71.4%) than anal infections (50.0%) were concordant with a cervicovaginal infection of the same type. Conclusions: We detected HR cervicovaginal, oral, and anal HPV in TGD people AFAB. It is essential that we reduce barriers to cancer screening for TGD populations, such as through the development of a clinically approved self-screening HPV test.

A Model-Based 13C-Sucrose Breath Test Diagnostic for Gut Function Disorders Characterized by a Loss of Sucrase-Isomaltase Enzymatic Activity.

BACKGROUND: Environmental enteric dysfunction (EED) causes malnutrition in children in low-resource settings. Stable-isotope breath tests have been proposed as noninvasive tests of altered nutrient metabolism and absorption in EED, but uncertainty over interpreting the breath curves has limited their use. The activity of sucrose-isomaltase, the glucosidase enzyme responsible for sucrose hydrolysis, may be reduced in EED. We previously developed a mechanistic model describing the dynamics of the 13C-sucrose breath test (13C-SBT) as a function of underlying metabolic processes. OBJECTIVES: This study aimed to determine which breath test curve dynamics are associated with sucrose hydrolysis and with the transport and metabolism of the fructose and glucose moieties and to propose and evaluate a model-based diagnostic for the loss of activity of sucrase-isomaltase. METHODS: We applied the mechanistic model to 2 sets of exploratory 13C-SBT experiments in healthy adult participants. First, 19 participants received differently labeled sucrose tracers (U-13C fructose, U-13C glucose, and U-13C sucrose) in a crossover study. Second, 16 participants received a sucrose tracer accompanied by 0, 100, and 750 mg of Reducose, a sucrase-isomaltase inhibitor. We evaluated a model-based diagnostic distinguishing between inhibitor concentrations using receiver operator curves, comparing with conventional statistics. RESULTS: Sucrose hydrolysis and the transport and metabolism of the fructose and glucose moieties were reflected in the same mechanistic process. The model distinguishes these processes from the fraction of tracer exhaled and an exponential metabolic process. The model-based diagnostic performed as well as the conventional summary statistics in distinguishing between no and low inhibition [area under the curve (AUC): 0.77 vs. 0.66-0.79] and for low vs. high inhibition (AUC 0.92 vs. 0.91-0.99). CONCLUSIONS: Current summary approaches to interpreting 13C breath test curves may be limited to identifying only gross gut dysfunction. A mechanistic model-based approach improved interpretation of breath test curves characterizing sucrose metabolism.

Opportunities to Interrupt Transmission of Enteropathogens of Poultry Origin in Maputo, Mozambique: A Transmission Model Analysis.

BACKGROUND: The burden of diarrheal diseases remains high among children in low-income countries. Enteropathogens are challenging to control because they are transmitted via multiple pathways. Chickens are an important animal protein source, but live chickens and their products are often highly contaminated with enteropathogens. OBJECTIVES: We conducted this study to a) understand the contribution of multiple transmission pathways to the force of infection of Campylobacter spp. and nontyphoidal Salmonella spp., b) quantify the potential impact of reducing each pathway on human infection, and c) quantify hypothesized pathway reduction from the context of Maputo, Mozambique. METHODS: We developed transmission models for Campylobacter and Salmonella that captured person-to-person, water-to-person, food-to-person, soil-to-person, animal-to-person, and all-other-sources-to-person in an urban, low-income setting in Mozambique. We calibrated these models using prevalence data from Maputo, Mozambique and estimates of attributable fraction of transmission pathways for the region. We simulated the prevalence of human infection after reducing transmission through each pathway. RESULTS: Simulation results indicated that if foodborne transmission were reduced by 90%, the prevalence of Campylobacter and Salmonella infection would decline by [52.2%; 95% credible interval (CrI): 39.7, 63.8] and (46.9%; 95% CrI: 39, 55.4), respectively. Interruption of any other pathway did not have a substantial impact. Combined with survey and microbiology data, if contamination of broiler chicken meat at informal markets in Maputo could be reduced by 90%, the total infection of Campylobacter and Salmonella could be reduced by 21% (16-26%) and 12% (10-13%), respectively. DISCUSSION: Our transmission models showed that the foodborne transmission has to be reduced to control enteropathogen infections in our study site, and likely in other similar contexts, but mitigation of this transmission pathway has not received sufficient attention. Our model can serve as a tool to identify effective mitigation opportunities to control zoonotic enteropathogens. https://doi.org/10.1289/EHP12314.

Changing patterns of cigarette and ENDS transitions in the USA: a multistate transition analysis of adults in the PATH Study in 2017-2019 vs 2019-2021.

Introduction: The use of cigarettes and electronic nicotine delivery system (ENDS) has likely changed since 2019 with the rise of pods and disposables, the outbreak of lung injuries related to vaping THC, flavor bans, and the COVID pandemic. We analyzed patterns of initiation, cessation, and transitions between cigarettes, ENDS, and dual use before and after 2019. Methods: Using the Population Assessment of Tobacco and Health (PATH) Study, we applied a multistate transition model to 28,061 adults in Waves 4-5 (2017-19) and 24,751 adults in Waves 5-6 (2019-21), estimating transition rates for initiation, cessation, and switching products for each period overall and by age group. Results: Cigarette initiation among adults who never used either product decreased from 2017-19 to 2019-21, but ENDS initiation did not significantly change. Persistence of ENDS-only use remained high, with 75-80% still using ENDS only after 1 year. Cigarette-only use transitions remained similar, with about 88% remaining, 7% transitioning to non-current use, and 5% transitioning to dual or ENDS-only use. In contrast, dual use to ENDS-only transitions increased from 9.5% (95%CI: 7.3-11.7%) to 20.1% (95%CI: 17.5-22.7%) per year from 2017-19 to 2019-21, decreasing the persistence of dual use. The dual use to cigarette-only transition remained at about 25%. These changes were qualitatively similar across adult age groups, though adults ages 18-24 years exhibited the highest probability of switching from cigarette-only use to dual use and from dual use to ENDS-only use. Conclusions: Persistence of ENDS use among adults remained high in 2019-21, but a larger fraction of dual users transitioned to ENDS-only use compared to 2017-19. Because the fraction of cigarette-only users switching to dual use remained low, the public health implications of the increased dual use to ENDS-only transition are minimal.

Prevalence and determinants of cervicovaginal, oral, and anal HPV infection in a population of transgender and gender diverse people assigned female at birth.

Introduction: HPV causes oral, cervicovaginal, and anogenital cancer, and cervical cancer screening options include HPV testing of a physician-collected sample. Transgender and gender diverse (TGD) people assigned female at birth (AFAB) face discrimination and stigma in many healthcare settings; are believed to be a lower risk for cervical cancer by many physicians; are less likely to be up to date on preventive health care services such as pelvic health exams; and are more likely to have inadequate results from screening tests. Self-sampling options may increase access and participation in HPV testing and cancer screening. Methods: We recruited 137 TGD individuals AFAB for an observational study, mailing them a kit to self-collect cervicovaginal, oral, and anal samples at home. We tested samples for HPV genotypes 6, 11, 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66, 68, 73 and 90 using a PCR mass array test. Results: 102 participants completed the study. Among those with valid tests, 8.8% were positive for oral HPV, 30.5% were positive for cervicovaginal HPV, and 39.6% were positive for anal HPV. A large fraction of anal (50.0%) and oral (71.4%) infections were concordant with a cervicovaginal infection of the same type. Conclusions: HPV infection in TGD people AFAB may be just as high, if not higher, than in cisgender women. It is essential that we reduce barriers to cancer screening for TGD populations, such as through the development of a clinically approved self-screening HPV test.

Cervicovaginal and anal self-sampling for HPV testing in a transgender and gender diverse population assigned female at birth: comfort, difficulty, and willingness to use.

Background: Transgender and gender diverse (TGD) people assigned female at birth (AFAB) face numerous barriers to preventive care, including for HPV and cervical cancer screening. Self-sampling options may expand access to HPV testing for TGD people AFAB. Methods: We recruited TGD individuals AFAB to collect cervicovaginal and anal specimens at-home using self-sampling for HPV testing, and individuals reported their perceptions of self-sampling. Associations between demographic and health characteristics and each of comfort of use, ease of use, and willingness to use self-sampling were estimated using robust Poisson regression. Results: The majority of the 101 participants who completed the study reported that the cervicovaginal self-swab was not uncomfortable (68.3%) and not difficult to use (86.1%), and nearly all (96.0%) were willing to use the swab in the future. Fewer participants found the anal swab to not be uncomfortable (47.5%), but most participants still found the anal swab to not be difficult to use (70.2%) and were willing to use the swab in the future (89.1%). Participants were more willing to use either swab if they had not seen a medical professional in the past year. About 70% of participants who reported negative experiences with either self-swab were still willing to use that swab in the future. Conclusions: TGD AFAB individuals were willing to use and preferred self-sampling methods for cervicovaginal and anal HPV testing. Developing clinically approved self-sampling options for cancer screening could expand access to HPV screening for TGD AFAB populations.

Longitudinal and quantitative fecal shedding dynamics of SARS-CoV-2, pepper mild mottle virus, and crAssphage.

Wastewater-based epidemiology (WBE) emerged during the coronavirus disease 2019 (COVID-19) pandemic as a scalable and broadly applicable method for community-level monitoring of infectious disease burden. The lack of high-resolution fecal shedding data for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) limits our ability to link WBE measurements to disease burden. In this study, we present longitudinal, quantitative fecal shedding data for SARS-CoV-2 RNA, as well as for the commonly used fecal indicators pepper mild mottle virus (PMMoV) RNA and crAss-like phage (crAssphage) DNA. The shedding trajectories from 48 SARS-CoV-2-infected individuals suggest a highly individualized, dynamic course of SARS-CoV-2 RNA fecal shedding. Of the individuals that provided at least three stool samples spanning more than 14 days, 77% had one or more samples that tested positive for SARS-CoV-2 RNA. We detected PMMoV RNA in at least one sample from all individuals and in 96% (352/367) of samples overall. CrAssphage DNA was detected in at least one sample from 80% (38/48) of individuals and was detected in 48% (179/371) of all samples. The geometric mean concentrations of PMMoV and crAssphage in stool across all individuals were 8.7 × 104 and 1.4 × 104 gene copies/milligram-dry weight, respectively, and crAssphage shedding was more consistent for individuals than PMMoV shedding. These results provide us with a missing link needed to connect laboratory WBE results with mechanistic models, and this will aid in more accurate estimates of COVID-19 burden in sewersheds. Additionally, the PMMoV and crAssphage data are critical for evaluating their utility as fecal strength normalizing measures and for source-tracking applications. IMPORTANCE This research represents a critical step in the advancement of wastewater monitoring for public health. To date, mechanistic materials balance modeling of wastewater-based epidemiology has relied on SARS-CoV-2 fecal shedding estimates from small-scale clinical reports or meta-analyses of research using a wide range of analytical methodologies. Additionally, previous SARS-CoV-2 fecal shedding data have not contained sufficient methodological information for building accurate materials balance models. Like SARS-CoV-2, fecal shedding of PMMoV and crAssphage has been understudied to date. The data presented here provide externally valid and longitudinal fecal shedding data for SARS-CoV-2, PMMoV, and crAssphage which can be directly applied to WBE models and ultimately increase the utility of WBE.

Patterns of poly tobacco use among adults in the Population Assessment of Tobacco and Health (PATH) study, 2013-2017: a multistate Markov transition analysis.

BACKGROUND: A better understanding of sociodemographic transition patterns between single, dual and poly tobacco product use may help improve tobacco control policy interventions. METHODS: HRs of transition between never, non-current (no past 30-day use), cigarette, e-cigarette, other combustible, smokeless tobacco (SLT), dual and poly tobacco use states in adults were estimated for age, sex, race/ethnicity, education and income using a multistate model for waves 1-4 of the Population Assessment of Tobacco and Health study (2013-2017), a US-based cohort study, accounting for complex survey design. RESULTS: Sole cigarette and SLT use were persistent, with 77% and 78% of adults continuing use after one wave. Other use states were more transient, with 29%-48% of adults reporting the same pattern after one wave. If single-product users transitioned, it was most likely to non-current use while dual or poly cigarette users were most likely to transition to exclusive cigarette use. Males were more likely than females to initiate combustible product use after a history of no use, and after a period of tobacco use cessation. Hispanic and non-Hispanic black participants initiated cigarette use at higher rates than non-Hispanic white participants, and had higher rates of experimentation with tobacco products between study waves. Lower socioeconomic status was associated with higher rates of transition into combustible tobacco use. CONCLUSIONS: Dual and poly tobacco use is largely transient, while single-use patterns are more stable over time. Transitions differ by age, sex, race/ethnicity, education and income, which may influence the impact of current and future tobacco control efforts.

Long-term projections of the impacts of warming temperatures on Zika and dengue risk in four Brazilian cities using a temperature-dependent basic reproduction number.

For vector-borne diseases the basic reproduction number [Formula: see text], a measure of a disease's epidemic potential, is highly temperature-dependent. Recent work characterizing these temperature dependencies has highlighted how climate change may impact geographic disease spread. We extend this prior work by examining how newly emerging diseases, like Zika, will be impacted by specific future climate change scenarios in four diverse regions of Brazil, a country that has been profoundly impacted by Zika. We estimated a [Formula: see text], derived from a compartmental transmission model, characterizing Zika (and, for comparison, dengue) transmission potential as a function of temperature-dependent biological parameters specific to Aedes aegypti. We obtained historical temperature data for the five-year period 2015-2019 and projections for 2045-2049 by fitting cubic spline interpolations to data from simulated atmospheric data provided by the CMIP-6 project (specifically, generated by the GFDL-ESM4 model), which provides projections under four Shared Socioeconomic Pathways (SSP). These four SSP scenarios correspond to varying levels of climate change severity. We applied this approach to four Brazilian cities (Manaus, Recife, Rio de Janeiro, and São Paulo) that represent diverse climatic regions. Our model predicts that the [Formula: see text] for Zika peaks at 2.7 around 30°C, while for dengue it peaks at 6.8 around 31°C. We find that the epidemic potential of Zika will increase beyond current levels in Brazil in all of the climate scenarios. For Manaus, we predict that the annual [Formula: see text] range will increase from 2.1-2.5, to 2.3-2.7, for Recife we project an increase from 0.4-1.9 to 0.6-2.3, for Rio de Janeiro from 0-1.9 to 0-2.3, and for São Paulo from 0-0.3 to 0-0.7. As Zika immunity wanes and temperatures increase, there will be increasing epidemic potential and longer transmission seasons, especially in regions where transmission is currently marginal. Surveillance systems should be implemented and sustained for early detection.

Changing patterns of cigarette and ENDS transitions in the USA: a multistate transition analysis of youth and adults in the PATH Study in 2015-2017 vs 2017-2019.

INTRODUCTION: It is unknown how recent changes in the tobacco product marketplace have impacted transitions in cigarette and electronic nicotine delivery system (ENDS) use. METHODS: A multistate transition model was applied to 24 242 adults and 12 067 youth in waves 2-4 (2015-2017) and 28 061 adults and 12 538 youth in waves 4 and 5 (2017-2019) of the Population Assessment of Tobacco and Health Study. Transition rates for initiation, cessation and product transitions were estimated in multivariable models, accounting for gender, age group, race/ethnicity and daily versus non-daily product use. RESULTS: Changes in ENDS initiation/relapse rates depended on age, including among adults. Among youth who had never established tobacco use, the 1-year probability of ENDS initiation increased after 2017 from 1.6% (95% CI 1.4% to 1.8%) to 3.8% (95% CI 3.4% to 4.2%). Persistence of ENDS-only use (ie, 1-year probability of continuing to use ENDS only) increased for youth from 40.7% (95% CI 34.4% to 46.9%) to 65.7% (95% CI 60.5% to 71.1%) and for adults from 57.8% (95% CI 54.4% to 61.3%) to 78.2% (95% CI 76.0% to 80.4%). Persistence of dual use similarly increased for youth from 48.3% (95% CI 37.4% to 59.2%) to 60.9% (95% CI 43.0% to 78.8%) and for adults from 40.1% (95% CI 37.0% to 43.2%) to 63.8% (95% CI 59.6% to 67.6%). Youth and young adults who used both products became more likely to transition to ENDS-only use, but middle-aged and older adults did not. CONCLUSIONS: ENDS-only and dual use became more persistent. Middle-aged and older adults who used both products became less likely to transition to cigarette-only use but not more likely to discontinue cigarettes. Youth and young adults became more likely to transition to ENDS-only use.

Mechanistic inference of the metabolic rates underlying [Formula: see text]C breath test curves.

Carbon stable isotope breath tests offer new opportunities to better understand gastrointestinal function in health and disease. However, it is often not clear how to isolate information about a gastrointestinal or metabolic process of interest from a breath test curve, and it is generally unknown how well summary statistics from empirical curve fitting correlate with underlying biological rates. We developed a framework that can be used to make mechanistic inference about the metabolic rates underlying a 13C breath test curve, and we applied it to a pilot study of 13C-sucrose breath test in 20 healthy adults. Starting from a standard conceptual model of sucrose metabolism, we determined the structural and practical identifiability of the model, using algebra and profile likelihoods, respectively, and we used these results to develop a reduced, identifiable model as a function of a gamma-distributed process; a slower, rate-limiting process; and a scaling term related to the fraction of the substrate that is exhaled as opposed to sequestered or excreted through urine. We demonstrated how the identifiable model parameters impacted curve dynamics and how these parameters correlated with commonly used breath test summary measures. Our work develops a better understanding of how the underlying biological processes impact different aspect of 13C breath test curves, enhancing the clinical and research potential of these 13C breath tests.

Public health impact of a US ban on menthol in cigarettes and cigars: a simulation study.

INTRODUCTION: The US Food and Drug Administration most recently announced its intention to ban menthol cigarettes and cigars nationwide in April 2021. Implementation of the ban will require evidence that it would improve public health. This paper simulates the potential public health impact of a ban on menthol in cigarettes and cigars through its impacts on smoking initiation, smoking cessation and switching to nicotine vaping products (NVPs). METHODS: After calibrating an established US simulation model to reflect recent use trends in cigarette and NVP use, we extended the model to incorporate menthol and non-menthol cigarette use under a status quo scenario. Applying estimates from a recent expert elicitation on the behavioural impacts of a menthol ban, we developed a menthol ban scenario with the ban starting in 2021. We estimated the public health impact as the difference between smoking and vaping-attributable deaths and life-years lost in the status quo scenario and the menthol ban scenario from 2021 to 2060. RESULTS: As a result of the ban, overall smoking was estimated to decline by 15% as early as 2026 due to menthol smokers quitting both NVP and combustible use or switching to NVPs. These transitions are projected to reduce cumulative smoking and vaping-attributable deaths from 2021 to 2060 by 5% (650 000 in total) and reduce life-years lost by 8.8% (11.3 million). Sensitivity analyses showed appreciable public health benefits across different parameter specifications. CONCLUSIONS AND RELEVANCE: Our findings strongly support the implementation of a ban on menthol in cigarettes and cigars.

Associations of Demographics, Dependence, and Biomarkers With Transitions in Tobacco Product Use in a Cohort of Cigarette Users and Dual Users of Cigarettes and E-cigarettes.

INTRODUCTION: It is uncertain whether e-cigarettes facilitate smoking cessation in the real world. We aimed to understand whether and how transitions among cigarette, e-cigarette, and dual use are associated with sociodemographics, dependence measures, and biomarkers. AIMS AND METHODS: We followed 380 adult daily cigarette users and dual users every 2 months for up to 2 years. We estimated transition rates between noncurrent, cigarette-only, e-cigarette-only, and dual use states using a multistate transition model. We estimated univariable hazard ratios (HR) for demographics, dependence measures for cigarettes and e-cigarettes, biomarkers, spousal or partner behaviors, and other measures. RESULTS: We estimated that participants transitioned from cigarette-only to e-cigarette-only through a period of dual use. Dual users ceased smoking (transitioning to e-cigarette-only use) at a greater rate than cigarette-only users did (HR 2.44, 95% CI: 1.49, 4.02). However, of the 60% of dual users estimated to transition to single product use in 1 year, 83% would transition to cigarette-only use and only 17% to e-cigarette-only use. E-cigarette dependence measures were generally associated with reduced e-cigarette cessation rather than enhanced cigarette cessation. E-cigarette users motivated by harm or toxicity reduction or because of restrictions on where or when they could smoke had reduced rates of smoking relapse. Cigarette dependence and spousal smoking were barriers to cigarette cessation for dual users, while using e-cigarettes first in the morning, motivation to quit smoking, and sensory, social, and emotional enjoyment of e-cigarettes (secondary dependence motives) were facilitators of smoking cessation among dual users. CONCLUSIONS: Tobacco control policy and interventions may be informed by the barriers and facilitators of product transitions. IMPLICATIONS: Although e-cigarettes have the potential to promote smoking cessation, their real-world impact is uncertain. In this cohort, dual users were more likely to quit smoking than cigarette-only users, but the overall impact was small because most dual users returned to cigarette-only use. Moreover, e-cigarette dependence promoted continued dual use rather than smoking cessation. Yet, high motivation to quit smoking and the sensory, social, and emotional enjoyment of e-cigarettes facilitated smoking cessation in dual users. Better understanding the barriers and facilitators of transitions can help to develop regulations and interventions that lead to more effective use of e-cigarettes for smoking cessation.

Leveraging infectious disease models to interpret randomized controlled trials: Controlling enteric pathogen transmission through water, sanitation, and hygiene interventions.

Randomized controlled trials (RCTs) evaluate hypotheses in specific contexts and are often considered the gold standard of evidence for infectious disease interventions, but their results cannot immediately generalize to other contexts (e.g., different populations, interventions, or disease burdens). Mechanistic models are one approach to generalizing findings between contexts, but infectious disease transmission models (IDTMs) are not immediately suited for analyzing RCTs, since they often rely on time-series surveillance data. We developed an IDTM framework to explain relative risk outcomes of an infectious disease RCT and applied it to a water, sanitation, and hygiene (WASH) RCT. This model can generalize the RCT results to other contexts and conditions. We developed this compartmental IDTM framework to account for key WASH RCT factors: i) transmission across multiple environmental pathways, ii) multiple interventions applied individually and in combination, iii) adherence to interventions or preexisting conditions, and iv) the impact of individuals not enrolled in the study. We employed a hybrid sampling and estimation framework to obtain posterior estimates of mechanistic parameter sets consistent with empirical outcomes. We illustrated our model using WASH Benefits Bangladesh RCT data (n = 17,187). Our model reproduced reported diarrheal prevalence in this RCT. The baseline estimate of the basic reproduction number [Formula: see text] for the control arm (1.10, 95% CrI: 1.07, 1.16) corresponded to an endemic prevalence of 9.5% (95% CrI: 7.4, 13.7%) in the absence of interventions or preexisting WASH conditions. No single pathway was likely able to sustain transmission: pathway-specific [Formula: see text] for water, fomites, and all other pathways were 0.42 (95% CrI: 0.03, 0.97), 0.20 (95% CrI: 0.02, 0.59), and 0.48 (95% CrI: 0.02, 0.94), respectively. An IDTM approach to evaluating RCTs can complement RCT analysis by providing a rigorous framework for generating data-driven hypotheses that explain trial findings, particularly unexpected null results, opening up existing data to deeper epidemiological understanding.

Structural identifiability of compartmental models for infectious disease transmission is influenced by data type.

If model identifiability is not confirmed, inferences from infectious disease transmission models may not be reliable, so they might result in misleading recommendations. Structural identifiability analysis characterises whether it is possible to obtain unique solutions for all unknown model parameters, given the model structure. In this work, we studied the structural identifiability of some typical deterministic compartmental models for infectious disease transmission, focusing on the influence of the data type considered as model output on the identifiability of unknown model parameters, including initial conditions. We defined 26 model versions, each having a unique combination of underlying compartmental structure and data type(s) considered as model output(s). Four compartmental model structures and three common data types in disease surveillance (incidence, prevalence and detected vector counts) were studied. The structural identifiability of some parameters varied depending on the type of model output. In general, models with multiple data types as outputs had more structurally identifiable parameters, than did models with a single data type as output. This study highlights the importance of a careful consideration of data types as an integral part of the inference process with compartmental infectious disease transmission models.

Why the Spectral Radius? An intuition-building introduction to the basic reproduction number.

The basic reproduction number [Formula: see text] is a fundamental concept in mathematical epidemiology and infectious disease modeling. Loosely speaking, it describes the number of people that an infectious person is expected to infect. The basic reproduction number has profound implications for epidemic trajectories and disease control strategies. It is well known that the basic reproduction number can be calculated as the spectral radius of the next generation matrix, but why this is the case may not be intuitively obvious. Here, we walk through how the discrete, next generation process connects to the ordinary differential equation disease system of interest, linearized at the disease-free equilibrium. Then, we use linear algebra to develop a geometric explanation of why the spectral radius of the next generation matrix is an epidemic threshold. Finally, we work through a series of examples that help to build familiarity with the kinds of patterns that arise in parameter combinations produced by the next generation method. This article is intended to help new infectious disease modelers develop intuition for the form and interpretation of the basic reproduction number in their disease systems of interest.

Understanding the mechanisms of HPV-related carcinogenesis: Implications for cell cycle dynamics.

The role of human papillomavirus (HPV) as a causative agent for epithelial cancers is well-known, but many open questions remain regarding the downstream gene regulatory effects of viral proteins E6 and E7 on the cell cycle. Here, we extend a cell cycle model originally presented by Gérard and Goldbeter (2009) in order to capture the effects of E6 and E7 on key actors in the cell cycle. Results suggest that E6 is sufficient to reverse p53-induced quiescence, while E7 is sufficient to reverse p16INK4a-induced quiescence; both E6 and E7 are necessary when p53 and p16INK4a are both active. Moreover, E7 appears to play a role as a "growth factor substitute", inducing cell division in the absence of growth factor. Low levels of E7 may permit regular cell division, but the results suggest that higher levels of E7 dysregulate the cell cycle in ways that may destabilize the cellular genome. The mechanisms explored here provide opportunities for developing new treatment targets that take advantage of the cell cycle regulatory system to prevent HPV-related cancer effects.