A Longitudinal Clinical Trajectory Analysis Examining the Accumulation of Co-morbidity in People with Type 2 Diabetes (T2D) Compared with Non-T2D Individuals.

BACKGROUND: Type 2 diabetes mellitus (T2D) is commonly associated with an increasing complexity of multimorbidity. While some progress has been made in identifying genetic and non-genetic risk factors for T2D, understanding the longitudinal clinical history of individuals before/after T2D diagnosis may provide additional insights. METHODS: In this study, we utilised longitudinal data from the DARE (Diabetes Alliance for Research in England) study to examine the trajectory of clinical conditions in individuals with and without T2D. Data from 1932 individuals (T2D n = 1196 vs. matched non-T2D controls n = 736) were extracted and subjected to trajectory analysis over a period of up to 50 years (25 years pre-diagnosis/25 years post-diagnosis). We also analysed the cumulative proportion of people with diagnosed coronary artery disease (CAD) in their general practice (GP) record with an analysis of lower respiratory tract infection (RTI) as a comparator group. RESULTS: The mean age of diagnosis of T2D was 52.6 (95% confidence interval 52.0-53.4) years. In the years leading up to T2D diagnosis, individuals who eventually received a T2D diagnosis consistently exhibited a considerable increase in several clinical phenotypes. Additionally, immediately prior to T2D diagnosis, a significantly greater prevalence of hypertension (35%)/RTI (34%)/heart conditions (17%)/eye, nose, throat infection (19%) and asthma (12%) were observed. The corresponding trajectory of each of these conditions was much less dramatic in the matched controls. Post-T2D diagnosis, proportions of T2D individuals exhibiting hypertension/chronic kidney disease/retinopathy/infections climbed rapidly before plateauing. At the last follow-up by quintile of disadvantage, the proportion (%) of people with diagnosed CAD was 6.4% for quintile 1 (least disadvantaged) and 11% for quintile 5 (F = 3.4, p = 0.01 for the difference between quintiles). CONCLUSION: These findings provide novel insights into the onset/natural progression of T2D, suggesting an early phase of inflammation-related disease activity before any clinical diagnosis of T2D is made. Measures that reduce social inequality have the potential in the longer term to reduce the social gradient in health outcomes reported here.

Evaluating socioeconomic inequalities in influenza vaccine uptake during the COVID-19 pandemic: A cohort study in Greater Manchester, England.

BACKGROUND: There are known socioeconomic inequalities in annual seasonal influenza (flu) vaccine uptake. The Coronavirus Disease 2019 (COVID-19) pandemic was associated with multiple factors that may have affected flu vaccine uptake, including widespread disruption to healthcare services, changes to flu vaccination eligibility and delivery, and increased public awareness and debate about vaccination due to high-profile COVID-19 vaccination campaigns. However, to the best of our knowledge, no existing studies have investigated the consequences for inequalities in flu vaccine uptake, so we aimed to investigate whether socioeconomic inequalities in flu vaccine uptake have widened since the onset of the COVID-19 pandemic. METHODS AND FINDINGS: We used deidentified data from electronic health records for a large city region (Greater Manchester, population 2.8 million), focusing on 3 age groups eligible for National Health Service (NHS) flu vaccination: preschool children (age 2 to 3 years), primary school children (age 4 to 9 years), and older adults (age 65 years plus). The sample population varied between 418,790 (2015/16) and 758,483 (2021/22) across each vaccination season. We estimated age-adjusted neighbourhood-level income deprivation-related inequalities in flu vaccine uptake using Cox proportional hazards models and the slope index of inequality (SII), comparing 7 flu vaccination seasons (2015/16 to 2021/22). Among older adults, the SII (i.e., the gap in uptake between the least and most income-deprived areas) doubled over the 7 seasons from 8.48 (95% CI [7.91,9.04]) percentage points to 16.91 (95% CI [16.46,17.36]) percentage points, with approximately 80% of this increase occurring during the pandemic. Before the pandemic, income-related uptake gaps were wider among children, ranging from 15.59 (95% CI [14.52,16.67]) percentage points to 20.07 (95% CI [18.94,21.20]) percentage points across age groups and vaccination seasons. Among preschool children, the uptake gap increased in 2020/21 to 25.25 (95% CI [24.04,26.45]) percentage points, before decreasing to 20.86 (95% CI [19.65,22.05]) percentage points in 2021/22. Among primary school children, inequalities increased in both pandemic years to reach 30.27 (95% CI [29.58,30.95]) percentage points in 2021/22. Although vaccine uptake increased during the pandemic, disproportionately larger increases in uptake in less deprived areas created wider inequalities in all age groups. The main limitation of our approach is the use of a local dataset, which may limit generalisability to other geographical settings. CONCLUSIONS: The COVID-19 pandemic led to increased inequalities in flu vaccine uptake, likely due to changes in demand for vaccination, new delivery models, and disruptions to healthcare and schooling. It will be important to investigate the causes of these increased inequalities and to examine whether these increased inequalities also occurred in the uptake of other routine vaccinations. These new wider inequalities in flu vaccine uptake may exacerbate inequalities in flu-related morbidity and mortality.

Energy budget diagnosis of changing climate feedback.

The climate feedback determines how Earth's climate responds to anthropogenic forcing. It is thought to have been more negative in recent decades due to a sea surface temperature "pattern effect," whereby warming is concentrated in the western tropical Pacific, where nonlocal radiative feedbacks are very negative. This phenomenon has however primarily been studied within climate models. We diagnose a pattern effect from historical records as an evolution of the climate feedback over the past five decades. Our analysis assumes a constant rate of change of the climate feedback, which is justified post hoc. We find a decrease in climate feedback by 0.8 ± 0.5 W m-2 K-1 over the past 50 years, corresponding to a reduction in climate sensitivity. Earth system models' climate feedbacks instead increase over this period. Understanding and simulating this historical trend and its future evolution are critical for reliable climate projections.

Traction of 3D and 4D Printing in the Healthcare Industry: From Drug Delivery and Analysis to Regenerative Medicine.

Three-dimensional (3D) printing and 3D bioprinting are promising technologies for a broad range of healthcare applications from frontier regenerative medicine and tissue engineering therapies to pharmaceutical advancements yet must overcome the challenges of biocompatibility and resolution. Through comparison of traditional biofabrication methods with 3D (bio)printing, this review highlights the promise of 3D printing for the production of on-demand, personalized, and complex products that enhance the accessibility, effectiveness, and safety of drug therapies and delivery systems. In addition, this review describes the capacity of 3D bioprinting to fabricate patient-specific tissues and living cell systems (e.g., vascular networks, organs, muscles, and skeletal systems) as well as its applications in the delivery of cells and genes, microfluidics, and organ-on-chip constructs. This review summarizes how tailoring selected parameters (i.e., accurately selecting the appropriate printing method, materials, and printing parameters based on the desired application and behavior) can better facilitate the development of optimized 3D-printed products and how dynamic 4D-printed strategies (printing materials designed to change with time or stimulus) may be deployed to overcome many of the inherent limitations of conventional 3D-printed technologies. Comprehensive insights into a critical perspective of the future of 4D bioprinting, crucial requirements for 4D printing including the programmability of a material, multimaterial printing methods, and precise designs for meticulous transformations or even clinical applications are also given.

Correction: Ethnic inequalities in COVID-19 vaccine uptake and comparison to seasonal influenza vaccine uptake in Greater Manchester, UK: A cohort study.

[This corrects the article DOI: 10.1371/journal.pmed.1003932.].

Ethnic inequalities in COVID-19 vaccine uptake and comparison to seasonal influenza vaccine uptake in Greater Manchester, UK: A cohort study.

BACKGROUND: COVID-19 vaccine uptake is lower amongst most minority ethnic groups compared to the White British group in England, despite higher COVID-19 mortality rates. Here, we add to existing evidence by estimating inequalities for 16 minority ethnic groups, examining ethnic inequalities within population subgroups, and comparing the magnitudes of ethnic inequalities in COVID-19 vaccine uptake to those for routine seasonal influenza vaccine uptake. METHODS AND FINDINGS: We conducted a retrospective cohort study using the Greater Manchester Care Record, which contains de-identified electronic health record data for the population of Greater Manchester, England. We used Cox proportional hazards models to estimate ethnic inequalities in time to COVID-19 vaccination amongst people eligible for vaccination on health or age (50+ years) criteria between 1 December 2020 and 18 April 2021 (138 days of follow-up). We included vaccination with any approved COVID-19 vaccine, and analysed first-dose vaccination only. We compared inequalities between COVID-19 and influenza vaccine uptake adjusting by age group and clinical risk, and used subgroup analysis to identify populations where inequalities were widest. The majority of individuals (871,231; 79.24%) were White British. The largest minority ethnic groups were Pakistani (50,268; 4.75%), 'other White background' (43,195; 3.93%), 'other ethnic group' (34,568; 3.14%), and Black African (18,802; 1.71%). In total, 83.64% (919,636/1,099,503) of eligible individuals received a COVID-19 vaccine. Uptake was lower compared to the White British group for 15 of 16 minority ethnic groups, with particularly wide inequalities amongst the groups 'other Black background' (hazard ratio [HR] 0.42, 95% CI 0.40 to 0.44), Black African (HR 0.43, 95% CI 0.42 to 0.44), Arab (HR 0.43, 95% CI 0.40 to 0.48), and Black Caribbean (HR 0.43, 95% CI 0.42 to 0.45). In total, 55.71% (419,314/752,715) of eligible individuals took up influenza vaccination. Compared to the White British group, inequalities in influenza vaccine uptake were widest amongst the groups 'White and Black Caribbean' (HR 0.63, 95% CI 0.58 to 0.68) and 'White and Black African' (HR 0.67, 95% CI 0.63 to 0.72). In contrast, uptake was slightly higher than the White British group amongst the groups 'other ethnic group' (HR 1.11, 95% CI 1.09 to 1.12) and Bangladeshi (HR 1.08, 95% CI 1.05 to 1.11). Overall, ethnic inequalities in vaccine uptake were wider for COVID-19 than influenza vaccination for 15 of 16 minority ethnic groups. COVID-19 vaccine uptake inequalities also existed amongst individuals who previously took up influenza vaccination. Ethnic inequalities in COVID-19 vaccine uptake were concentrated amongst older and extremely clinically vulnerable adults, and the most income-deprived. A limitation of this study is the focus on uptake of the first dose of COVID-19 vaccination, rather than full COVID-19 vaccination. CONCLUSIONS: Ethnic inequalities in COVID-19 vaccine uptake exceeded those for influenza vaccine uptake, existed amongst those recently vaccinated against influenza, and were widest amongst those with greatest COVID-19 risk. This suggests the COVID-19 vaccination programme has created additional and different inequalities beyond pre-existing health inequalities. We suggest that further research and policy action is needed to understand and remove barriers to vaccine uptake, and to build trust and confidence amongst minority ethnic communities.

National-scale assessment of decadal river migration at critical bridge infrastructure in the Philippines.

River migration represents a geomorphic hazard at sites of critical bridge infrastructure, particularly in rivers where migration rates are high, as in the tropics. In the Philippines, where exposure to flooding and geomorphic risk are considerable, the recent expansion of infrastructural developments warrants quantification of river migration in the vicinity of bridge assets. We analysed publicly available bridge inventory data from the Philippines Department of Public Works and Highways (DPWH) to complete multi-temporal geospatial analysis using three decades worth of Landsat satellite imagery in Google Earth Engine (GEE). For 74 large bridges, we calculated similarity coefficients and quantified changes in width for the active river channel (defined as the wetted channel and unvegetated alluvial deposits) over decadal and engineering (30-year) timescales. Monitoring revealed the diversity of river planform adjustment at bridges in the Philippines (including channel migration, contraction, expansion and avulsion). The mean Jaccard index over decadal (0.65) and engineering (0.50) timescales indicated considerable planform adjustment throughout the national-scale inventory. However, planform adjustment and morphological behaviour varied between bridges. For bridges with substantial planform adjustment, maximum active channel contraction and expansion was equal to 25% of the active channel width over decadal timescales. This magnitude of lateral adjustment is sufficient to imply the need for bridge design to accommodate channel dynamism. For other bridges, the planform remained stable and changes in channel width were limited. Fundamental differences in channel characteristics and morphological behaviours emerged between different valley confinement settings, and between rivers with different channel patterns, indicating the importance of the local geomorphic setting. We recommend satellite remote sensing as a low-cost approach to monitor river planform adjustment with large-scale planimetric changes detectable in Landsat products; these approaches can be applied to other critical infrastructure adjacent to rivers (e.g. road, rail, pipelines) and extended elsewhere to other dynamic riverine settings.

Mortality in the USA, the UK and Other Western Countries, 1989-2015: What Is Wrong With the US?

This population-based study compares U.S. effectiveness with 20 Other Western Countries (OWC) in reducing mortality 1989-1991 and 2013-2015 and, responding to criticisms of Britain's National Health Service, directly compares U.S. with U.K. child (0-4), adult (55-74), and 24 global mortality categories. World Health Organization Age-Standardized Death Rates (ASDR) data are used to compare American and OWC mortality over the period, juxtaposed against national average percentages of Gross Domestic Product (GDP) Expenditure on Health (%GDPEH) drawn from World Bank data. America's average %GDPEH was highest at 13.53% and Britain's the lowest at 7.68%. Every OWC had significantly greater ASDR reductions than America. Current U.S. child and adult mortality rates are 46% and 19% higher than Britain's. Of 24 global diagnostic mortalities, America had 16 higher rates than Britain, notably for Circulatory Disease (24%), Endocrine Disorders (70%), External Deaths (53%), Genitourinary (44%), Infectious Disease (65%), and Perinatal Deaths (34%). Conversely, U.S. rates were lower than Britain's for Neoplasms (11%), Respiratory (12%), and Digestive Disorder Deaths (11%). However, had America matched the United Kingdom's ASDR, there would have been 488,453 fewer U.S. deaths. In view of American %GDPHE and their mortality rates, which were significantly higher than those of the OWC, these results suggests that the U.S. health care system is the least efficient in the Western world.

Evaluation of a pharmacist-led actionable audit and feedback intervention for improving medication safety in UK primary care: An interrupted time series analysis.

BACKGROUND: We evaluated the impact of the pharmacist-led Safety Medication dASHboard (SMASH) intervention on medication safety in primary care. METHODS AND FINDINGS: SMASH comprised (1) training of clinical pharmacists to deliver the intervention; (2) a web-based dashboard providing actionable, patient-level feedback; and (3) pharmacists reviewing individual at-risk patients, and initiating remedial actions or advising general practitioners on doing so. It was implemented in 43 general practices covering a population of 235,595 people in Salford (Greater Manchester), UK. All practices started receiving the intervention between 18 April 2016 and 26 September 2017. We used an interrupted time series analysis of rates (prevalence) of potentially hazardous prescribing and inadequate blood-test monitoring, comparing observed rates post-intervention to extrapolations from a 24-month pre-intervention trend. The number of people registered to participating practices and having 1 or more risk factors for being exposed to hazardous prescribing or inadequate blood-test monitoring at the start of the intervention was 47,413 (males: 23,073 [48.7%]; mean age: 60 years [standard deviation: 21]). At baseline, 95% of practices had rates of potentially hazardous prescribing (composite of 10 indicators) between 0.88% and 6.19%. The prevalence of potentially hazardous prescribing reduced by 27.9% (95% CI 20.3% to 36.8%, p < 0.001) at 24 weeks and by 40.7% (95% CI 29.1% to 54.2%, p < 0.001) at 12 months after introduction of SMASH. The rate of inadequate blood-test monitoring (composite of 2 indicators) reduced by 22.0% (95% CI 0.2% to 50.7%, p = 0.046) at 24 weeks; the change at 12 months (23.5%) was no longer significant (95% CI -4.5% to 61.6%, p = 0.127). After 12 months, 95% of practices had rates of potentially hazardous prescribing between 0.74% and 3.02%. Study limitations include the fact that practices were not randomised, and therefore unmeasured confounding may have influenced our findings. CONCLUSIONS: The SMASH intervention was associated with reduced rates of potentially hazardous prescribing and inadequate blood-test monitoring in general practices. This reduction was sustained over 12 months after the start of the intervention for prescribing but not for monitoring of medication. There was a marked reduction in the variation in rates of hazardous prescribing between practices.

Kidney disease pathways, options and decisions: an environmental scan of international patient decision aids.

BACKGROUND: Conservative management is recognized as an acceptable treatment for people with worsening chronic kidney disease; however, patients consistently report they lack understanding about their changing disease state and feel unsupported in making shared decisions about future treatment. The purpose of this review was to critically evaluate patient decision aids (PtDAs) developed to support patient-professional shared decision-making between dialysis and conservative management treatment pathways. METHODS: We performed a systematic review of resources accessible in English using environmental scan methods. Data sources included online databases of research publications, repositories for clinical guidelines, research projects and PtDAs, international PtDA expert lists and reference lists from relevant publications. The resource selection was from 56 screened records; 17 PtDAs were included. A data extraction sheet was applied to all eligible resources, eliciting resource characteristics, decision architecture to boost/bias thinking, indicators of quality such as International Standards for Patient Decision Aids Standards checklist and engagement with health services. RESULTS: PtDAs were developed in five countries; eleven were publically available via the Internet. Treatment options described were dialysis (n = 17), conservative management (n = 9) and transplant (n = 5). Eight resources signposted conservative management as an option rather than an active choice. Ten different labels across 14 resources were used to name 'conservative management'. The readability of the resources was good. Six publications detail decision aid development and/or evaluation research. Using PtDAs improved treatment decision-making by patients. Only resources identified as PtDAs and available in English were included. CONCLUSIONS: PtDAs are used by some services to support patients choosing between dialysis options or end-of-life options. PtDAs developed to proactively support people making informed decisions between conservative management and dialysis treatments are likely to enable services to meet current best practice.

Discovering New Social Determinants of Health Concepts from Unstructured Data: Framework and Evaluation.

Social determinants of health (SDoH) are the complex set of circumstances in which individuals are born, or with which they live, that impact their health. Integrating SDoH into practice requires that information systems are able to identify SDoH-related concepts from charts and case notes through vocabularies or terminologies. Despite significant standardisation efforts across healthcare domains, SDoH coverage remains sparse in existing terminologies due to the broad spectrum of this domain, ranging from family relations, risk factors, to social programs and benefits, which are not consistently captured across administrative and clinical settings. This paper presents a framework to mine, evaluate and recommend new multidisciplinary concepts that relate to or impact the health and well-being of individuals using a word embedding model trained from a large dynamic corpus of unstructured data. Five key SDoH domains were selected and evaluated by domain experts. The concepts resulting from the trained model were matched against well-established meta-thesaurus UMLS and terminology SNOMED-CT and, overall, a significant proportion of concepts from a set of 10,000 candidates were not found (31% and 28% respectively). The results confirm both the gaps in current terminologies and the feasibility and impact of the methods presented in this paper for the incremental discovery and validation of new SDoH concepts together with domain experts. This sustainable approach facilitates the development and refinement of new and existing terminologies and, in turn, it allows systems such as Natural Language Processing (NLP) annotators to leverage SDoH concepts across integrated care settings.

Lymphocytic thrombophilic arteritis and cutaneous polyarteritis nodosa: Clinicopathologic comparison with blinded histologic assessment.

BACKGROUND: Lymphocytic thrombophilic arteritis (LTA), or macular lymphocytic arteritis, is defined by a primary lymphocytic vasculitis. However, the nosology of LTA has been controversial, with speculation that it may represent an indolent non-nodule-forming variant of cutaneous polyarteritis nodosa (cPAN). OBJECTIVE: This study compares the clinicopathologic features of patients with LTA or cPAN to assess if these conditions should be considered distinct entities. METHODS: This is a cross-sectional study of all LTA and cPAN cases at a single tertiary center using prospectively collected clinical data and blinded histologic assessment. RESULTS: The study included 17 patients with LTA and 13 patients with cPAN. Clinically, cases of LTA were distinguished by a more widespread pattern of livedo racemosa, which was noninfiltrated and asymptomatic. In contrast, cPAN was associated with localized starburst livedo, purpura, and episodic features including nodules, pain, and large inflammatory ulcers. When patients were separated according to the presence (>5%) or paucity (≤5%) of neutrophils on blinded histology review, they had distinct clinical features and differences in disease course. LIMITATIONS: This was a single-center study. CONCLUSION: Our data support the classification of LTA and cPAN as separate entities rather than a spectrum of the same disorder and highlight the importance of clinicopathologic correlation in distinguishing these conditions.

Student nurses' perceptions of the importance of their Practice Assessment Record (PAR): A qualitative study.

BACKGROUND: Pre-registration nursing programmes aim to prepare students to function effectively within an environment that provides front-line health care, with the over-riding concern being patient safety. Exhibiting the ability to assess practice-based situations and make decisions is critical to demonstrating effective clinical, professional and leadership competence. AIM: This small scale qualitative study explores first year student nurses' understanding of the importance of recording achievement of practice competence and identifying the factors which influence them when prioritising completion of their Practice Assessment Record. Participants were drawn from a University in the North West of England, UK. METHOD: Designed as an exploratory study inspired by a phenomenological approach. Data was collected through interviews and analysed using Colaizzi's approach to qualitative thematic analysis. RESULTS: Participants experienced wide variation in learning opportunities, availability of mentors and mentor engagement in the assessment process. Some levels of resistance from mentors are unavoidably influenced by clinically orientated priorities which is not always fully appreciated by first year student nurses. Two themes: Unwarranted Variation and Unknowingly Ill-informed, revealed that the importance of practice learning experiences, the acquisition of competence and the subsequent recording of those achievements was understood by students, but not always by mentors.

The Violence Epidemic in the African American Community: A Call by the National Medical Association for Comprehensive Reform.

While much progress has occurred since the civil rights act of 1964, minorities have continued to suffer disparate and discriminatory access to economic opportunities, education, housing, health care and criminal justice. The latest challenge faced by the physicians and public health providers who serve the African American community is the detrimental, and seemingly insurmountable, causes and effects of violence in impoverished communities of color. According to statistics from the Centers for Disease Control (CDC), the number one killer of black males ages 10-35 is homicide, indicating a higher rate of violence than any other group. Black females are four times more likely to be murdered by a boyfriend or girlfriend than their white counterparts, and although intimate partner violence has declined for both black and white females, black women are still disproportionately killed. In addition, anxiety and depression that can lead to suicide is on the rise among African American adolescents and adults. Through an examination of the role of racism in the perpetuation of the violent environment and an exploration of the effects of gang violence, intimate partner violence/child maltreatment and police use of excessive force, this work attempts to highlight the repercussions of violence in the African American community. The members of the National Medical Association have served the African American community since 1895 and have been advocates for the patients they serve for more than a century. This paper, while not intended to be a comprehensive literature review, has been written to reinforce the need to treat violence as a public health issue, to emphasize the effect of particular forms of violence in the African American community and to advocate for comprehensive policy reforms that can lead to the eradication of this epidemic. The community of African American physicians must play a vital role in the treatment and prevention of violence as well as advocating for our patients, family members and neighbors who suffer from the preventable effects of violence.

The free healthcare initiative in Sierra Leone: Evaluating a health system reform, 2010-2015.

This article presents the findings of a theory-based evaluation of the Sierra Leone Free Health Care Initiative (FHCI), using mixed methods. Analytical approaches included time-series analysis of national survey data to examine mortality and morbidity trends, as well as modelling of impact using the Lives Saved Tool and expenditure trend analysis. We find that the FHCI responded to a clear need in Sierra Leone, was well designed to bring about needed changes in the health system to deliver services to the target beneficiaries, and did indeed bring funds and momentum to produce important systemic reforms. However, its ambition was also a risk, and weaknesses in implementation have been evident in a number of core areas, such as drugs supply. We conclude that the FHCI was one important factor contributing to improvements in coverage and equity of coverage of essential services for mothers and children. Modelled cost-effectiveness is high-in the region of US$ 420 to US$ 444 per life year saved. The findings suggest that even-or perhaps especially-in a weak health system, a reform-like fee removal, if tackled in a systematic way, can bring about important health system gains that benefit vulnerable groups in particular.

Aquatic exposures of chemical mixtures in urban environments: Approaches to impact assessment.

Urban regions of the world are expanding rapidly, placing additional stress on water resources. Urban water bodies serve many purposes, from washing and sources of drinking water to transport and conduits for storm drainage and effluent discharge. These water bodies receive chemical emissions arising from either single or multiple point sources, diffuse sources which can be continuous, intermittent, or seasonal. Thus, aquatic organisms in these water bodies are exposed to temporally and compositionally variable mixtures. We have delineated source-specific signatures of these mixtures for diffuse urban runoff and urban point source exposure scenarios to support risk assessment and management of these mixtures. The first step in a tiered approach to assessing chemical exposure has been developed based on the event mean concentration concept, with chemical concentrations in runoff defined by volumes of water leaving each surface and the chemical exposure mixture profiles for different urban scenarios. Although generalizations can be made about the chemical composition of urban sources and event mean exposure predictions for initial prioritization, such modeling needs to be complemented with biological monitoring data. It is highly unlikely that the current paradigm of routine regulatory chemical monitoring alone will provide a realistic appraisal of urban aquatic chemical mixture exposures. Future consideration is also needed of the role of nonchemical stressors in such highly modified urban water bodies. Environ Toxicol Chem 2018;37:703-714. © 2017 The Authors. Environmental Toxicology and Chemistry published by Wiley Periodicals, Inc. on behalf of SETAC.

Fixed-Dose Versus Off-Label Combination of Isosorbide Dinitrate Plus Hydralazine Hydrochloride: Retrospective Propensity-Matched Analysis in Black Medicare Patients with Heart Failure.

INTRODUCTION: Based upon the findings of the African-American Heart Failure Trial, the US Food and Drug Administration approved the fixed-dose combination of isosorbide dinitrate (ISDN) and hydralazine hydrochloride (HYD) (FDC-ISDN/HYD) as a new drug for treatment of heart failure (HF) in self-identified African Americans. According to the FDA, FDC-ISDN/HYD has no therapeutic equivalent. However, off-label combinations of the separate generic drugs ISDN and HYD (OLC-ISDN+HYD) or isosorbide mononitrate (ISMN) and HYD (OLC-ISMN+HYD) are routinely substituted without any supporting outcome data. We conducted an exploratory retrospective propensity-matched cohort study using Medicare data to determine whether a survival difference exists between these treatments in medication-adherent patients. METHODS: Black Medicare beneficiaries with HF were matched with Medicare Part D data to identify patients with prescriptions to FDC-ISDN/HYD or the off-label combinations. Only patients with 1-year adherence levels ≥80% were included in the analysis. Propensity-matched scoring created two sets of matched cohort pairs on a 1:1 basis, each set comparing FDC-ISDN/HYD with one of the off-label combinations. Kaplan-Meier (KM) survival curves with the log-rank test were then calculated for each pair for the year of medication adherence. RESULTS: The analysis population was relatively older (77 years) and mainly female (66.7%), with a high burden of comorbid disease. The KM estimates of 1-year survival were 87.9% (95% CI 85.6-89.9%) and 83.0% (95% CI 80.3-85.3%) (log rank p = 0.0024), respectively, for the matched cohorts FDC-ISDN/HYD and OLC-ISDN+HYD (n = 886 in each group) and 88.2% (95% CI 85.9-90.2%) and 84.8% (95% CI 82.2-87.0%) (log rank p = 0.0320), respectively, for the matched cohorts FDC-ISDN/HYD and OLC-ISMN+HYD (n = 868 in each group). CONCLUSION: The 1-year survival advantage for FDC-ISDN/HYD compared with off-label combinations in adherent black Medicare beneficiaries with HF suggests a genuine difference between these medications and warrants prospective investigation.