Innovations in social health delivery to advance equitable pediatric and adolescent life course health development: A review and roadmap forward.

Recognizing the influence of social determinants on health and development, health care has increasingly advocated for interventions that target upstream factors as part of routine pediatric care delivery. In response, clinic-based social risk screening and referral programs have proliferated wherein patients are screened for health-related social needs (HRSNs, such as food and housing insecurity) and referred to community-based organizations (CBOs) and social service providers to address those needs. In recent years, an array of digital platforms, known as Social Health Access and Referral Platforms (SHARPs), have emerged to facilitate the scale and implementation of these models amidst growing system demand. Recent evidence on the effectiveness of social risk screen and refer models and SHARPs has been mixed, giving researchers pause and calling for more nuanced understanding of the limitations of such models, especially for promoting child and family health. Design thinking informed by the Life-Course Health Development (LCHD) framework provides a particularly useful lens for synthesizing emerging limitations of such models in the pediatric context, given the dynamic and developmentally-driven circumstances that shape family health and well-being in the early life course. By (1) focusing on addressing deficits-based social risks, (2) scoping to act upon narrow, downstream needs, (3) timing to react to social needs that have already caused harm rather than preventing them, and (4) limiting scale to individual-by-individual responses rather than structural and population-wide interventions, the current design of prevailing social risk screen and refer programs fundamentally limits their potential impact and misses opportunities to improve health equity over the life course. How can health care, social care, and technology partners move forward in collaboration with families and communities to better support equitable lifelong health and social development? In this narrative review, we will summarize the current design, implementation, and limitations of the predominant social risk screen and refer approach in the context of early childhood and adolescent care delivery. We then will apply LCHD principles to advance and improve on this approach from a reactionary focus towards a Family Journey Model that better supports life course health development.

A Framework for Cross-Sector Partnerships to Address Childhood Adversity and Improve Life Course Health.

Childhood adversity and its structural causes drive lifelong and intergenerational inequities in health and well-being. Health care systems increasingly understand the influence of childhood adversity on health outcomes but cannot treat these deep and complex issues alone. Cross-sector partnerships, which integrate health care, food support, legal, housing, and financial services among others, are becoming increasingly recognized as effective approaches address health inequities. What principles should guide the design of cross-sector partnerships that address childhood adversity and promote Life Course Health Development (LCHD)? The complex effects of childhood adversity on health development are explained by LCHD concepts, which serve as the foundation for a cross-sector partnership that optimizes lifelong health. We review the evolution of cross-sector partnerships in health care to inform the development of an LCHD-informed partnership framework geared to address childhood adversity and LCHD. This framework outlines guiding principles to direct partnerships toward life course-oriented action: (1) proactive, developmental, and longitudinal investment; (2) integration and codesign of care networks; (3) collective, community and systemic impact; and (4) equity in praxis and outcomes. Additionally, the framework articulates foundational structures necessary for implementation: (1) a shared cross-sector theory of change; (2) relational structures enabling shared leadership, trust, and learning; (3) linked data and communication platforms; and (4) alternative funding models for shared savings and prospective investment. The LCHD-informed cross-sector partnership framework presented here can be a guide for the design and implementation of cross-sector partnerships that effectively address childhood adversity and advance health equity through individual-, family-, community-, and system-level intervention.

Assessment of Hypothetical Out-of-Pocket Costs of Guideline-Recommended Medications for the Treatment of Older Adults With Multiple Chronic Conditions, 2009 and 2019.

IMPORTANCE: Most adults 65 years or older have multiple chronic conditions. Managing these conditions with prescription drugs can be costly, particularly for older adults with limited incomes. OBJECTIVE: To estimate hypothetical out-of-pocket costs associated with guideline-recommended outpatient medications for the initial treatment of 8 common chronic diseases among older adults with Medicare prescription drug plans (PDPs). DESIGN, SETTING, AND PARTICIPANTS: This retrospective cross-sectional study used 2009 and 2019 Medicare prescription drug plan formulary files to estimate annual out-of-pocket costs among hypothetical patients enrolled in Medicare Advantage or stand-alone Medicare Part D plans. A total of 3599 PDPs in 2009 and 3618 PDPs in 2019 were included after inclusion and exclusion criteria were applied. Costs associated with guideline-recommended medications for 8 of the most common chronic diseases (atrial fibrillation, chronic obstructive pulmonary disease [COPD], heart failure with reduced ejection fraction, hypercholesterolemia, hypertension, osteoarthritis, osteoporosis, and type 2 diabetes), alone and in 2 clusters of commonly comorbid conditions, were examined. MAIN OUTCOMES AND MEASURES: Annual out-of-pocket costs for each chronic condition, inflation adjusted to 2019 dollars. RESULTS: Among 3599 Medicare PDPs in 2009, 1998 were Medicare Advantage plans and 1601 were stand-alone plans; among 3618 Medicare PDPs in 2019, 2719 were Medicare Advantage plans and 899 were stand-alone plans. For an older adult enrolled in any Medicare PDP in 2019, the median annual out-of-pocket costs for individual conditions varied, from a minimum of $32 (IQR, $6-$48) for guideline-recommended management of osteoporosis (a decrease from $128 [IQR, $102-$183] in 2009) to a maximum of $1579 (IQR, $1524-$2229) for guideline-recommended management of atrial fibrillation (an increase from $91 [IQR, $73-$124] in 2009). For an older adult with a cluster of 5 commonly comorbid conditions (COPD, hypertension, osteoarthritis, osteoporosis, and type 2 diabetes) enrolled in any PDP, the median out-of-pocket cost in 2019 was $1999 (IQR, $1630-$2564), a 12% decrease from $2284 (IQR, $1920-$3107) in 2009. For an older adult with all 8 chronic conditions (atrial fibrillation, COPD, diabetes, hypercholesterolemia, heart failure, hypertension, osteoarthritis, and osteoporosis) enrolled in any PDP, the median out-of-pocket cost in 2019 was $3630 (IQR, $3234-$5197), a 41% increase from $2571 (IQR, $2185-$3719) in 2009. CONCLUSIONS AND RELEVANCE: In this cross-sectional study, out-of-pocket costs for guideline-recommended outpatient medications for the initial treatment of 8 common chronic diseases varied by condition. Although costs generally decreased between 2009 and 2019, particularly with regard to conditions for which generic drugs were available, out-of-pocket costs remained high and may have presented a substantial financial burden for Medicare beneficiaries, especially older adults with conditions for which brand-name drugs were guideline recommended.

Interest in Clinic-Based Financial Services among Low-Income Prenatal Patients and its Association with Health-Related Social Risk Factors.

BACKGROUND: Poverty and financial stress affect prenatal health and well-being as well as early childhood development. This study sought to examine interest in clinic-based financial services to address financial stress in low-income, Medicaid-enrolled prenatal patients and its relationship with self-reported social risks. METHODS: We conducted a cross-sectional study of patients at a large safety-net prenatal clinic. Participants completed a written survey on interest in linkage to financial services, poverty-related financial stress, difficulty affording social needs, and interest in services to address material hardships. We compared interest in financial and social needs services by level of financial stress using multivariate regression. RESULTS: Respondents (N = 108) were entirely Medicaid-enrolled, with a majority identifying as Hispanic/Latinx (57%) or Black/African American (20%). Sixty-four percent indicated interest in connection to any of the financial services surveyed. Interest was highest in employment (52%), savings and budgeting (49%), job training/adult education (49%), and financial counseling (48%) services. Individuals with high financial stress, compared to those with low financial stress, expressed a higher level of interest in financial services (aRR = 1.61 [95% CI 1.12-2.39]). Interest in financial services was associated with difficulty affording social needs (aRR = 2.24 [95% CI 1.33-4.43]) and interest in services addressing social needs (aRR = 1.45 [95% CI 1.13-1.92]). CONCLUSION: In this study of low-income, Medicaid-insured prenatal patients, there was a high degree of interest in clinic-based financial services. Integrating financial services into prenatal health care appears to be an approach that low-income patients would be interested in to directly address poverty and financial stress.

High dose escalation of intracoronary adenosine in the assessment of fractional flow reserve: A retrospective cohort study.

Maximal hyperaemia for fractional flow reserve (FFR) may not be achieved with the current recommended doses of intracoronary adenosine. Higher doses (up to 720 µg) have been reported to optimize hyperaemic stimuli in small dose-response studies. Real-world data from a large cohort of patients is needed to evaluate FFR results and the safety of high-dose escalation. This is a retrospective study aimed to evaluate the safety and frequency of FFR ≤0.8 after high-dose escalation of intracoronary adenosine. Data were extracted from the medical databases of two university hospitals. Increasing doses (100, 200, 400, 600, and 800 µg) of adenosine were administered as intracoronary boluses until FFR ≤0.8 was achieved or heart block developed. The percentage of FFR ≤0.8 after higher-dose escalation was compared with those at conventional doses, and the predictors for FFR ≤0.8 after higher doses were analysed. In the 1163 vessels of 878 patients, 402 vessels (34.6%) achieved FFR ≤0.8 at conventional doses and 623 vessels (53.6%) received high-dose escalation. An additional 84 vessels (13.5%) achieved FFR ≤0.8 after high-dose escalation. No major complications developed during high-dose escalation. Borderline FFR (0.81-0.85) at the conventional dose, stenosis >60%, and triple-vessel disease increased the likelihood of FFR ≤0.8 after high-dose escalation, but chronic kidney disease decreased it. For vessels of borderline FFR at conventional doses, 46% achieved FFR ≤0.8 after high-dose escalation. In conclusion, High-dose escalation of intracoronary adenosine increases the frequency of FFR ≤0.8 without major complications. It could be especially feasible for borderline FFR values near the 0.8 diagnostic threshold.

Medicare Prescription Drug Plan Coverage of Hormone Therapies Used by Transgender Individuals.

Purpose: Although pharmacologic hormone therapy represents one of the mainstays of gender-affirming therapy for transgender individuals, there are many access barriers for these therapies, including insurance coverage of these drugs. The purpose of this study was to examine Medicare coverage of hormone therapies used by transgender individuals. Methods: Using Centers for Medicare and Medicaid Services prescription drug plan formulary files, we determined plan coverage, coverage restrictions, and out-of-pocket (OOP) costs for all 10 drugs recommended in the 2009 and 2017 Endocrine Society treatment guidelines for transgender patients. Results: For masculinizing therapies, the proportion of plans providing unrestricted coverage ranged from 22% to 79% in 2010 and from 5% to 75% in 2018. For feminizing therapies, the proportion providing unrestricted coverage ranged from 24% to 100% in 2010 and from 13% to 100% in 2018. Median annual OOP costs for masculinizing therapies ranged from $232 to $1112 in 2010 and from $180 to $2176 in 2018. For feminizing therapies, OOP costs ranged from $84 to $2716 in 2010 and from $72 to $3792 in 2018. Conclusion: Our findings highlight the variability in access to guideline-recommended hormone therapies for individuals insured through Medicare.

Prostaglandin Coverage and Costs to Medicare and Medicare Beneficiaries, 2009-2017.

BACKGROUND: Prostaglandin analogs are the most effective treatment for glaucoma, a common condition among older adults. Despite the availability of generic drugs, the costs associated with these prescription drugs are rising. OBJECTIVE: To characterize Medicare prescription drug plan (PDP) formulary coverage and beneficiary out-of-pocket cost for prostaglandin analogs from 2009 to 2017 and Medicare spending on prostaglandin analogs from 2013 to 2017. METHODS: This study was a retrospective analysis. We used 2009, 2013, and 2017 Medicare PDP formulary, beneficiary cost, and pricing files to determine beneficiary first-prescription out-of-pocket costs and plan coverage (unrestricted, restricted, or not covered) of branded latanoprost 0.005%, travoprost 0.004%, bimatoprost 0.03% and 0.01%, and tafluprost 0.0015% and of generic latanoprost 0.005% and generic bimatoprost 0.03%. We also used Medicare Part D spending data to determine aggregate spend in 2013 and 2017. RESULTS: In 2009, 92% of plans covered branded latanoprost, 83% covered branded bimatoprost; and 49% covered branded travoprost, whereas in 2017, 6% of plans covered branded latanoprost; 95% covered branded bimatoprost; and 96% covered branded travoprost. Although generic latanoprost was universally covered, generic bimatoprost was only covered by 35% of plans in 2017. Median out-of-pocket cost of branded prostaglandins without generic equivalents was $35 (IQR = $29-$40) in 2009, $45 (IQR = $42-$101) in 2013, and $90 (IQR = $45-$159) in 2017. Median out-of-pocket cost of all available generic prostaglandins was $10 (IQR = $5-$33) in 2013 and $10 (IQR = $4-$15) in 2017. In 2013, Medicare spent $733 million on prostaglandin analogs; in 2017, this increased to $1.09 billion, with $943 million (86%) spent on branded prostaglandins and $148 million (14%) spent on generics. CONCLUSIONS: Medicare PDP coverage of branded prostaglandins remained stable from 2009 to 2017. While median beneficiary out-of-pocket costs associated with generic prostaglandins remained stable, those associated with branded prostaglandins increased nearly 3-fold. DISCLOSURES: Research reported in this publication was supported by National Heart, Lung and Blood Institute of the National Institutes of Health under Award Number T35HL007649. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Heart, Lung, and Blood Institute or the National Institutes of Health. Shah has received research support through Mayo Clinic from the U.S. Food and Drug Administration (FDA) to establish Yale-Mayo Clinic Center for Excellence in Regulatory Science and Innovation (CERSI) program (U01FD005938); the Centers of Medicare and Medicaid Innovation under the Transforming Clinical Practice Initiative (TCPI); the Agency for Healthcare Research and Quality (U19HS024075, R01HS025164, R01HS025402, R03HS025517); and the National Heart, Lung and Blood Institute of the National Institutes of Health (NIH) (R56HL130496, R01HL131535), National Science Foundation, and the Patient Centered Outcomes Research Institute to develop a clinical data research network. Ross has received research support through Yale University from Johnson & Johnson to develop methods of clinical trial data sharing; Medtronic and the FDA to develop methods for postmarket surveillance of medical devices (U01FD004585); the FDA to establish Yale-Mayo Clinic Center for Excellence in Regulatory Science and Innovation program (U01FD005938); the Blue Cross Blue Shield Association to better understand medical technology evaluation; the Centers of Medicare & Medicaid Services to develop and maintain performance measures that are used for public reporting (HHSM-500-2013-13018I); the Agency for Healthcare Research and Quality (R01HS022882); the National Heart, Lung and Blood Institute of the NIH (R01HS025164); and the Laura and John Arnold Foundation to establish the Good Pharma Scorecard at Bioethics International and the Collaboration on Research Integrity and Transparency at Yale. The other authors have nothing to disclose.

Medicare beneficiaries' out-of-pocket costs for commonly used generic drugs, 2009-2017.

OBJECTIVES: To examine differences in the out-of-pocket costs for common generic drugs used to treat chronic conditions when individuals used their Medicare prescription drug plan (PDP) or when purchased through Walmart's generic drug discount programs (GDDPs) from 2009 to 2017. STUDY DESIGN: A retrospective analysis of Medicare PDP Formulary files and Walmart's GDDP retail drug lists from 2009 to 2017. METHODS: We identified all generic drugs used to treat chronic conditions that were on Walmart's GDDP retail drug list from 2009 to 2017. We then determined the out-of-pocket costs for each drug for each Medicare PDP and compared those costs with Walmart's GDDP cash price. RESULTS: There were 62 and 43 generic medications used to treat common chronic diseases available through Walmart's GDDP in 2009 and 2017, respectively. Across all PDPs, the median beneficiary out-of-pocket expenditure for a 30-day supply of the GDDP-available medications for chronic diseases decreased from $5.70 (interquartile range [IQR], $2.55-$7.98) in 2009 to $2.00 (IQR, $0.00-$4.00) in 2017 (P <.001) Approximately three-fifths (60.2%) of PDPs required beneficiaries to pay out-of-pocket costs higher than those of Walmart's GDDP in 2009, but only one-third (33.4%) did so in 2017. CONCLUSIONS: Although Medicare beneficiary out-of-pocket costs for commonly used generic drug prescriptions generally decreased over time, Medicare beneficiaries may still be paying more for the same drugs than they would through Walmart's GDDP. Increased generic drug price transparency, including enforcing bans on gag clauses, is needed to ensure that Medicare beneficiaries obtain drugs using the most affordable options.

Mapping diphtheria-pertussis-tetanus vaccine coverage in Africa, 2000-2016: a spatial and temporal modelling study.

BACKGROUND: Routine childhood vaccination is among the most cost-effective, successful public health interventions available. Amid substantial investments to expand vaccine delivery throughout Africa and strengthen administrative reporting systems, most countries still require robust measures of local routine vaccine coverage and changes in geographical inequalities over time. METHODS: This analysis drew from 183 surveys done between 2000 and 2016, including data from 881 268 children in 49 African countries. We used a Bayesian geostatistical model calibrated to results from the Global Burden of Diseases, Injuries, and Risk Factors Study 2017, to produce annual estimates with high-spatial resolution (5 ×    5 km) of diphtheria-pertussis-tetanus (DPT) vaccine coverage and dropout for children aged 12-23 months in 52 African countries from 2000 to 2016. FINDINGS: Estimated third-dose (DPT3) coverage increased in 72·3% (95% uncertainty interval [UI] 64·6-80·3) of second-level administrative units in Africa from 2000 to 2016, but substantial geographical inequalities in DPT coverage remained across and within African countries. In 2016, DPT3 coverage at the second administrative (ie, district) level varied by more than 25% in 29 of 52 countries, with only two (Morocco and Rwanda) of 52 countries meeting the Global Vaccine Action Plan target of 80% DPT3 coverage or higher in all second-level administrative units with high confidence (posterior probability ≥95%). Large areas of low DPT3 coverage (≤50%) were identified in the Sahel, Somalia, eastern Ethiopia, and in Angola. Low first-dose (DPT1) coverage (≤50%) and high relative dropout (≥30%) together drove low DPT3 coverage across the Sahel, Somalia, eastern Ethiopia, Guinea, and Angola. INTERPRETATION: Despite substantial progress in Africa, marked national and subnational inequalities in DPT coverage persist throughout the continent. These results can help identify areas of low coverage and vaccine delivery system vulnerabilities and can ultimately support more precise targeting of resources to improve vaccine coverage and health outcomes for African children. FUNDING: Bill & Melinda Gates Foundation.

Forecasting life expectancy, years of life lost, and all-cause and cause-specific mortality for 250 causes of death: reference and alternative scenarios for 2016-40 for 195 countries and territories.

BACKGROUND: Understanding potential trajectories in health and drivers of health is crucial to guiding long-term investments and policy implementation. Past work on forecasting has provided an incomplete landscape of future health scenarios, highlighting a need for a more robust modelling platform from which policy options and potential health trajectories can be assessed. This study provides a novel approach to modelling life expectancy, all-cause mortality and cause of death forecasts -and alternative future scenarios-for 250 causes of death from 2016 to 2040 in 195 countries and territories. METHODS: We modelled 250 causes and cause groups organised by the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) hierarchical cause structure, using GBD 2016 estimates from 1990-2016, to generate predictions for 2017-40. Our modelling framework used data from the GBD 2016 study to systematically account for the relationships between risk factors and health outcomes for 79 independent drivers of health. We developed a three-component model of cause-specific mortality: a component due to changes in risk factors and select interventions; the underlying mortality rate for each cause that is a function of income per capita, educational attainment, and total fertility rate under 25 years and time; and an autoregressive integrated moving average model for unexplained changes correlated with time. We assessed the performance by fitting models with data from 1990-2006 and using these to forecast for 2007-16. Our final model used for generating forecasts and alternative scenarios was fitted to data from 1990-2016. We used this model for 195 countries and territories to generate a reference scenario or forecast through 2040 for each measure by location. Additionally, we generated better health and worse health scenarios based on the 85th and 15th percentiles, respectively, of annualised rates of change across location-years for all the GBD risk factors, income per person, educational attainment, select intervention coverage, and total fertility rate under 25 years in the past. We used the model to generate all-cause age-sex specific mortality, life expectancy, and years of life lost (YLLs) for 250 causes. Scenarios for fertility were also generated and used in a cohort component model to generate population scenarios. For each reference forecast, better health, and worse health scenarios, we generated estimates of mortality and YLLs attributable to each risk factor in the future. FINDINGS: Globally, most independent drivers of health were forecast to improve by 2040, but 36 were forecast to worsen. As shown by the better health scenarios, greater progress might be possible, yet for some drivers such as high body-mass index (BMI), their toll will rise in the absence of intervention. We forecasted global life expectancy to increase by 4·4 years (95% UI 2·2 to 6·4) for men and 4·4 years (2·1 to 6·4) for women by 2040, but based on better and worse health scenarios, trajectories could range from a gain of 7·8 years (5·9 to 9·8) to a non-significant loss of 0·4 years (-2·8 to 2·2) for men, and an increase of 7·2 years (5·3 to 9·1) to essentially no change (0·1 years [-2·7 to 2·5]) for women. In 2040, Japan, Singapore, Spain, and Switzerland had a forecasted life expectancy exceeding 85 years for both sexes, and 59 countries including China were projected to surpass a life expectancy of 80 years by 2040. At the same time, Central African Republic, Lesotho, Somalia, and Zimbabwe had projected life expectancies below 65 years in 2040, indicating global disparities in survival are likely to persist if current trends hold. Forecasted YLLs showed a rising toll from several non-communicable diseases (NCDs), partly driven by population growth and ageing. Differences between the reference forecast and alternative scenarios were most striking for HIV/AIDS, for which a potential increase of 120·2% (95% UI 67·2-190·3) in YLLs (nearly 118 million) was projected globally from 2016-40 under the worse health scenario. Compared with 2016, NCDs were forecast to account for a greater proportion of YLLs in all GBD regions by 2040 (67·3% of YLLs [95% UI 61·9-72·3] globally); nonetheless, in many lower-income countries, communicable, maternal, neonatal, and nutritional (CMNN) diseases still accounted for a large share of YLLs in 2040 (eg, 53·5% of YLLs [95% UI 48·3-58·5] in Sub-Saharan Africa). There were large gaps for many health risks between the reference forecast and better health scenario for attributable YLLs. In most countries, metabolic risks amenable to health care (eg, high blood pressure and high plasma fasting glucose) and risks best targeted by population-level or intersectoral interventions (eg, tobacco, high BMI, and ambient particulate matter pollution) had some of the largest differences between reference and better health scenarios. The main exception was sub-Saharan Africa, where many risks associated with poverty and lower levels of development (eg, unsafe water and sanitation, household air pollution, and child malnutrition) were projected to still account for substantive disparities between reference and better health scenarios in 2040. INTERPRETATION: With the present study, we provide a robust, flexible forecasting platform from which reference forecasts and alternative health scenarios can be explored in relation to a wide range of independent drivers of health. Our reference forecast points to overall improvements through 2040 in most countries, yet the range found across better and worse health scenarios renders a precarious vision of the future-a world with accelerating progress from technical innovation but with the potential for worsening health outcomes in the absence of deliberate policy action. For some causes of YLLs, large differences between the reference forecast and alternative scenarios reflect the opportunity to accelerate gains if countries move their trajectories toward better health scenarios-or alarming challenges if countries fall behind their reference forecasts. Generally, decision makers should plan for the likely continued shift toward NCDs and target resources toward the modifiable risks that drive substantial premature mortality. If such modifiable risks are prioritised today, there is opportunity to reduce avoidable mortality in the future. However, CMNN causes and related risks will remain the predominant health priority among lower-income countries. Based on our 2040 worse health scenario, there is a real risk of HIV mortality rebounding if countries lose momentum against the HIV epidemic, jeopardising decades of progress against the disease. Continued technical innovation and increased health spending, including development assistance for health targeted to the world's poorest people, are likely to remain vital components to charting a future where all populations can live full, healthy lives. FUNDING: Bill & Melinda Gates Foundation.

Immunogenicity assessment of tbo-filgrastim in cancer patients receiving chemotherapy.

AIM: This integrated analysis examined the immunogenicity of tbo-filgrastim and its potential clinical impact in three Phase III randomized studies in patients with breast cancer, lung cancer and non-Hodgkin lymphoma receiving chemotherapy. RESULTS: Treatment-emergent antidrug antibodies (ADA) occurred in 3/213 (1.4%) breast cancer patients, 2/160 (1.3%) lung cancer patients and 1/63 (1.6%) patients with non-Hodgkin lymphoma. None of the treatment-emergent ADA showed cross-reactivity toward native granulocyte-colony stimulating factors or exhibited neutralizing activity against tbo-filgrastim. Among patients with treatment-emergent ADA, there was no treatment-related hypersensitivity or anaphylaxis and no evidence of loss of clinical efficacy. CONCLUSION: Tbo-filgrastim has demonstrated low immunogenicity in cancer patients receiving chemotherapy and ADA response does not impact safety and efficacy in the patients.

Method establishment for discerned immunogenicity assessment of a recombinant glycoprotein containing nonhuman sialic acid Neu5Gc residues.

AIM: Recombinant glycoprotein produced in nonhuman mammalian cell lines can be modified with the immunogenic nonhuman sialic N-glycolylneuraminic acid (Neu5Gc). We describe here a validated method for detection of antidrug antibodies against both protein and Neu5Gc-containing glycan epitopes. RESULTS: An electrochemiluminescent method was established with drug conjugates as capture and detection reagents. Rabbit antidrug polyclonal antibodies were used as the positive control for protein moiety-specific antibodies, while chicken anti-Neu5Gc polyclonal antibodies were used as the positive control for antibodies against Neu5Gc glycan epitope. Specificity to Neu5Gc was verified by signal inhibition with bovine γ-globulin that contains Neu5Gc. CONCLUSION: The assay illustrated here discerns the immunogenicity of the protein backbone and the sialic acid Neu5Gc glycan moiety of a recombinant protein containing Neu5Gc.

Global Burden of Hypertension and Systolic Blood Pressure of at Least 110 to 115 mm Hg, 1990-2015.

Importance: Elevated systolic blood (SBP) pressure is a leading global health risk. Quantifying the levels of SBP is important to guide prevention policies and interventions. Objective: To estimate the association between SBP of at least 110 to 115 mm Hg and SBP of 140 mm Hg or higher and the burden of different causes of death and disability by age and sex for 195 countries and territories, 1990-2015. Design: A comparative risk assessment of health loss related to SBP. Estimated distribution of SBP was based on 844 studies from 154 countries (published 1980-2015) of 8.69 million participants. Spatiotemporal Gaussian process regression was used to generate estimates of mean SBP and adjusted variance for each age, sex, country, and year. Diseases with sufficient evidence for a causal relationship with high SBP (eg, ischemic heart disease, ischemic stroke, and hemorrhagic stroke) were included in the primary analysis. Main Outcomes and Measures: Mean SBP level, cause-specific deaths, and health burden related to SBP (≥110-115 mm Hg and also ≥140 mm Hg) by age, sex, country, and year. Results: Between 1990-2015, the rate of SBP of at least 110 to 115 mm Hg increased from 73 119 (95% uncertainty interval [UI], 67 949-78 241) to 81 373 (95% UI, 76 814-85 770) per 100 000, and SBP of 140 mm Hg or higher increased from 17 307 (95% UI, 17 117-17 492) to 20 526 (95% UI, 20 283-20 746) per 100 000. The estimated annual death rate per 100 000 associated with SBP of at least 110 to 115 mm Hg increased from 135.6 (95% UI, 122.4-148.1) to 145.2 (95% UI 130.3-159.9) and the rate for SBP of 140 mm Hg or higher increased from 97.9 (95% UI, 87.5-108.1) to 106.3 (95% UI, 94.6-118.1). For loss of DALYs associated with systolic blood pressure of 140 mm Hg or higher, the loss increased from 95.9 million (95% uncertainty interval [UI], 87.0-104.9 million) to 143.0 million (95% UI, 130.2-157.0 million) [corrected], and for SBP of 140 mm Hg or higher, the loss increased from 5.2 million (95% UI, 4.6-5.7 million) to 7.8 million (95% UI, 7.0-8.7 million). The largest numbers of SBP-related deaths were caused by ischemic heart disease (4.9 million [95% UI, 4.0-5.7 million]; 54.5%), hemorrhagic stroke (2.0 million [95% UI, 1.6-2.3 million]; 58.3%), and ischemic stroke (1.5 million [95% UI, 1.2-1.8 million]; 50.0%). In 2015, China, India, Russia, Indonesia, and the United States accounted for more than half of the global DALYs related to SBP of at least 110 to 115 mm Hg. Conclusions and Relevance: In international surveys, although there is uncertainty in some estimates, the rate of elevated SBP (≥110-115 and ≥140 mm Hg) increased substantially between 1990 and 2015, and DALYs and deaths associated with elevated SBP also increased. Projections based on this sample suggest that in 2015, an estimated 3.5 billion adults had SBP of at least 110 to 115 mm Hg and 874 million adults had SBP of 140 mm Hg or higher.

Immunogenicity Assessment of Lipegfilgrastim in Patients with Breast Cancer Receiving Chemotherapy.

Lipegfilgrastim is a long-acting, once-per-cycle, glycopegylated recombinant granulocyte colony-stimulating factor (G-CSF) used to prevent neutropenia in patients receiving myelosuppressive chemotherapy. This integrated analysis examined the immunogenicity of lipegfilgrastim and its potential clinical impact in two double-blind randomized studies (phases II and III) of patients with breast cancer receiving chemotherapy. Serum samples were analyzed using sequential assays for screening, confirmation, antibody titer, and characterization of antidrug antibodies (ADA). Neutropenia-related efficacy measures were reviewed for each ADA-positive patient. Among 255 patients receiving lipegfilgrastim (154 in phase II, 101 in phase III) and 155 patients receiving pegfilgrastim (54 in phase II, 101 in phase III), the incidence of treatment-emergent ADA was low and similar between the lipegfilgrastim (phase II: 1.3%; phase III: 1.0%) and pegfilgrastim (phase II: 1.9%; phase III: 1.0%) arms. None of the treatment-emergent ADA-positive samples exhibited neutralizing activity against lipegfilgrastim, pegfilgrastim, or glycosylated G-CSF in a cell-based neutralizing antibody assay. No changes were observed in neutropenia-related efficacy measures among ADA-positive patients, and no treatment-related hypersensitivity or anaphylaxis occurred. These results indicate that there is no apparent impact of ADA on lipegfilgrastim efficacy and safety.

Vaccine Assistance To Low- And Middle-Income Countries Increased To $3.6 Billion In 2014.

In the 2012 Global Vaccine Action Plan, development assistance partners committed to providing sustainable financing for vaccines and expanding vaccination coverage to all children in low- and middle-income countries by 2020. To assess progress toward these goals, the Institute for Health Metrics and Evaluation produced estimates of development assistance for vaccinations. These estimates reveal major increases in the assistance provided since 2000. In 2014, $3.6 billion in development assistance for vaccinations was provided for low- and middle-income countries, up from $822 million in 2000. The funding increase was driven predominantly by the establishment of Gavi, the Vaccine Alliance, supported by the Bill & Melinda Gates Foundation and the governments of the United States and United Kingdom. Despite stagnation in total development assistance for health from donors from 2010 onward, development assistance for vaccination has continued to grow.

Comparative immunogenicity assessment: a critical consideration for biosimilar development.

An appropriate assessment strategy with validated anti-drug antibody (ADA) assays is critical for comparative evaluation of immunogenicity between a proposed biosimilar and its reference product. The strategy should aim to identify potential differences in immune responses between these products. While an ADA assay employing the proposed biosimilar product as the detecting reagent has been generally recommended for such evaluation, a product-specific assay using the product of interest may be of use as it offers a capability of detecting antibodies against specific epitopes from the respective product. Regardless of assay strategy, the performance of the assay must be fully assessed and method needs to be validated to meet the comparative purpose of immunogenicity assessment.

Impact of a quality assessment program on radiologist performance in ultrasound-guided renal transplant biopsy.

PURPOSE: The purpose of this study was to analyze the impact of a quality assessment (QA) program on radiologist performance in ultrasound-guided renal transplant biopsy. METHODS: The numbers of glomeruli and small arteries obtained during ultrasound-guided renal transplant biopsy of all consecutive patients performed by any of 8 radiologists in an ultrasound section between September 1, 2007, and May 31, 2010, were recorded. Procedural success was assessed using Banff 97 criteria. Two subgroups were defined on the basis of each radiologist's approximate fractional full-time equivalent effort in the section, with 2 radiologists who were engaged 100% of their clinical noncall time in the ultrasound section constituting the primary ultrasound subgroup and 6 radiologists who were engaged <25% of their clinical noncall time in the ultrasound section constituting the secondary ultrasound subgroup. The biopsy success rate for individuals, subgroups, and the entire section for 9 months before (pre-QA) and 24 months after (post-QA) the onset of quarterly dissemination of the QA data was analyzed. RESULTS: Of 339 biopsies in the pre-QA period, 90.5% were successful. Of 1,063 biopsies in the post-QA period, 96.0% were successful (P < .001). The pre-QA individual radiologist success rates ranged between 71.4% and 96.7% (mean, 86.2 ± 10.3%). The post-QA individual radiologist success rates ranged between 80.0% and 97.9% (mean, 92.5 ± 6.6%). The primary ultrasound subgroup success rate increased from 93.4% to 97.5% (P = .005). The secondary ultrasound subgroup success rate increased from 85.7% to 93.8% (P = .004). CONCLUSIONS: A renal transplant biopsy QA program improves operator performance.