Cumulative Exposure Days Research Articles

Association between short-term ambient particulate matters and acute liver injury outpatient visits: A hospital-based study

Acute liver injury (ALI) manifests as a sudden liver malfunction, posing a serious, sometimes fatal, threat. This condition is of global medical significance due to its high prevalence and mortality rates. The link between ALI and environmental air contamination remains unstudied. This research delves into the potential connections between brief exposures to particulate matters (PMs) and daily ALI-related outpatient visits in China. Our study encompassed an analysis of 32,261 cases of ALI from January 1, 2013, to December 31, 2019, covering 2,549 days in total. We applied over-dispersed Poisson generalized additive models, incorporating both meteorological factors and day of the week. Notably, a 10 μg/m3 uptick in PM2.5 and PM10 led to 0.41% (95% Cl: 0.06%, 0.75%) and 0.34% (95% Cl: 0.13%, 0.56%) rises in ALI visits at lag 01, PMc exhibited a clear positive trend with ALI across cumulative exposure days, most notably at lag 02, where an increase of 10 μg/m3 in PMc corresponded to a 0.64% (95% CI: 0.23%, 1.05%) rise in outpatient attendances, respectively. The stratified analyses indicated that PMs exhibited stronger effects in females, individuals aged 36–59, and during the warm seasons. This study unveils initial findings suggesting that short-lived PM exposures could indirectly enhance the ALI risk.

Institutional and Regional Variation in Opioid Prescribing for Hospitalized Infants in the US

High-risk infants, defined as newborns with substantial neonatal-perinatal morbidities, often undergo multiple procedures and require prolonged intubation, resulting in extended opioid exposure that is associated with poor outcomes. Understanding variation in opioid prescribing can inform quality improvement and best-practice initiatives. To examine regional and institutional variation in opioid prescribing, including short- and long-acting agents, in high-risk hospitalized infants. This retrospective cohort study assessed high-risk infants younger than 1 year from January 1, 2016, to December 31, 2022, at 47 children's hospitals participating in the Pediatric Health Information System (PHIS). The cohort was stratified by US Census region (Northeast, South, Midwest, and West). Variation in cumulative days of opioid exposure and methadone treatment was examined among institutions using a hierarchical generalized linear model. High-risk infants were identified by International Statistical Classification of Diseases and Related Health Problems, Tenth Revision codes for congenital heart disease surgery, medical and surgical necrotizing enterocolitis, extremely low birth weight, very low birth weight, hypoxemic ischemic encephalopathy, extracorporeal membrane oxygenation, and other abdominal surgery. Infants with neonatal opioid withdrawal syndrome, in utero substance exposure, or malignant tumors were excluded. Any opioid exposure and methadone treatment. Regional and institutional variations in opioid exposure. Overall, 132 658 high-risk infants were identified (median [IQR] gestational age, 34 [28-38] weeks; 54.5% male). Prematurity occurred in 30.3%, and 55.3% underwent surgery. During hospitalization, 76.5% of high-risk infants were exposed to opioids and 7.9% received methadone. Median (IQR) length of any opioid exposure was 5 (2-12) cumulative days, and median (IQR) length of methadone treatment was 19 (7-46) cumulative days. There was significant hospital-level variation in opioid and methadone exposure and cumulative days of exposure within each US region. The computed intraclass correlation coefficient estimated that 16% of the variability in overall opioid prescribing and 20% of the variability in methadone treatment was attributed to the individual hospital. In this retrospective cohort study of high-risk hospitalized infants, institution-level variation in overall opioid exposure and methadone treatment persisted across the US. These findings highlight the need for standardization of opioid prescribing in this vulnerable population.

The association between participant-reported ratings of comfort, dryness and vision quality in soft contact lens wearers.

Previous literature has indicated an association between participant-reported perceptions (e.g., ratings) of comfort, dryness and vision quality during soft contact lens wear. However, these reports do not account for participant- and lens-specific factors which may impact the interpretation of these results. The purpose of this project was to quantify the association between these participant-reported ratings while accounting for both participant- and lens-specific factors. Participant-reported ratings (scale 0-100) of comfort, dryness and quality of vision for 675 soft contact lens wearers (1207 eyes) were aggregated across 31 studies completed at Indiana University. Linear mixed-effects regression modelling was performed on each outcome rating individually. Covariate-adjusted models incorporated both participant- (e.g., age, sex) and lens-related (e.g., lens material, edge and optics) factors. The models were statistically adjusted for the duration of lens wear in hours and cumulative days of exposure. Consistent with estimates from covariate-adjusted regression models, pairwise Spearman correlations [95% CI] between dryness and comfort (rs = 0.71,[0.69, 0.74]), vision quality and comfort (rs = 0.53, [0.49, 0.57]) and vision quality and dryness (rs = 0.49, [0.42, 0.54]) were all positive and had p < 0.001. Average participant-reported ratings of comfort, dryness and vision quality decreased by (bs [95% CI]) = -0.81 [-1.15, -0.46] -0.34 [-0.67, 0.0005] and -0.90 [-1.19, -0.60] rating units, respectively, for each hour of lens wear. Significant positive associations were found between participant-reported measures of comfort, dryness and vision quality during soft contact lens wear. The associations between these ratings and the participant- and lens-related factors that drive them should be considered by clinicians and manufacturers when fitting and designing soft contact lenses.

Associations Between Self-Reported Burn Pit Exposure andFunctional Status, 1990-2021.

The Airborne Hazards and Open Burn Pit Registry (AHOBPR) allows service members to self-report exposure to burn pits during military deployments and functional status (a composite metric of physical fitness status). This study investigated whether general exposure to burn pits, specific performance of burn pit duties, or the cumulative number of days deployed in Southwest Asia was associated with a change in functional status. A retrospective cross-sectional analysis of 234,061 participants in the AHOBPR who completed questionnaires before August 2021 was conducted. Exposure was presumed if an individual reported any burn pits exposure during deployment or if an individual reported having to work at a burn pit as part of their duties and was quantified by the cumulative-reported exposure days. The outcome was the reported composite functional score. Statistical analysis used linear regression, which was adjusted for significant variables. A possible dose-response effect from cumulative deployment and burn pits exposure days was evaluated. Statistical significance was determined at P < 0.05. The burn pit exposure groups were notably different in size (exposed: 230,079, non-exposed: 3982) and were significantly different for all compared variables. There was a negative association between cumulative exposure days and functional score with a significant test for trend. There was a marginal positive significant association between cumulative deployment days and functional score with a significant test for trend. Reporting exposure to burn pit duties was also significantly associated with a lower functional score. This study suggests a dose-response relationship between cumulative burn pit exposure and decreased functional status. It also suggests a modest positive relationship between cumulative deployment days and reported function, which may represent a "healthy deployer" effect.

Flares, Rotation, Activity Cycles, and a Magnetic Star–Planet Interaction Hypothesis for the Far-ultraviolet Emission of GJ 436

Variability in the far-ultraviolet (FUV) emission produced by stellar activity affects photochemistry and heating in orbiting planetary atmospheres. We present a comprehensive analysis of the FUV variability of GJ 436, a field-age M2.5V star (P rot ≈ 44 days) that is orbited by a warm Neptune-sized planet (M ≈ 25 M ⊕, R ≈ 4.1 M ⊕, P orb ≈ 2.6 days). Observations at three epochs from 2012 to 2018 span nearly a full activity cycle, sample two rotations of the star and two orbital periods of the planet, and reveal a multitude of brief flares. From 2012 to 2018, the star’s 7.75 ± 0.10 yr activity cycle produced the largest observed variations, 38% ± 3% in the summed flux of the major FUV emission lines. In 2018, the variability due to rotation was 8% ± 2%. An additional 11% ± 1% scatter at a cadence of 10 minutes, which is treated as white noise in the fits, likely has both instrumental and astrophysical origins. Flares increased time-averaged emission by 15% over the 0.88 days of cumulative exposure, peaking as high as 25× quiescence. We interpret these flare values as lower limits given that flares too weak or too infrequent to have been observed likely exist. GJ 436’s flare frequency distribution at FUV wavelengths is unusual compared to other field-age M dwarfs, exhibiting a statistically significant dearth of high-energy (>4 × 1028 erg) events, which we hypothesize to be the result of a magnetic star–planet interaction (SPI) triggering premature flares. If an SPI is present, GJ 436 b’s magnetic field strength must be ≲100 G to explain the statistically insignificant increase in the orbit-phased FUV emission.

Haloperidol and Other Antipsychotics Exposure before Endometrial Cancer Diagnosis: A Population-based Case-control Study.

ObjectiveEndometrial cancer is the most common malignancy of the female genital tract worldwide, and the associated relationship between endometrial cancer formation and various antipsychotics need to be confirmed.MethodsWe conducted a case-control study by using data from Taiwan National Health Insurance Research Database to compare individual antipsychotic exposure between females with and without endometrial cancer. Among 14,079,089 females in the 12-year population-based national dataset, 9,502 females with endometrial cancer were identified. Their medical records of exposure to antipsychotics, including quetiapine, haloperidol, risperidone, olanzapine, amisulpride, clozapine, and aripiprazole, for up to 3 years before endometrial cancer diagnosis were reviewed. Daily dosage and cumulative exposure days were analyzed in the risky antipsychotic users. Additionally, the subsequent 5-year mortality rate of endometrial cancer among users of the risky antipsychotic were also analyzed.ResultsAmong endometrial cancer patients, the proportion of those who have used haloperidol before being diagnosed with endometrial cancer is significantly higher than other antipsychotic users. The significant odds ratio (OR) and a 95% confidence interval of 1.75 (1.31−2.34) were noted. Furthermore, haloperidol users were associated with a significantly higher 5-year mortality rate after getting endometrial cancer than non-users.ConclusionThere is a high correlation between the use of haloperidol and endometrial cancer formation. However, the underlying pathological biomechanisms require additional investigations.

Treatment‐related risk factors for inhibitor development in non‐severe hemophilia A after 50 cumulative exposure days: A case‐control study

BackgroundNon‐severe hemophilia A patients have a life‐long inhibitor risk. Yet, no studies have analyzed risk factors for inhibitor development after 50 factor VIII (FVIII) exposure days (EDs). ObjectivesThis case‐control study investigated treatment‐related risk factors for inhibitor development in non‐severe hemophilia A and assessed whether these risk factors were different for early versus late inhibitor development. Patients/MethodsNon‐severe hemophilia A patients (FVIII:C 2%–40%) were selected from the INSIGHT study. Inhibitor‐positive patients were defined as early (<50 EDs) or late (>50EDs) cases and matched to 1–4 inhibitor‐negative controls by year of birth, cumulative number of EDs, and center/country. We investigated treatment intensity during the last 10 EDs prior to inhibitor development. Intensive treatment was defined as: surgery, peak treatment (10 consecutive EDs), and high mean FVIII dose (>45 IU/kg/ED). Odds ratios (OR) were calculated by logistic regression. ResultsOf 2709 patients, we analyzed 63 early and 26 late cases and 195 and 71 respectively matched controls. Peak treatment was associated with early and late inhibitor risk (crude OR 1.8, 95% confidence interval [CI] 1.0–3.4; 4.0, 95%CI 1.1–14.3). This association was slightly less pronounced after adjustment for mean FVIII dose. High mean FVIII dose was also associated with early and late inhibitor risk (crude OR 2.8, 95%CI 1.5–5.1; 4.5, 95%CI 1.2–16.6). Surgery increased inhibitor risk for early cases. This was less pronounced for late cases. ConclusionsOur findings suggest that intensive FVIII treatment remains a risk factor for inhibitor development in non‐severe hemophilia A after more than 50 EDs. Therefore, persistent caution is required throughout the life‐time treatment course.

Cinacalcet and gastrointestinal bleeding risk in patients receiving hemodialysis.

Secondary hyperparathyroidism (SHPT) is common among dialysis patients, and calcimimetics are a mainstay of treatment. This study assessed whether cinacalcet use is associated with gastrointestinal bleeding in a large hemodialysis cohort. A linked database of clinical records and medical claims for patients receiving hemodialysis in a large dialysis organization, 2007-2010, was used. A nested case-control study was performed among patients aged ≥18 years who had received hemodialysis for ≥90 days, had Medicare Parts A, B, and D coverage for ≥1year, and had clinical evidence of SHPT (parathyroid hormone >300 pg/mL). Cases were those who experienced death or hospitalization caused by gastrointestinal bleeding. Each case was matched to up to four controls. Exposure was measured by any cinacalcet use, current use, past use, cumulative exposure days, and cumulative dosage. Conditional logistic models were used to assess the association. Of 48 437 patients included, 2570 experienced gastrointestinal bleeding events (2498 non-fatal, 72 fatal), and 2465 (2397 non-fatal, 68 fatal) were matched to 9500 controls; 17.2% of cases and 15.8% of controls had cinacalcet exposure and 11.1% of both cases and controls had current use. The adjusted odds ratios (95% CI) of gastrointestinal bleeding for any use, current use, and past use of cinacalcet were 1.04 (0.91-1.19), 0.97 (0.83-1.13), and 1.22 (0.99-1.50), respectively, with no use as the reference. The results do not suggest an elevated risk of gastrointestinal bleeding resulting in hospitalization or death for hemodialysis patients exposed to cinacalcet.

Association Between Antipsychotic Treatment and Neurological Adverse Events in Pediatric Patients: A Population-Based Cohort Study in Korea.

Background: Potential adverse effects might be caused by increasing the number of antipsychotic prescriptions. However, the empirical evidence regarding pediatric psychiatric patients is insufficient. Therefore, we explored the antipsychotic-induced adverse effects focusing on the neurological system.Method: Using the medical information of pediatric patients retrieved from the claims data of Health Insurance Review and Assessment in Korea, we identified those psychiatric patients who were started on antipsychotic treatment at age 2–18 years between 2010 and 2018 (n = 10,969). In this study, movement disorders and seizures were considered as major neurological adverse events. The extended Cox model with time-varying covariates was applied to explore the association between antipsychotic medication and adverse events.Findings: Total 1,894 and 1,267 cases of movement disorders and seizures occurred in 32,046 and 33,280 person-years, respectively. The hazard risks of neurological adverse events were 3–8 times higher in the exposed to antipsychotics period than in the non-exposure period. Among the exposure periods, the most dangerous period was within 30 days of cumulative exposure. High doses or polypharmacy of antipsychotics was associated with increased risks of neurological adverse events. Among individual antipsychotics, haloperidol showed the highest risk of developing movement disorders among the examined agents. Quetiapine showed a lower risk of developing movement disorders but a higher risk of developing seizures than risperidone.Conclusion: These findings suggest that antipsychotics should be used with caution in pediatric patients, especially regarding initial exposure, high dose, and polypharmacy.

Effects of fine particulate matter on acute health events during critics episodes: a case crossover study in Medellín-Colombia 2015

During March of 2015, two critics episodes of PM2.5 were observed in Medellín-Colombia (levels over 75 µg/m3: three times the recommended by the World Health Organization, for three days or more). A case- crossover study stratified over time was carried out to establish the effects of these episodes in the use of emergency services for respiratory and cardiovascular events. Conditional logistic regression models were used to estimate the relative risks with 95% confidence intervals. Data of atmospheric conditions, particulate matter and the diagnostics in emergencia services were collected from public environmental information system and the individual records of health service provision. The analysis was made in populations under 5 years old and and adults aged 65 years and over. In under 5 years old population every 10 μg/m³ increase in PM2.5 was associated with increases in the risk percentage of emergency room visits for asthma (2.8%), acute respiratory infection (2.0%) and pneumonia (2.2%) in the same day of exposure, and for acute respiratory infection (3.6%) in the first day of exposure. For adults 65 and older the increase of 10 μg/m³ in PM2.5 were associated to excess risks for emergencies room visits due to COPD complications in the first day of exposure (0.8%), cerebrovascular disease after two days of (7.2%) and acute respiratory infection in the same day of exposure and after seven days of cumulative exposure with increases in risk pecentages of 0.6% and 0.5% respectively.These results confirm clear associations between ambient PM2.5 and negative health effects in respiratory and cardiovascular systems during critc episodes in Colombia

Modeling Fish Movement in 3-D in the Gulf of Mexico Hypoxic Zone

The hypoxic zone on the Louisiana-Texas shelf varies in its area, volume, and vertical distribution. Vertical movement to avoid hypoxia (dissolved oxygen (DO) concentration < 2 mg/L) can be important to understanding fish exposure to low DO. Fish movement was simulated in 2-D (bottom layer) and 3-D with movement algorithms that depended on DO fields generated by a 3-D coupled hydrodynamic-water quality model. Fish exposure to low DO was simulated using two alternative movement algorithm groups, good and bad avoidance competency, and three perception ranges for detecting DO. The algorithm groups (default and avoidance) differed in whether the default movement included a downward bias. Avoidance competencies differed in the degree of random variation imposed on the avoidance movement. Fish exposures to low DO were simulated in 2-D and 3-D for July 24 to August 2 of 2002 during which hypoxia showed both horizontal and vertical variations. The addition of vertical movement (3-D) resulted in mean cumulative hypoxia exposures (days with DO< 2 mg/L) typically about 8 times lower than the 2-D movement results (e.g., ∼0.1 days versus 0.8 days with good avoidance), but vertical avoidance did not decrease the cumulative days of exposure of fish to moderate hypoxia (2–4 mg/L). The differences between the 2-D and 3-D model results, coupled with the limited data on vertical fish movement in response to hypoxia, suggest that 3-D movement could affect exposure to hypoxia and should be considered for spatially complex habitats.

Antithrombotic Therapy Management in Patients with Inherited Bleeding Disorders and Ischaemic Heart Disease: A Single-Center Experience

Introduction: In the last decades, the life expectancy of patients with hemophilia A (HA), hemophilia B (HB) and von Willebrand disease (VWD) has substantially improved. As a result, these patients experience age-related comorbidities, especially ischaemic heart disease. Safety and efficacy of antiplatelet drugs in patients with inherited bleeding disorders remain unclear, while there is no evidence-based guideline for the antithrombotic management in this population. The aims of our study were to describe the management of patients with HA, HB and VWD at the occurrence of ischaemic heart disease in our regional referral center; to compare this management to experts' recommendations; and to evaluate the safety and the efficacy of antiplatelet drugs in this population.Methods: The source of population was the 2008-2018 cohort of patients with HA (n=565), HB (n=115) and VWD (n=618) followed at Toulouse University hospital (France). Their follow-up is recorded in electronic medical files. We retrospectively identified the patients who experienced an ischaemic heart disease treated by antiplatelet therapy. Ischaemic heart disease included ST- and non-ST-segment elevation acute myocardial infarction, stable and unstable angina, and silent coronary artery disease. We described the reperfusion therapy, the use of antiplatelet drugs and replacement factors, and the occurrence of bleeding or thrombotic complications during the follow-up.Results: Eight patients had an ischaemic heart disease: 5 HA, 1 HB and 2 VWD patients. Four of the haemophilic patients had minor hemophilia; the two others had moderate hemophilia. VWD patients were one type 1 (FVIII 26%, VWF:Ag 13%) and one type 2B (FVIII 29%, VWF:Ag 75%, VWF :Act 24%, low platelet count). Age at the time of the cardiac event ranged from 49 to 80 years. All patients were men except the patient with type 2B VWD. Cardiovascular risk factors were frequent (overweight, n=5; hypercholesterolemia, n=4; smoking, n=4). Four patients were investigated because of cardiac symptoms (unstable angina, angina, dyspnea, palpitations, n=1 each), and one patient because of family history. The last 3 patients were investigated as part of a screening program including patients with a high cardiovascular risk estimation.The initial management was as follows: 4 patients underwent a percutaneous coronary intervention (PCI) and 4 had a triple coronary artery bypass grafting (CABG). All patients treated with PCI had dual antiplatelet therapy for one month, then low-dose aspirin. CABG patients were initiated with low-dose aspirin. FVIII exposure was lower in PCI patients than in CABG patients (13 ± 10.42 versus 19 ± 9.35 cumulative exposure days to FVIII).Four patients were managed with differences from current guidelines1-3: first, the woman with type 2B VWD was treated with two drug-eluting stents whereas bare-metal stents are recommended. Dual antiplatelet therapy was then initiated but stopped at one month because of microcytic anemia. She was then treated with acid acetylsalicylic, 160mg per day instead of 75mg, and presented a severe gastrointestinal bleeding. Second, the patient with HB (FIX 34%) received no replacement therapy during PCI and no proton pump inhibitors while treated by antiplatelet drug, but he experienced no bleeding. Third, a HA patient (FVIII 6%) had a trough level of FVIII slightly lower than recommended (FVIII 37% versus > 50%) at day 7 after CABG. He presented a hemopericardium the next day, complicated with cardiac tamponade. Lastly, a moderate HA patient had no long-term antiplatelet therapy after CABG. However, he did not experience any new cardiovascular event during the following 4 years.During the follow-up (median: 24,5 months), only one HA (FVIII 20%) patient had a new cardiovascular event: a critical lower limb ischemia complicated with an arterial ulcer at the age of 91 years, 11 years after CABG. In contrast, 3 patients experienced a severe bleeding while treated by dual or low-dose aspirin: one hemopericardium, one gastrointestinal bleeding and one intracranial bleeding at J7 post-CABG, 13 months and 11 years after the cardiac event, respectively.Conclusion: This series of 8 patients confirms the significant risk of severe bleeding complications when antiplatelet drug is initiated in patients with hemophilia or VWD. In 1/3 cases, the severe bleeding occurred despite strict adherence to current recommendations. DisclosuresNo relevant conflicts of interest to declare.

Temporal variability of short term effects of PM10 on mortality in Seoul, Korea

Health effects of PM10 on mortality have been studies worldwide. However, not many studies have questioned possibility that short-term effects of PM10 can be changed over time. Identifying temporal variability of the effects would be of help to getting more valid PM10 effect estimates which are a major basis for public health policies. In this study, temporal variability of short-term effects of PM10 for mortality was investigated from 2001 to 2015 in Seoul, Korea.A time series analysis was used to estimate the effects of PM10 on all-cause, circulatory, and respiratory mortality. Study period was divided into five years of moving time window, and relative risks and its 95% confidence intervals were estimated using distributed lag model for each time window.The annual average of PM10 in Seoul decreased from 52.6 μg/m3 in 2001 to 40.5 μg/m3 in 2015. There were significant temporal trends in PM10 effects regarding each mortality. The effects of PM10 tend to slightly increase in early of the study period and then dropped in recent years. An increase of 2 days of cumulative exposure of PM10 was associated with 0.31% (95% confidence interval: 0.15, 0.46) increase in all-cause mortality for 2001–2005 period, 0.61% (95% confidence interval: 0.34, 0.89) increase in 2005–2009 period, and −0.06% (95% confidence interval: −0.38, 0.25) increase in 2011–2015 period.We found evidence that short-term effects of PM10 on mortality have been changed over time in Seoul, Korea. The observed temporal trend might attributable from two factors which are change of PM10 compositions and population vulnerability. If effects of PM10 vary over time, considering its change would be necessary not only in the estimation of the PM10 effect but also its application for a variety of public health policies.

DMARD use is associated with a higher risk of dementia in patients with rheumatoid arthritis: A propensity score-matched case–control study

BackgroundPatients with rheumatoid arthritis (RA) exhibit an increased risk of dementia. Disease-modifying antirheumatic drugs (DMARDs) are commonly used to slow RA progression, but studies investigating the relationship between DMARDs and dementia in patients with RA are lacking. We investigated the relationship between DMARDs and dementia in patients with RA. MethodsUsing the National Health Insurance Research Database, patients aged ≥20years, who were newly diagnosed with RA between 2000 and 2011 were identified. Patients with RA who had dementia comprised the dementia group, and patients with RA who did not have dementia comprised the control group. The groups were matched at a 1:1 ratio by the propensity score. DMARDs were categorized into conventional synthetic DMARDs (csDMARDs) and biological DMARDs (bDMARDs). Logistic regression models were used to calculate the odds ratio and 95% confidence interval (CI) to evaluate the association between DMARD use and the risk of dementia in patients with RA. ResultsA total of 957 patients with RA and dementia, and 957 patients with RA but not dementia, were enrolled. The risk of dementia was determined to be 1.63-fold higher in patients with RA with csDMARD use than in those without csDMARD use (95% CI=1.33–2.00). No significant risk of dementia was observed in patients with RA who used bDMARDs compared with their counterparts. However, patients with RA who used hydroxychloroquine, methotrexate, and sulfasalazine exhibited significant risks of dementia, irrespective of cumulative exposure days. ConclusionPatients with RA who used csDMARDs exhibit significant association with dementia.

Clinical Outcomes in Adults/Adolescents with Hemophilia B Treated Long Term with Recombinant Factor IX Fc Fusion Protein (rFIXFc) Prophylaxis: Interim Results of the B-Yond Extension Study

Clinical Outcomes in Adults/Adolescents with Hemophilia B Treated Long Term with Recombinant Factor IX Fc Fusion Protein (rFIXFc) Prophylaxis: Interim Results of the B-Yond Extension Study

Clinical Outcomes in Children with Hemophilia B Treated Long Term with rFIXFc: Interim Results of the B-YOND Extension Study

Background: Early prophylactic replacement of coagulation factor IX (FIX) improves clinical outcomes in children with hemophilia B; however, frequent intravenous infusions (2-3 times/week) are often required due to the short half-life of conventional FIX products. Recombinant FIX Fc fusion protein (rFIXFc), which is produced in a human cell line, binds the neonatal Fc receptor and utilizes the natural IgG recycling pathway to prolong the half-life of FIX.The phase 3 Kids B-LONG study (NCT01425723) demonstrated the safety, efficacy and prolonged half-life of once weekly recombinant factor IX Fc fusion protein (rFIXFc) in children aged Methods: Upon completing Kids B-LONG, eligible subjects could participate in one of 3 treatment groups in B-YOND: weekly prophylaxis (WP; 20-100 IU/kg every 7 days), individualized prophylaxis (IP; 100 IU/kg every 8-16 days), or modified prophylaxis (MP; for subjects not achieving optimal prophylactic dosing with individualized or weekly prophylaxis). Subjects could change treatment groups at the start of or at any time during the study; for efficacy analyses, data were summarized according to the treatment group in which they participated, for the time period they were in that treatment group. The primary endpoint was development of inhibitors (neutralizing antibodies; confirmed at a central laboratory per Nijmegen-modified Bethesda assay result ≥0.6 BU/mL observed twice within 2-4 weeks). Secondary outcomes included incidence of adverse events (AEs), annualized bleeding rate (ABR), and rFIXFc exposure days (EDs). Post hoc analyses of subjects9 prophylactic dose and dosing interval were performed to evaluate the stability of prophylactic dosing regimens over time. Results: At the time of the B-YOND interim data cut (17 October 2014), 23 subjects had completed Kids B-LONG; all enrolled in B-YOND ( Conclusions: These data confirm the long-term safety of rFIXFc and the maintenance of a low ABR in children treated with extended-interval prophylaxis. Disclosures Kulkarni:Kedrion: Membership on an entity9s Board of Directors or advisory committees; Pfizer: Membership on an entity9s Board of Directors or advisory committees; Novo Nordisk: Membership on an entity9s Board of Directors or advisory committees, Research Funding, Speakers Bureau; Bayer: Membership on an entity9s Board of Directors or advisory committees, Research Funding; Baxter: Membership on an entity9s Board of Directors or advisory committees, Research Funding; Biogen: Research Funding, Speakers Bureau; BPL: Membership on an entity9s Board of Directors or advisory committees. Nolan:Biogen and Sobi: Research Funding. Fischer:Baxalta/Baxter, Bayer, Pfizer, Novo Nordisk, and Biogen: Consultancy; Baxalta/Baxter, Bayer, Pfizer, and Novo Nordisk: Research Funding; Baxalta/Baxter, Bayer, Pfizer, Novo Nordisk, CSL Behring, and Octopharma: Speakers Bureau. Perry:Biogen: Consultancy, Honoraria; Novo Nordisk: Consultancy, Membership on an entity9s Board of Directors or advisory committees. Barnes:Bayer, Novo Nordisk, and Pfizer: Research Funding; Bayer, Baxter, and Novo Nordisk: Membership on an entity9s Board of Directors or advisory committees. Yuan:Biogen: Employment, Equity Ownership. Ramirez-Santiago:Biogen: Employment, Equity Ownership. Pierce:Biogen: Equity Ownership, Other: Former employee. Mei:Biogen: Employment, Equity Ownership.

Extended-Interval Prophylaxis with rFIXFc in Adults and Adolescents with Hemophilia B: Interim Results of the B-YOND Extension Study

Extended-Interval Prophylaxis with rFIXFc in Adults and Adolescents with Hemophilia B: Interim Results of the B-YOND Extension Study

Pesticide Exposures and Body Mass Index (BMI) of Pesticide Applicators From the Agricultural Health Study

Endocrine-disrupting chemicals, including pesticides, may be associated with weight gain. This is the first longitudinal study to examine a potential association between weight gain and pesticides using data on 8,365 male pesticide applicators from the Agricultural Health Study (AHS) cohort established in 1993. The relationship between total cumulative days of exposure to pesticide functional/chemical classes and to the four most frequently used individual pesticides was studied in relation to body mass index (BMI) at the time of 5-yr follow-up (beginning in 1998) with the length of the exposure period dating back to age 20 yr. Multiple regression, Spearman correlation, ordinal logistic regression, and logistic regression models all utilized a Bonferroni-adjusted p value, were adjusted for relevant covariates, and were stratified by state of residence (Iowa/North Carolina) and presence/absence of weight-related health conditions. Adjusted multiple regression yielded statistically significant positive parameter estimates for the study sample and Iowa subgroups with consistent findings for triazine herbicides and atrazine: Change in BMI per 100 cumulative pesticide exposure days ranged from 0.07 to 0.11 for triazine herbicides and from 0.10 to 0.19 for atrazine. Ordinal logistic regression compared normal weight with overweight and with obese using the zero exposure category as referent. Statistically significant adjusted odds ratios identified for the study sample and both state subgroups for the highest level of atrazine exposure ranged from 1.4 to 1.7. Further investigation is warranted to evaluate the associations identified here.

Pioglitazone and bladder cancer risk: a multipopulation pooled, cumulative exposure analysis.

The evidence on the association between pioglitazone use and bladder cancer is contradictory, with many studies subject to allocation bias. The aim of our study was to examine the effect of exposure to pioglitazone on bladder cancer risk internationally across several cohorts. The potential for allocation bias was minimised by focusing on the cumulative effect of pioglitazone as the primary endpoint using a time-dependent approach. Prescription, cancer and mortality data from people with type 2 diabetes were obtained from six populations across the world (British Columbia, Finland, Manchester, Rotterdam, Scotland and the UK Clinical Practice Research Datalink). A discrete time failure analysis using Poisson regression was applied separately to data from each centre to model the effect of cumulative drug exposure on bladder cancer incidence, with time-dependent adjustment for ever use of pioglitazone. These were then pooled using fixed and random effects meta-regression. Data were collated on 1.01 million persons over 5.9 million person-years. There were 3,248 cases of incident bladder cancer, with 117 exposed cases and a median follow-up duration of 4.0 to 7.4 years. Overall, there was no evidence for any association between cumulative exposure to pioglitazone and bladder cancer in men (rate ratio [RR] per 100 days of cumulative exposure, 1.01; 95% CI 0.97, 1.06) or women (RR 1.04; 95% CI 0.97, 1.11) after adjustment for age, calendar year, diabetes duration, smoking and any ever use of pioglitazone. No association was observed between rosiglitazone and bladder cancer in men (RR 1.01; 95% CI 0.98, 1.03) or women (RR 1.00; 95% CI 0.94, 1.07). The cumulative use of pioglitazone or rosiglitazone was not associated with the incidence of bladder cancer in this large, pooled multipopulation analysis.

Development of inhibitory antibodies to therapeutic factor VIII in severe hemophilia A is associated with microsatellite polymorphisms in the HMOX1 promoter

Induction of heme oxygenase-1, a stress-inducible enzyme with anti-inflammatory activity, reduces the immunogenicity of therapeutic factor VIII in experimental hemophilia A. In humans, heme oxygenase-1 expression is modulated by polymorphisms in the promoter of the heme oxygenase-1-encoding gene (HMOX1). We investigated the relationship between polymorphisms in the HMOX1 promoter and factor VIII inhibitor development in severe hemophilia A. We performed a case-control study on 99 inhibitor-positive patients and 263 patients who did not develop inhibitors within the first 150 cumulative days of exposure to therapeutic factor VIII. Direct sequencing and DNA fragment analysis were used to study (GT)n polymorphism and single nucleotide polymorphisms located at -1135 and -413 in the promoter of HMOX1. We assessed associations between the individual allele frequencies or genotypes, and inhibitor development. Our results demonstrate that inhibitor-positive patients had a higher frequency of alleles with large (GT)n repeats (L: n≥30), which are associated with lesser heme oxygenase-1 expression (odds ratio 2.31; 95% confidence interval 1.46-3.66; P<0.001]. Six genotypes (L/L, L/M, L/S, M/M, M/S and S/S) of (GT)n repeats were identified (S: n<21; M: 21≤n<30). The genotype group including L alleles (L/L, L/M and L/S) was statistically more frequent among inhibitor-positive than inhibitor-negative patients, as compared to the other genotypes (33.3% versus 17.1%) (odds ratio 2.21, 95% confidence interval 1.30-3.76; P<0.01). To our knowledge, this is the first association identified between HMOX1 promoter polymorphism and development of anti-drug antibodies. Our study paves the way towards modulation of the endogenous anti-inflammatory machinery of hemophilia patients to reduce the risk of inhibitor development.