Pharmacokinetics and Safety of Remdesivir in Pregnant and Non-Pregnant Women with COVID-19: Results from IMPAACT 2032.

BACKGROUND: Pregnant people with COVID-19 experience higher risk for severe disease and adverse pregnancy outcomes, but no pharmacokinetic (PK) data exist to support dosing of COVID-19 therapeutics during pregnancy. We report PK and safety data for intravenous remdesivir in pregnancy. METHODS: IMPAACT 2032 was a phase IV prospective, open-label, non-randomized opportunistic study of hospitalized pregnant and non-pregnant women receiving intravenous remdesivir as part of clinical care. Intensive PK sampling was performed on infusion days 3, 4, or 5 with collection of plasma and peripheral blood mononuclear cells (PBMCs). Safety data were recorded from first infusion through 4 weeks post-last infusion and at delivery. Geometric mean ratios (GMR) (90% confidence intervals [CI]) of PK parameters between pregnant and non-pregnant women were calculated. RESULTS: Fifty-three participants initiated remdesivir (25 pregnant; median (IQR) gestational age 27.6 (24.9, 31.0) weeks). Plasma exposures of remdesivir, its two major metabolites (GS-704277 and GS-441524), and the free remdesivir fraction were similar between pregnant and non-pregnant participants. Concentrations of the active triphosphate (GS-443902) in PBMCs increased 2.04-fold (90% CI 1.35, 3.03) with each additional infusion in non-pregnant versus pregnant participants. Three adverse events in non-pregnant participants were related to treatment (one Grade 3; two Grade 2 resulting in treatment discontinuation). There were no treatment-related adverse pregnancy outcomes or congenital anomalies detected. CONCLUSIONS: Plasma remdesivir PK parameters were comparable between pregnant and non-pregnant women, and no safety concerns were identified based on our limited data. These findings suggest no dose adjustments are indicated for intravenous remdesivir during pregnancy.

Acceptability and tolerability of long-acting injectable cabotegravir or rilpivirine in the first cohort of virologically suppressed adolescents living with HIV (IMPAACT 2017/MOCHA): a secondary analysis of a phase 1/2, multicentre, open-label, non-comparative dose-finding study.

BACKGROUND: Long-acting injectable cabotegravir and rilpivirine have demonstrated safety, acceptability, and efficacy in adults living with HIV-1. The IMPAACT 2017 study (MOCHA study) was the first to use these injectable formulations in adolescents (aged 12-17 years) living with HIV-1. Herein, we report acceptability and tolerability outcomes in cohort 1 of the study. METHODS: In this a secondary analysis of a phase 1/2, multicentre, open-label, non-comparative dose-finding study, with continuation of pre-study oral combination antiretroviral treatment (ART), 55 adolescents living with HIV-1 were enrolled to receive sequential doses of either long-acting cabotegravir or rilpivirine and 52 received at least two injections. Participants had a body weight greater than 35 kg and BMI less than 31·5 kg/m2 and had been on stable ART for at least 90 consecutive days with an HIV-1 viral load of less than 50 copies per mL at a participating IMPAACT study site. Participants had to be willing to continue their pre-study ART during cohort 1. The primary objectives of the study were to confirm doses for oral and injectable cabotegravir and for injectable rilpivirine in adolescents living with HIV. This analysis of participant-reported outcomes included a face scale assessment of pain at each injection and a Pediatric Quality of Life Inventory (PedsQL) at baseline and week 16 for participants in the USA, South Africa, Botswana, and Thailand. A subset of 11 adolescents and 11 parents or caregivers in the USA underwent in-depth interviews after receipt of one or two injections. This trial is registered at ClinicalTrials.gov, NCT03497676. FINDINGS: Between March 19, 2019, and Nov 25, 2021, 55 participants were enrolled into cohort 1. Using the six-point face scale, 43 (83%) of participants at week 4 and 38 (73%) at week 8 reported that the injection caused "no hurt" or "hurts little bit", while only a single (2%) participant for each week rated the pain as one of the two highest pain levels. Quality of life was not diminished by the addition of one injectable antiretroviral. In-depth interviews revealed that parents and caregivers in the USA frequently had more hesitancy than adolescents about use of long-acting formulations, but parental acceptance was higher after their children received injections. INTERPRETATION: High acceptability and tolerability of long-acting cabotegravir or rilpivirine injections suggests that these are likely to be favoured treatment options for some adolescents living with HIV. FUNDING: National Institutes of Health and ViiV Healthcare.

Safety and pharmacokinetics of oral and long-acting injectable cabotegravir or long-acting injectable rilpivirine in virologically suppressed adolescents with HIV (IMPAACT 2017/MOCHA): a phase 1/2, multicentre, open-label, non-comparative, dose-finding study.

BACKGROUND: Combined intramuscular long-acting cabotegravir and long-acting rilpivirine constitute the first long-acting combination antiretroviral therapy (ART) regimen approved for adults with HIV. The goal of the IMPAACT 2017 study (MOCHA [More Options for Children and Adolescents]) was to assess the safety and pharmacokinetics of these drugs in adolescents. METHODS: In this phase 1/2, multicentre, open-label, non-comparative, dose-finding study, virologically suppressed adolescents (aged 12-17 years; weight ≥35 kg; BMI ≤31·5 kg/m2) with HIV-1 on daily oral ART were enrolled at 15 centres in four countries (Botswana, South Africa, Thailand, and the USA). After 4-6 weeks of oral cabotegravir (cohort 1C) or rilpivirine (cohort 1R), participants received intramuscular long-acting cabotegravir or long-acting rilpivirine every 4 weeks or 8 weeks per the adult dosing regimens, while continuing pre-study ART. The primary outcomes were assessments of safety measures, including all adverse events, until week 4 for oral cabotegravir and until week 16 for long-acting cabotegravir and long-acting rilpivirine, and pharmacokinetic measures, including the area under the plasma concentration versus time curve during the dosing interval (AUC0-tau) and drug concentrations, at week 2 for oral dosing of cabotegravir and at week 16 for intramuscular dosing of cabotegravir and rilpivirine. Enrolment into cohort 1C or cohort 1R was based on the participant's pre-study ART, meaning that masking was not done. For pharmacokinetic analyses, blood samples were drawn at weeks 2-4 after oral dosing and weeks 4-16 after intramuscular dosing. Safety outcome measures were summarised using frequencies, percentages, and exact 95% CIs; pharmacokinetic parameters were summarised using descriptive statistics. This trial is registered at ClinicalTrials.gov, NCT03497676, and is closed to enrolment. FINDINGS: Between March 19, 2019, and Nov 25, 2021, 55 participants were enrolled: 30 in cohort 1C and 25 in cohort 1R. At week 16, 28 (97%, 95% CI 82-100) of the 29 dose-evaluable participants in cohort 1C and 21 (91%; 72-99) of the 23 dose-evaluable participants in cohort 1R had reported at least one adverse event, with the most common being injection-site pain (nine [31%] in cohort 1C; nine [39%] in cohort 1R; none were severe). One (4%, 95% CI 0-22) participant in cohort 1R had an adverse event of grade 3 or higher, leading to treatment discontinuation, which was defined as acute rilpivirine-related allergic reaction (self-limiting generalised urticaria) after the first oral dose. No deaths or life-threatening events occurred. In cohort 1C, the week 2 median cabotegravir AUC0-tau was 148·5 (range 37·2-433·1) µg·h/mL. The week 16 median concentrations for the every-4-weeks and every-8-weeks dosing was 3·11 µg/mL (range 1·22-6·19) and 1·15 µg/mL (<0·025-5·29) for cabotegravir and 52·9 ng/mL (31·9-148·0) and 39·1 ng/mL (27·2-81·3) for rilpivirine, respectively. These concentrations were similar to those in adults. INTERPRETATION: Study data support using long-acting cabotegravir or long-acting rilpivirine, given every 4 weeks or 8 weeks, per the adult dosing regimens, in virologically suppressed adolescents aged 12 years and older and weighing at least 35 kg. FUNDING: The National Institutes of Health and ViiV Healthcare.

Bone and Renal Health in Infants With or Without Breastmilk Exposure to Tenofovir-Based Maternal Antiretroviral Treatment in the PROMISE Randomized Trial.

BACKGROUND: We assessed bone and kidney outcomes in infants randomized postdelivery as mother-infant pairs within the IMPAACT PROMISE trial to maternal tenofovir disoproxil fumarate-based antiretroviral treatment (mART) or infant nevirapine prophylaxis (iNVP) to prevent breastfeeding HIV transmission. METHODS: Infants were coenrolled in the P1084s substudy on randomization day and followed through Week 74. Lumbar spine bone mineral content (LS-BMC) was assessed at entry (6-21 age days) and Week 26 by dual-energy x-ray absorptiometry. Creatinine clearance (CrCl) was calculated at entry; Weeks 10, 26, and 74. Student t tests compared mean LS-BMC and CrCl at Week 26 and mean change from entry between arms. RESULTS: Of 400 enrolled infants, the mean (SD; n) for entry LS-BMC was 1.68 g (0.35; n = 363) and CrCl was 64.2 mL/min/1.73 m 2 (24.6; n = 357). At Week 26, 98% of infants were breastfeeding and 96% on their assigned HIV prevention strategy. The mean (SD) Week 26 LS-BMC was 2.64 g (0.48) for mART and 2.77 g (0.44) for iNVP; mean difference (95% confidence interval [CI]) -0.13 g (-0.22 to -0.04), P = 0.007, n = 375/398 (94%). Mean absolute (-0.14 g [-0.23 to -0.06]) and percent (-10.88% [-18.53 to -3.23]) increase in LS-BMC from entry was smaller for mART than iNVP. At Week 26, the mean (SD) CrCl was 130.0 mL/min/1.73 m 2 (34.9) for mART vs. 126.1 mL/min/1.73 m 2 (30.0) for iNVP; mean difference (95% CI) 3.8 (-3.0 to 10.7), P = 0.27, n = 349/398 (88%). CONCLUSION: Week 26 mean LS-BMC was lower in infants in the mART group compared with the iNVP group. However, this difference (∼0.23 g) was less than one-half SD, considered potentially clinically relevant. No infant renal safety concerns were observed.

Prevalence of neurotoxicity symptoms among postpartum women on isoniazid preventive therapy and efavirenz-based treatment for HIV: an exploratory objective of the IMPAACT P1078 randomized trial.

BACKGROUND: This exploratory analysis investigates the prevalence and risk factors of neurocognitive toxicity in postpartum women on HIV treatment in response to a concern of an Isoniazid Preventive Therapy (IPT)/Efavirenz interaction. TRIAL DESIGN: Pregnant women on HIV treatment from countries with high TB prevalence were randomized in IMPAACT P1078 to 28 weeks of IPT started either during pregnancy or at 12 weeks postpartum. Partway through study implementation, the Patient Health Questionnaire 9, the cognitive complaint questionnaire, and the Pittsburg Sleep Quality Index were added to evaluate depression, cognitive function, and sleep quality at postpartum weeks. Screening for peripheral neuropathy was conducted throughout the study. METHODS: We summarized percentages of women with depression symptoms, cognitive dysfunction, poor sleep quality and peripheral neuropathy and assessed the association of 11 baseline risk factors of neurotoxicity using logistic regression, adjusted for gestational age stratum. RESULTS: Of 956 women enrolled, 749 (78%) had at least one neurocognitive evaluation. During the postpartum period, the percentage of women reporting at least mild depression symptoms, cognitive complaint and poor sleep quality peaked at 13%, 8% and 10%, respectively, at 12 weeks, and the percentage of women reporting peripheral neuropathy peaked at 13% at 24 weeks. There was no evidence of study arm differences in odds of all four neurotoxic symptoms. CONCLUSIONS: Timing of IPT initiation and EFV use were not associated with symptoms of neurotoxicity. Further study is advised to formally assess risk factors of neurotoxicity.

Maternal and infant renal safety following tenofovir disoproxil fumarate exposure during pregnancy in a randomized control trial.

BACKGROUND: Tenofovir disoproxil fumarate (TDF) in combination with other antiretroviral (ARV) drugs has been in clinical use for HIV treatment since its approval in 2001. Although the effectiveness of TDF in preventing perinatal HIV infection is well established, information about renal safety during pregnancy is still limited. TRIAL DESIGN: The IMPAACT PROMISE study was an open-label, strategy trial that randomized pregnant women to one of three arms: TDF based antiretroviral therapy (ART), zidovudine (ZDV) based ART, and ZDV alone (standard of care at start of enrollment). The P1084s substudy was a nested, comparative study of renal outcomes in women and their infants. METHODS: PROMISE participants (n = 3543) were assessed for renal dysfunction using calculated creatinine clearance (CrCl) at study entry (> 14 weeks gestation), delivery, and postpartum weeks 6, 26, and 74. Of these women, 479 were enrolled in the P1084s substudy that also assessed maternal calcium and phosphate as well as infant calculated CrCl, calcium, and phosphate at birth. RESULTS: Among the 1338 women who could be randomized to TDF, less than 1% had a baseline calculated CrCl below 80 mL/min. The mean (standard deviation) maternal calculated CrCl at delivery in the TDF-ART arm [147.0 mL/min (51.4)] was lower than the ZDV-ART [155.0 mL/min (43.3); primary comparison] and the ZDV Alone [158.5 mL/min (45.0)] arms; the mean differences (95% confidence interval) were - 8.0 mL/min (- 14.5, - 1.5) and - 11.5 mL/min (- 18.0, - 4.9), respectively. The TDF-ART arm had lower mean maternal phosphate at delivery compared with the ZDV-ART [- 0.14 mg/dL (- 0.28, - 0.01)] and the ZDV Alone [- 0.17 mg/dL (- 0.31, - 0.02)] arms, and a greater percentage of maternal hypophosphatemia at delivery (4.23%) compared with the ZDV-ART (1.38%) and the ZDV Alone (1.46%) arms. Maternal calcium was similar between arms. In infants, mean calculated CrCl, calcium, and phosphate at birth were similar between arms (all CIs included 0). CONCLUSIONS: Although mean maternal calculated CrCl at Delivery was lower in the TDF-ART arm, the difference between arms is unlikely to be clinically significant. During pregnancy, the TDF-ART regimen had no observed safety concerns for maternal or infant renal function. TRIAL REGISTRATION: NCT01061151 on 10/02/2010 for PROMISE (1077BF). NCT01066858 on 10/02/2010 for P1084s.

Forty-Eight Week Outcomes of a Site-Randomized Trial of Combined Cognitive Behavioral Therapy and Medication Management Algorithm for Treatment of Depression Among Youth With HIV in the United States.

BACKGROUND: Studies suggest that manualized, measurement-guided, depression treatment is more efficacious than usual care but impact can wane. Our study among youth with HIV (YWH), aged 12-24 years at US clinical research sites in the International Maternal Pediatric Adolescent AIDS Clinical Trials Network, found a significant reduction in depressive symptoms among YWH who received a manualized, measurement-guided treatment. This paper reports outcomes up to 24 weeks after the intervention. METHODS: Eligibility included diagnosis of ongoing nonpsychotic depression. Using restricted randomization, sites were assigned to either combination cognitive behavioral therapy and medication management algorithm tailored for YWH or to enhanced standard of care, which provided psychotherapy and medication management. Site-level mean Quick Inventory for Depression Symptomatology Self-Report (QIDS-SR) scores and proportion of youth with treatment response (>50% decrease from baseline) and remission (QIDS-SR ≤ 5) were compared across arms using t tests. RESULTS: Thirteen sites enrolled 156 YWH, with baseline demographic factors, depression severity, and HIV disease status comparable across arms. At week 36, the site-level mean proportions of youth with a treatment response and remission were greater at combination cognitive behavioral therapy and medication management algorithm sites (52.0% vs. 18.8%, P = 0.02; 37.9% vs. 19.4%, P = 0.05), and the mean QIDS-SR was lower (7.45 vs. 9.75, P = 0.05). At week 48, the site-level mean proportion with a treatment response remained significantly greater (58.7% vs. 33.4%, P = 0.047). CONCLUSIONS: The impact of manualized, measurement-guided cognitive behavioral therapy and medication management algorithm tailored for YWH that was efficacious at week 24 continued to be evident at weeks 36 and 48.

Healthcare-Seeking Behavior for Respiratory Illness Among Flu Near You Participants in the United States During the 2015-2016 Through 2018-2019 Influenza Seasons.

BACKGROUND: Flu Near You (FNY) is an online participatory syndromic surveillance system that collects health-related information. In this article, we summarized the healthcare-seeking behavior of FNY participants who reported influenza-like illness (ILI) symptoms. METHODS: We applied inverse probability weighting to calculate age-adjusted estimates of the percentage of FNY participants in the United States who sought health care for ILI symptoms during the 2015-2016 through 2018-2019 influenza season and compared seasonal trends across different demographic and regional subgroups, including age group, sex, census region, and place of care using adjusted χ 2 tests. RESULTS: The overall age-adjusted percentage of FNY participants who sought healthcare for ILI symptoms varied by season and ranged from 22.8% to 35.6%. Across all seasons, healthcare seeking was highest for the <18 and 65+ years age groups, women had a greater percentage compared with men, and the South census region had the largest percentage while the West census region had the smallest percentage. CONCLUSIONS: The percentage of FNY participants who sought healthcare for ILI symptoms varied by season, geographical region, age group, and sex. FNY compliments existing surveillance systems and informs estimates of influenza-associated illness by adding important real-time insights into healthcare-seeking behavior.

Radiomics of Coronary Artery Calcium in the Framingham Heart Study.

PURPOSE: To extract radiomic features from coronary artery calcium (CAC) on CT images and to determine whether this approach could improve the ability to identify individuals at risk for a composite endpoint of clinical events. MATERIALS AND METHODS: Participants from the Offspring and Third Generation cohorts of the community-based Framingham Heart Study underwent noncontrast cardiac CT (2002-2005) and were followed for more than a median of 9.1 years for composite major events. A total of 624 participants with CAC Agatston score (AS) of greater than 0 and good or excellent CT image quality were included for manual CAC segmentation and extraction of a predefined set of radiomic features reflecting intensity, shape, and texture. In a discovery cohort (n = 318), machine learning was used to select the 20 most informative and nonredundant CAC radiomic features, classify features predicting events, and define a radiomic-based score (RS). Performance of the RS was tested independently for the prediction of events in a validation cohort (n = 306). RESULTS: The RS had a median value of 0.08 (interquartile range, 0.007-0.71) and a weak and modest correlation with Framingham risk score (FRS) (r = 0.2) and AS (r = 0.39), respectively. The continuous RS unadjusted, adjusted for age and sex, FRS, AS, and FRS plus AS were significantly associated with events (hazard ratio [HR] = 2.2, P < .001; HR = 1.8, P = .002; HR = 2.0, P < .001; HR = 1.7, P = .02; and HR = 1.8, P = .01, respectively). In participants with AS of less than 300, RS association with events remained significant when unadjusted and adjusted for age and sex, FRS, AS, and FRS plus AS (HR = 2.4, 2.8, 2.8, 2.3, and 2.6; P < .001, respectively). In the same subgroup of participants, adding the RS to AS resulted in a significant improvement in the discriminatory ability for events as compared with the AS (area under the receiver operating curve: 0.80 vs 0.68, respectively; P = .03). CONCLUSION: A radiomic-based score, including the complex properties of CAC, may constitute an imaging biomarker to be further developed to identify individuals at risk for major adverse cardiovascular events in a community-based cohort. Supplemental material is available for this article. © RSNA, 2020.

Differences in Regional Patterns of Influenza Activity Across Surveillance Systems in the United States: Comparative Evaluation.

BACKGROUND: The Centers for Disease Control and Prevention (CDC) tracks influenza-like illness (ILI) using information on patient visits to health care providers through the Outpatient Influenza-like Illness Surveillance Network (ILINet). As participation in this system is voluntary, the composition, coverage, and consistency of health care reports vary from state to state, leading to different measures of ILI activity between regions. The degree to which these measures reflect actual differences in influenza activity or systematic differences in the methods used to collect and aggregate the data is unclear. OBJECTIVE: The objective of our study was to qualitatively and quantitatively compare national and region-specific ILI activity in the United States across 4 surveillance data sources-CDC ILINet, Flu Near You (FNY), athenahealth, and HealthTweets.org-to determine whether these data sources, commonly used as input in influenza modeling efforts, show geographical patterns that are similar to those observed in CDC ILINet's data. We also compared the yearly percentage of FNY participants who sought health care for ILI symptoms across geographical areas. METHODS: We compared the national and regional 2018-2019 ILI activity baselines, calculated using noninfluenza weeks from previous years, for each surveillance data source. We also compared measures of ILI activity across geographical areas during 3 influenza seasons, 2015-2016, 2016-2017, and 2017-2018. Geographical differences in weekly ILI activity within each data source were also assessed using relative mean differences and time series heatmaps. National and regional age-adjusted health care-seeking percentages were calculated for each influenza season by dividing the number of FNY participants who sought medical care for ILI symptoms by the total number of ILI reports within an influenza season. Pearson correlations were used to assess the association between the health care-seeking percentages and baselines for each surveillance data source. RESULTS: We observed consistent differences in ILI activity across geographical areas for CDC ILINet and athenahealth data. ILI activity for FNY displayed little variation across geographical areas, whereas differences in ILI activity for HealthTweets.org were associated with the total number of tweets within a geographical area. The percentage of FNY participants who sought health care for ILI symptoms differed slightly across geographical areas, and these percentages were positively correlated with CDC ILINet and athenahealth baselines. CONCLUSIONS: Our findings suggest that differences in ILI activity across geographical areas as reported by a given surveillance system may not accurately reflect true differences in the prevalence of ILI. Instead, these differences may reflect systematic collection and aggregation biases that are particular to each system and consistent across influenza seasons. These findings are potentially relevant in the real-time analysis of the influenza season and in the definition of unbiased forecast models.

Density and morphology of coronary artery calcium for the prediction of cardiovascular events: insights from the Framingham Heart Study.

OBJECTIVES: To investigate the association between directly measured density and morphology of coronary artery calcium (CAC) with cardiovascular disease (CVD) events, using computed tomography (CT). METHODS: Framingham Heart Study (FHS) participants with CAC in noncontrast cardiac CT (2002-2005) were included and followed until 2016. Participants with known CVD or uninterpretable CT scans were excluded. We assessed and correlated (Spearman) CAC density, CAC volume, and the number of calcified segments. Moreover, we counted morphology features including shape (cylindrical, spherical, semi-tubular, and spotty), location (bifurcation, facing pericardium, or facing myocardium), and boundary regularity. In multivariate Cox regression analyses, we associated all CAC characteristics with CVD events (CVD-death, myocardial infarction, stroke). RESULTS: Among 1330 included participants (57.8 ± 11.7 years; 63% male), 73 (5.5%) experienced CVD events in a median follow-up of 9.1 (7.8-10.1) years. CAC density correlated strongly with CAC volume (Spearman's ρ = 0.75; p < 0.001) and lower number of calcified segments (ρ = - 0.86; p < 0.001; controlled for CAC volume). In the survival analysis, CAC density was associated with CVD events independent of Framingham risk score (HR (per SD) = 2.09; 95%CI, 1.30-3.34; p = 0.002) but not after adjustment for CAC volume (p = 0.648). The extent of spherically shaped and pericardially sided calcifications was associated with fewer CVD events accounting for the number of calcified segments (HR (per count) = 0.55; 95%CI, 0.31-0.98; p = 0.042 and HR = 0.66; 95%CI, 0.45-0.98; p = 0.039, respectively). CONCLUSIONS: Directly measured CAC density does not predict CVD events due to the strong correlation with CAC volume. The spherical shape and pericardial-sided location of CAC are associated with fewer CVD events and may represent morphological features related to stable coronary plaques. KEY POINTS: • Coronary calcium density may not be independently associated with cardiovascular events. • Coronary calcium density correlates strongly with calcium volume. • Spherical shape and pericardial-sided location of CAC are associated with fewer CVD events.

Comparison of crowd-sourced, electronic health records based, and traditional health-care based influenza-tracking systems at multiple spatial resolutions in the United States of America.

BACKGROUND: Influenza causes an estimated 3000 to 50,000 deaths per year in the United States of America (US). Timely and representative data can help local, state, and national public health officials monitor and respond to outbreaks of seasonal influenza. Data from cloud-based electronic health records (EHR) and crowd-sourced influenza surveillance systems have the potential to provide complementary, near real-time estimates of influenza activity. The objectives of this paper are to compare two novel influenza-tracking systems with three traditional healthcare-based influenza surveillance systems at four spatial resolutions: national, regional, state, and city, and to determine the minimum number of participants in these systems required to produce influenza activity estimates that resemble the historical trends recorded by traditional surveillance systems. METHODS: We compared influenza activity estimates from five influenza surveillance systems: 1) patient visits for influenza-like illness (ILI) from the US Outpatient ILI Surveillance Network (ILINet), 2) virologic data from World Health Organization (WHO) Collaborating and National Respiratory and Enteric Virus Surveillance System (NREVSS) Laboratories, 3) Emergency Department (ED) syndromic surveillance from Boston, Massachusetts, 4) patient visits for ILI from EHR, and 5) reports of ILI from the crowd-sourced system, Flu Near You (FNY), by calculating correlations between these systems across four influenza seasons, 2012-16, at four different spatial resolutions in the US. For the crowd-sourced system, we also used a bootstrapping statistical approach to estimate the minimum number of reports necessary to produce a meaningful signal at a given spatial resolution. RESULTS: In general, as the spatial resolution increased, correlation values between all influenza surveillance systems decreased. Influenza-like Illness rates in geographic areas with more than 250 crowd-sourced participants or with more than 20,000 visit counts for EHR tracked government-lead estimates of influenza activity. CONCLUSIONS: With a sufficient number of reports, data from novel influenza surveillance systems can complement traditional healthcare-based systems at multiple spatial resolutions.

Accurate Influenza Monitoring and Forecasting Using Novel Internet Data Streams: A Case Study in the Boston Metropolis.

BACKGROUND: Influenza outbreaks pose major challenges to public health around the world, leading to thousands of deaths a year in the United States alone. Accurate systems that track influenza activity at the city level are necessary to provide actionable information that can be used for clinical, hospital, and community outbreak preparation. OBJECTIVE: Although Internet-based real-time data sources such as Google searches and tweets have been successfully used to produce influenza activity estimates ahead of traditional health care-based systems at national and state levels, influenza tracking and forecasting at finer spatial resolutions, such as the city level, remain an open question. Our study aimed to present a precise, near real-time methodology capable of producing influenza estimates ahead of those collected and published by the Boston Public Health Commission (BPHC) for the Boston metropolitan area. This approach has great potential to be extended to other cities with access to similar data sources. METHODS: We first tested the ability of Google searches, Twitter posts, electronic health records, and a crowd-sourced influenza reporting system to detect influenza activity in the Boston metropolis separately. We then adapted a multivariate dynamic regression method named ARGO (autoregression with general online information), designed for tracking influenza at the national level, and showed that it effectively uses the above data sources to monitor and forecast influenza at the city level 1 week ahead of the current date. Finally, we presented an ensemble-based approach capable of combining information from models based on multiple data sources to more robustly nowcast as well as forecast influenza activity in the Boston metropolitan area. The performances of our models were evaluated in an out-of-sample fashion over 4 influenza seasons within 2012-2016, as well as a holdout validation period from 2016 to 2017. RESULTS: Our ensemble-based methods incorporating information from diverse models based on multiple data sources, including ARGO, produced the most robust and accurate results. The observed Pearson correlations between our out-of-sample flu activity estimates and those historically reported by the BPHC were 0.98 in nowcasting influenza and 0.94 in forecasting influenza 1 week ahead of the current date. CONCLUSIONS: We show that information from Internet-based data sources, when combined using an informed, robust methodology, can be effectively used as early indicators of influenza activity at fine geographic resolutions.

Pubertal Progression in Female Adolescents with Progeria.

STUDY OBJECTIVE: This study identified the prevalence of menarche and coincident sexual characteristics in female adolescents with Hutchinson-Gilford Progeria Syndrome (HGPS). DESIGN: Data were examined to determine the prevalence of menarche in female adolescents older than 12 years; all were participants in clinical trials between 2007 and 2016. SETTING: Pediatric hospital in Boston, Massachusetts. PARTICIPANTS: Fifteen female adolescents, median age 15 (range, 12.0-20.3) years with a confirmed diagnosis of HGPS. INTERVENTIONS AND MAIN OUTCOME MEASURES: Report of menarche, anthropometric and serum hormonal measures, Tanner pubertal staging, and body composition using dual-energy x-ray absorptiometry. RESULTS: Nine of 15 (60%) participants reported spontaneous menarche at a median age of 14.4 years (range, 12.0-16.5 years). In those experiencing menarche vs not, median age was older (16.5 vs 13.6 years; P = .02), whereas body mass index did not differ (10.5 vs 10.4; P = .53) nor percentage body fat (19.4% vs. 19.3%; P = .98) or serum leptin levels (0.40 vs 0.40 ng/mL; P = .23). Among those who achieved menarche, 2 of 9 (22%) had Tanner II breast development and 2 of 9 (22%) exhibited Tanner II Pubic hair, all reflecting minimal pubertal development. Only early signs of puberty were similarly seen in the non-menstruating group, including 1 of 6 (17%) with Tanner II breasts and 2 of 6 (33%) with Tanner II pubic hair, and Tanner staging did not differ between those who reported menarche vs those who did not (each P = 1.0). None of the participants achieved Tanner IV or V thelarche over the course of the study. CONCLUSION: Menarche was achieved in more than half of adolescent girls with HGPS, in the setting of little to no physical signs of pubertal development and minimal body fat.

Coronary Artery Calcium Distribution Is an Independent Predictor of Incident Major Coronary Heart Disease Events: Results From the Framingham Heart Study.

BACKGROUND: The presence and extent of coronary artery calcium (CAC) are associated with increased risk for cardiovascular events. We determined whether information on the distribution of CAC and coronary dominance as detected by cardiac computed tomography were incremental to traditional Agatston score (AS) in predicting incident major coronary heart disease (CHD). METHODS AND RESULTS: We assessed total AS and the presence of CAC per coronary artery, per segment, and coronary dominance by computed tomography in participants from the offspring and third-generation cohorts of the Framingham Heart Study. The primary outcome was major CHD (myocardial infarction or CHD death). We performed multivariable Cox proportional hazards analysis and calculated relative integrated discrimination improvement. In 1268 subjects (mean age, 56.2±10.3 years, 63.2% men) with AS >0 and no history of major CHD, a total of 42 major CHD events occurred during median follow-up of 7.4 years. The number of coronary arteries with CAC (hazard ratio, 1.68 per artery; 95% confidence interval, 1.10-2.57; P=0.02) and the presence of CAC in the proximal dominant coronary artery (hazard ratio, 2.59; 95% confidence interval, 1.15-5.83; P=0.02) were associated with major CHD events after multivariable adjustment for Framingham risk score and categories of AS. In addition, measures of CAC distribution improved discriminatory capacity for major CHD events (relative integrated discrimination improvement, 0.14). CONCLUSIONS: Distribution of coronary atherosclerosis, especially CAC in the proximal dominant coronary artery and an increased number of coronary arteries with CAC, predict major CHD events independently of the traditional AS in community-dwelling men and women.

Determinants of Participants' Follow-Up and Characterization of Representativeness in Flu Near You, A Participatory Disease Surveillance System.

BACKGROUND: Flu Near You (FNY) is an Internet-based participatory surveillance system in the United States and Canada that allows volunteers to report influenza-like symptoms using a brief weekly symptom report. OBJECTIVE: Our objective was to evaluate the representativeness of the FNY population compared with the general population of the United States, explore the demographic and behavioral characteristics associated with FNY's high-participation users, and summarize results from a user survey of a cohort of FNY participants. METHODS: We compared (1) the representativeness of sex and age groups of FNY participants during the 2014-2015 flu season versus the general US population and (2) the distribution of Human Development Index (HDI) scores of FNY participants versus that of the general US population. We analyzed associations between demographic and behavioral factors and the level of participant follow-up (ie, high vs low). Finally, descriptive statistics of responses from FNY's 2015 and 2016 end-of-season user surveys were calculated. RESULTS: During the 2014-2015 influenza season, 47,234 unique participants had at least one FNY symptom report that was either self-reported (users) or submitted on their behalf (household members). The proportion of female FNY participants was significantly higher than that of the general US population (n=28,906, 61.2% vs 51.1%, P<.001). Although each age group was represented in the FNY population, the age distribution was significantly different from that of the US population (P<.001). Compared with the US population, FNY had a greater proportion of individuals with HDI >5.0, signaling that the FNY user distribution was more affluent and educated than the US population baseline. We found that high-participation use (ie, higher participation in follow-up symptom reports) was associated with sex (females were 25% less likely than men to be high-participation users), higher HDI, not reporting an influenza-like illness at the first symptom report, older age, and reporting for household members (all differences between high- and low-participation users P<.001). Approximately 10% of FNY users completed an additional survey at the end of the flu season that assessed detailed user characteristics (3217/33,324 in 2015; 4850/44,313 in 2016). Of these users, most identified as being either retired or employed in the health, education, and social services sectors and indicated that they achieved a bachelor's degree or higher. CONCLUSIONS: The representativeness of the FNY population and characteristics of its high-participation users are consistent with what has been observed in other Internet-based influenza surveillance systems. With targeted recruitment of underrepresented populations, FNY may improve as a complementary system to timely tracking of flu activity, especially in populations that do not seek medical attention and in areas with poor official surveillance data.

Flu Near You: Crowdsourced Symptom Reporting Spanning 2 Influenza Seasons.

OBJECTIVES: We summarized Flu Near You (FNY) data from the 2012-2013 and 2013-2014 influenza seasons in the United States. METHODS: FNY collects limited demographic characteristic information upon registration, and prompts users each Monday to report symptoms of influenza-like illness (ILI) experienced during the previous week. We calculated the descriptive statistics and rates of ILI for the 2012-2013 and 2013-2014 seasons. We compared raw and noise-filtered ILI rates with ILI rates from the Centers for Disease Control and Prevention ILINet surveillance system. RESULTS: More than 61 000 participants submitted at least 1 report during the 2012-2013 season, totaling 327 773 reports. Nearly 40 000 participants submitted at least 1 report during the 2013-2014 season, totaling 336 933 reports. Rates of ILI as reported by FNY tracked closely with ILINet in both timing and magnitude. CONCLUSIONS: With increased participation, FNY has the potential to serve as a viable complement to existing outpatient, hospital-based, and laboratory surveillance systems. Although many established systems have the benefits of specificity and credibility, participatory systems offer advantages in the areas of speed, sensitivity, and scalability.