Impact of the COVID-19 pandemic on cancer care in Ireland - Perspectives from a COVID-19 and Cancer Working Group.

Upon the COVID-19 pandemic onset in Ireland, cancer service disruptions occurred due to prioritisation of COVID-19 related care, redeployment of staff, initial pausing of screening, diagnostic, medical and surgical oncology procedures, staff shortages due to COVID-19 infection and impacts on the physical and mental health of cancer healthcare workers. This was coupled with reluctance among people with symptoms suspicious for cancer to attend for clinical evaluation, due to concerns of contracting the virus. This was further compounded by a cyber-attack on national health service IT systems on May 14th 2021. The Irish Cancer Society, a national cancer charity with a role in advocacy, research and patient supports, convened a multi-disciplinary stakeholder group (COVID-19 and Cancer Working Group) to reflect on and understand the impact of the pandemic on cancer patients and services in Ireland, and discuss potential mitigation strategies. Perspectives on experiences were gathered across domains including timeliness of data acquisition and its conversion into intelligence, and the resourcing of cancer care to address cancer service impacts. The group highlighted aspects for future research to understand the long-term pandemic impact on cancer outcomes, while also highlighting potential strategies to support cancer services, build resilience and address delayed diagnosis. Additional measures include the need for cancer workforce recruitment and retention, increased mental health supports for both patients and oncology professionals, improvements to public health messaging, a near real-time multimodal national cancer database, and robust digital and physical infrastructure to mitigate impacts of the current pandemic and future challenges to cancer care systems.

Effectiveness of rapid antigen testing for screening of asymptomatic individuals to limit the transmission of SARS-CoV-2: A rapid review.

Rapid antigen detection tests (RADTs) offer advantages over gold-standard reverse transcription polymerase chain reaction (RT-PCR) tests in that they are cheaper and provide faster results, thus enabling prompt isolation of positive SARS-CoV-2 cases and quarantine of close contacts. The aim of this study was to collate and synthesise empirical evidence on the effectiveness of rapid antigen testing for the screening (including serial testing) and surveillance of asymptomatic individuals to limit the transmission of SARS-CoV-2. A rapid review was undertaken in MEDLINE (EBSCO), EMBASE (OVID), Cochrane Library, Europe PMC and Google Scholar up until 19 July 2021, supplemented by a grey literature search. Of the identified 1222 records, 19 reports referring to 16 studies were included. Eight included studies examined the effectiveness of RADTs for population-level screening, four for pre-event screening and four for serial testing (schools, a prison, a university sports programme and in care homes). Overall, there is uncertainty regarding the effectiveness of rapid antigen testing for the screening of asymptomatic individuals to limit the transmission of SARS-CoV-2. This uncertainty is due to the inconsistent results, the relatively low number of studies identified, the predominantly observational and/or uncontrolled nature of the study designs used, and concerns regarding methodological quality. Given this uncertainty, more real-world research evidence in relevant settings, which is of good quality and timely, as well as economic evaluation, is required to inform public policy on the widespread use of RADTs in asymptomatic individuals.

Trends in Opioid Use Among Cancer Patients in the United States: 2013-2018.

Background: In response to the US opioid epidemic, the Centers for Disease Control and Prevention updated their guideline on prescription opioids for chronic pain management in March 2016. The aim of this study was to provide detailed analysis of trends in opioid claims among cancer patients in the United States during 2013-2018. Methods: We analyzed pharmaceutical dispensing data from Symphony Health's Integrated Dataverse database, which covers approximately 80% of the US population. We examined annual trends in dispensed opioids in cancer patients during 2013-2018. We examined quarterly trends of the prevalence, mean number of days, and dose (stated as morphine milligram equivalents) of opioid dispensing in cancer patients. Results: Dispensing records of an average of over 3.7 million cancer patients contributed to the study annually in 2013-2018. The annual prevalence of opioid dispensing claims declined from 40.2% in 2013 to 34.5% in 2018. Annual declines occurred across cancer sites, and particularly among patients with metastatic cancer (decline of 19.8%), breast cancer (18.2%), and lung cancer (13.8%). By quarter, the prevalence of opioid claims declined statistically significantly from 26.6% in Q1 2013 to 21.2% in Q4 2018; this decline was more pronounced after Q3 2016 (2-sided P = .004). Both quarterly trends in mean days and morphine milligram equivalents of opioids supplied showed a gradual decline from 2013 to 2018, with a slightly larger decline after 2016. Conclusions: We observed a decline in opioid use among cancer patients, particularly after 2016, coinciding with the publication of the Centers for Disease Control and Prevention's guideline on prescription opioids for chronic pain management.

Interventions in an Ambulatory Setting to Prevent Progression to Severe Disease in Patients With COVID-19: A Systematic Review.

OBJECTIVE: To conduct a systematic review on the effectiveness and safety of pharmacological and nonpharmacological interventions, in the ambulatory setting, aimed at preventing severe disease in patients with COVID-19. DATA SOURCES: Electronic databases (PubMed, EMBASE, and EuropePMC) were searched on January 6, 2021. STUDY SELECTION AND DATA EXTRACTION: A systematic review was conducted, adhering to PRISMA guidelines. The quality of individual trials was assessed using the Cochrane Risk-of-Bias Tool 2, and the certainty of evidence was assessed using GRADE. DATA SYNTHESIS: The collective search retrieved 3818 citations. Eight trials relating to 9 pharmacological interventions were identified. No evidence for nonpharmacological interventions was identified. Low certainty evidence of effectiveness in preventing severe disease was found for fluvoxamine (absolute difference: -8.7%; 95% CI: -1.8% to -16.4%) and bamlanivimab plus etesevimab (absolute difference: -4.9%; 95% CI: -0.8% to -8.9%). Both trials were limited by small sample sizes and short durations of follow-up. In addition, very low certainty evidence of effect was found for ivermectin plus doxycycline and sulodexide. Based on published data, insufficient evidence of effect was found for bamlanivimab (monotherapy), casirivimab plus imdevimab, ivermectin (monotherapy), nitazoxanide, and peginterferon lambda. RELEVANCE TO PATIENT CARE AND CLINICAL PRACTICE: This review assessed all ambulatory treatments for COVID-19 that may improve patient outcomes and reduce hospitalizations. CONCLUSION: Recent trials have shown promising results for a number of pharmacological agents to treat COVID-19 in the ambulatory setting. However, larger, more robust trials are needed to support the routine use of these agents outside of monitored clinical trials.

The duration of infectiousness of individuals infected with SARS-CoV-2.

OBJECTIVES: To summarise the evidence on the duration of infectiousness of individuals in whom SARS-CoV-2 ribonucleic acid is detected. METHODS: A rapid review was undertaken in PubMed, Europe PubMed Central and EMBASE from 1 January 2020 to 26 August 2020. RESULTS: We identified 15 relevant studies, including 13 virus culture and 2 contact tracing studies. For 5 virus culture studies, the last day on which SARS-CoV-2 was isolated occurred within 10 days of symptom onset. For another 5 studies, SARS-CoV-2 was isolated beyond day 10 for approximately 3% of included patients. The remaining 3 virus culture studies included patients with severe or critical disease; SARS-CoV-2 was isolated up to day 32 in one study. Two studies identified immunocompromised patients from whom SARS-CoV-2 was isolated for up to 20 days. Both contact tracing studies, when close contacts were first exposed greater than 5 days after symptom onset in the index case, found no evidence of laboratory-confirmed onward transmission of SARS-CoV-2. CONCLUSION: COVID-19 patients with mild-to-moderate illness are highly unlikely to be infectious beyond 10 days of symptoms. However, evidence from a limited number of studies indicates that patients with severe-to-critical illness or who are immunocompromised, may shed infectious virus for longer.

Organ Dysfunction in Patients with Advanced Melanoma Treated with Immune Checkpoint Inhibitors.

BACKGROUND: Real-world data enables evaluation of immune checkpoint inhibitor (ICI) use in advanced melanoma management. We examined characteristics and outcomes of ICI-treated patients with advanced melanoma and organ dysfunction (baseline and emergent). MATERIALS AND METHODS: This retrospective observational study used electronic health records derived from a nationwide data set to examine advanced melanoma patients treated with first-line ICIs (2011-2018). Clinical characteristics, real-world time to treatment discontinuation (rwTTD), and overall survival (OS) were analyzed for patients with normal organ function and those with organ dysfunction prior to ICI initiation. Patients with emergent dysfunction in the 90 days following ICI initiation were identified, and potentially associated characteristics were explored. RESULTS: Of 2,407 patients included, 1,884 and 1,717 had evaluable renal and hepatic laboratory values, respectively. Patients with baseline renal dysfunction (2.4%) were older and more frequently male, and less frequently treated with ICI combinations, than patients with normal renal function. Patients with baseline hepatic dysfunction (2.8%) were similar to patients with normal hepatic function regarding demographics and treatments received. Patients with baseline organ dysfunction displayed shorter rwTTD and OS. Among patients with normal baseline organ function, 4.6% and 7.4% developed renal and hepatic dysfunction within 90 days of ICI initiation, respectively; this was associated with combination ICI treatment. CONCLUSION: Patients with advanced melanoma and baseline organ dysfunction frequently receive ICI treatment but have poorer clinical outcomes than patients with normal organ function. Among patients with normal renal and hepatic function at ICI initiation, emergent organ dysfunction rates in this real-world cohort are similar to those reported in clinical trials. IMPLICATIONS FOR PRACTICE: Real-world data provide an opportunity to understand treatment patterns, toxicity, and clinical outcomes among patients treated outside of clinical trials. This study confirms that patients with advanced melanoma and baseline renal or hepatic dysfunction are being treated with ICI therapy more frequently as monotherapy than in combination therapy. For those real-world patients with normal baseline organ function, emergent renal and hepatic dysfunction are both more common in patients treated with combination versus ICI monotherapy.

Trends in Mortality From Drug Poisonings, Suicide, and Alcohol-Induced Deaths in the United States From 2000 to 2017.

Importance: Life expectancy has decreased in the US, driven largely by increases in drug poisoning, suicide, and alcohol-induced deaths. Assessing whether patterns of these causes differ is required to inform public health interventions. Objective: To compare patterns and trends in drug poisoning, suicide, and alcohol-induced death rates by geography and demographic characteristics. Design, Setting, and Participants: This serial cross-sectional study used national vital statistics data from the entire US population from January 1, 2000, to December 31, 2017, among US residents aged 20 to 64 years. Data were analyzed from January through August 2019. Exposures: Age, sex, race/ethnicity, county-level percentage of unemployment, rurality, and geography. Main Outcomes and Measures: Deaths were categorized as due to drug poisoning, suicide, or alcohol-induced causes based on underlying cause of death. Age-standardized incidence rates and annual percentage changes (APCs) in rates were estimated. Clusters of high-rate counties were identified with hot spot analysis. Excess deaths during 2001 to 2017 were estimated for each cause as the difference between the number of deaths observed and expected if rates had remained stable starting in 2000. Results: During 2000 to 2017, 1 446 177 drug poisoning, suicide, and alcohol-induced premature deaths occurred in the US, including 563 765 drug poisoning deaths (age-standardized rate: 17.6 per 100 000 person-years [PYs]), 517 679 suicides (age-standardized rate: 15.8 per 100 000 PYs), and 364 733 alcohol-induced deaths (age-standardized rate: 10.5 per 100 000 PYs), totaling 451 596 more deaths than expected based on 2000 rates. High drug poisoning death rates were clustered in the Northeast through Appalachia, yet rates of suicide and alcohol-induced deaths were highest in the West. Only suicide death rates were highest in rural areas. Drug poisoning death rates were highest among people aged 35 to 49 years (age-standardized rate: 23.7 per 100 000 PYs), whereas suicide and alcohol-induced death rates peaked among people aged 50 to 64 years (suicide age-standardized rate: 19.6 per 100 000 PYs; alcohol-induced age-standardized death rate: 26.8 per 100 000 PYs). Increases occurred over time across racial/ethnic groups, although trajectories and inflection years varied. Drug poisoning (2013-2017 APC, 15.0% [95% CI, 11-8%-18.3%] per year) and alcohol-induced death rates (2012-2017 APC, 4.1% [95% CI, 3.3%-4.9%] per year) have accelerated recently, while increases in suicide death rates have largely increased at a constant trajectory (2000-2017 APC, 1.8% [95% CI, 1.7%-1.9%] per year). Conclusions and Relevance: This cross-sectional study found that demographic characteristics and geographic patterns varied by cause of death, suggesting that increasing death rates from these causes were not concentrated in 1 group or region. Specialized interventions tailored for the underlying drivers of each cause of death are urgently needed.

Trends in Alcohol-Induced Deaths in the United States, 2000-2016.

Importance: Notable increases in mortality from alcohol-induced causes over the past 2 decades in the United States have been reported. However, comprehensive assessments of trends in alcohol-induced mortality by sex, age, race/ethnicity, and social and geographic factors are lacking. Objective: To examine trends in alcohol-induced mortality rates from 2000 to 2016, comparing results by demographic characteristics including sex, race/ethnicity, age, county-level socioeconomic status, and geographic location. Design, Setting, and Participants: This serial cross-sectional study used US national vital statistics data for years 2000 to 2016 for all US residents older than 15 years. Data analysis was conducted from January to September 2019. Exposures: Trends in alcohol-induced mortality by sex, race/ethnicity, age, county-level socioeconomic status (ie, median income, percentage of unemployed residents, percentage of residents with a bachelor's degree), rurality level, and US state. Main Outcomes and Measures: Alcohol-induced mortality, ie, deaths for which alcohol holds a population-attributable fraction of 1. Deaths were expressed per 100 000 residents as absolute and age-standardized rates. Mortality trends were measured as average annual percentage changes (AAPCs) for the entire period (ie, 2000-2016) and annual percentage changes (APCs) for individual periods of change within the study period. Results: A total of 425 045 alcohol-induced deaths were identified from 2000 to 2016 (2000: 19 627 deaths; 14 979 [76.3%] men; 2016: 34 857 deaths; 25 213 [73.3%] men). The rate of alcohol-induced deaths increased substantially among men (AAPC, 1.4%; 95% CI, 1.0% to 1.8%) and women (AAPC, 3.1%; 95% CI, 2.6% to 3.6%) and accelerated recently (men, 2012-2016: APC, 4.2%; 95% CI, 3.1% to 5.3%; women, 2013-2016: APC, 7.1%; 95% CI, 5.1% to 9.1%). The largest increases by race/ethnicity were observed among American Indian and Alaska Native men (AAPC, 3.3%; 95% CI, 2.6% to 4.0%), American Indian and Alaska Native women (AAPC, 4.2%; 95% CI, 3.8% to 4.6%), and white women (AAPC, 4.1%; 95% CI, 3.6% to 4.7%). Despite initial declines among black women, black men, and Latino men (eg, Latino men, 2000-2003: APC, -5.1%; 95% CI, -9.8% to -0.1%; 2003-2013: APC, -0.6%; 95% CI, -1.4% to 0.2%), increases occurred later in the study period (eg, Latino men, 2013-2016: APC, 4.1%; 95% CI, 0.3% to 8.1%). The rates of increase varied by age group and in turn by racial/ethnic group. Among white individuals, large absolute increases occurred in midlife (eg, men aged 55-59 years, 2000-2003: 25.5 deaths per 100 000 residents; 2013-2016: 43.3 deaths per 100 000 residents; women aged 50-54 years, 2000-2003: 7.4 deaths per 100 000 residents; 2013-2016: 16.5 deaths per 100 000 residents), although APCs were also large for ages 25 to 34 years, ranging from 4.6% to 6.9% per year among men and from 7.3% to 12.0% among women. Among American Indian and Alaska Native individuals, increases throughout the age range were observed, with the largest absolute increase occurring for ages 45 to 49 years among men (2000-2013: 113.6 deaths per 100 000 residents; 2013-2016: 193.1 deaths per 100 000 residents) and for ages 50 to 54 among women (2000-2013: from 56.1 deaths per 100 000 residents; 2013-2016: 105.1 deaths per 100 000 residents). Conclusions and Relevance: This study found large increases in alcohol-induced death rates across age and racial/ethnic subgroups of the US population, which have accelerated over recent years. Large increases in alcohol-induced deaths among younger age groups may be associated with future increases in alcohol-related disease.

Trends in Premature Deaths Among Adults in the United States and Latin America.

Importance: Premature death rates vary in the United States by race/ethnicity. Despite their socioeconomic disadvantages, US Latino populations have lower premature mortality rates than do US white populations, a phenomenon termed the "Latino or Hispanic paradox." Objective: To investigate whether there is a broader Latin American paradox by comparing premature mortality rates in the United States according to race/ethnicity with rates in Latin America and Puerto Rico from 2001 to 2015. Design, Setting, and Participants: This descriptive cross-sectional study used mortality data from the World Health Organization Mortality Database. All deaths occurring in individuals aged 20 to 64 years among US Latino, African American, white, and Puerto Rican and 12 other Latin American populations from January 2001 to December 2015 were selected. The data analysis began in October 2018. Exposures: Age, sex, race/ethnicity, and country. Main Outcomes and Measures: All-cause mortality, cause-specific mortality, age-standardized mortality rates (AMSRs), and average annual percentage change in mortality rates during 2001 to 2015. Results: During 2001 to 2015, 22 million deaths (8 million women and 14 million men) occurred among individuals aged 20 to 64 years in the selected populations. Among women, US Latina individuals had the lowest premature mortality rates (ASMR for 2015, 144 deaths per 100 000 population) and US African American women had the highest premature mortality rate (ASMR for 2015, 340 deaths per 100 000 population) of the 16 populations studied. Rates among US white women shifted from the sixth lowest in 2001 (ASMR, 231 deaths per 100 000 population) to the 12th lowest in 2015 (ASMR, 235 deaths per 100 000 population). Among men, Peru had the lowest premature mortality rates (ASMR for 2015, 219 deaths per 100 000 population), and Belize had the highest premature mortality rates (ASMR for 2015, 702 deaths per 100 000 population). White men in the United States shifted from the fifth lowest rates in 2001 (ASMR, 396 deaths per 100 000 population) to the eighth lowest rates in 2015 (ASMR, 394 deaths per 100 000 population). Rates for both women and men decreased in all the populations studied from 2001 to 2015 (average annual percentage change range, 0.4% to 3.8% per year) except among US white populations, for which the rate plateaued (average annual percentage change, 0.02% per year [95% CI, -0.3% to 0.2% per year] for women; -0.2% per year [95% CI, -0.4% to 0.0% per year] for men) and among Nicaraguan men, for whom the rates increased (0.6% per year [95% CI, 0.2% to 1.0% per year]). The populations with the lowest mortality rates in 2015 had lower rates from all major causes, but rates were particularly lower for heart disease (21 deaths per 100 000 population) and cancer (50 deaths per 100 000 population). Conclusions and Relevance: Premature mortality rates are lower for US Latino populations and several Latin American countries than for US white populations, suggesting that there may be a broader Latin American paradox. This analysis also highlights the high premature mortality rates among US African American populations, especially women, compared with many Latin American populations.

Creating an academic research organization to efficiently design, conduct, coordinate, and analyze clinical trials: The Center for Clinical Trials & Data Coordination.

When properly executed, the randomized controlled trial is one of the best vehicles for assessing the effectiveness of one or more interventions. However, numerous challenges may emerge in the areas of study startup, recruitment, data quality, cost, and reporting of results. The use of well-run coordinating centers could help prevent these issues, but very little exists in the literature describing their creation or the guiding principles behind their inception. The Center for Clinical Trials & Data Coordination (CCDC) was established in 2015 through institutional funds with the intent of 1) providing relevant expertise in clinical trial design, conduct, coordination, and analysis; 2) advancing the careers of clinical investigators and CCDC-affiliated faculty; and 3) obtaining large data coordinating center (DCC) grants. We describe the organizational structure of the CCDC as well as the homegrown clinical trial management system integrating nine crucial elements: electronic data capture, eligibility and randomization, drug and external data tracking, safety reporting, outcome adjudication, data and safety monitoring, statistical analysis and reporting, data sharing, and regulatory compliance. Lastly, we share numerous lessons that can be taken from our experience. Specifically, we focus on 1) funding for DCCs, 2) the importance of DCCs to clinical researchers, 3) the expertise of DCC personnel, and 4) continually striving to improve. In conclusion, the CCDC strives to provide high-quality support for the design, conduct, coordination, and analyses of clinical trials, and we hope this paper will serve as a blueprint for future clinical trialists involved in DCCs.

Association of Cardiovascular Disease With Premature Mortality in the United States.

Importance: Cardiovascular disease (CVD) is a leading cause of morbidity and mortality in the United States. Despite substantial declines in CVD mortality rates during past decades, progress against cardiovascular deaths in midlife has stagnated, with rates increased in some US racial/ethnic groups. Objective: To examine the trends in premature (ages 25-64 years) mortality from CVD from 2000 to 2015 by demographics and county-level factors, including education, rurality, and the prevalence of smoking, obesity, and diabetes. Design, Setting, and Participants: This descriptive study used US national mortality data from the Surveillance, Epidemiology, and End Results data set and included all CVD deaths among individuals ages 25 to 64 years from January 2000 to December 2015. The data analysis began in February 2018. Exposures: Age, sex, race/ethnicity, and county-level factors. Main Outcomes and Measures: Age-standardized mortality rates and average annual percent change (AAPC) in rates by age, sex, race/ethnicity, and county-level factors (in quintiles) and relative risks of CVD mortality across quintiles of each county-level factor. Results: In 2000 to 2015, 2.3 million CVD deaths occurred among individuals age 25 to 64 years in the United States. There were significant declines in CVD mortality for black, Latinx, and Asian and Pacific Islander individuals (AAPC: range, -1.7 to -3.2%), although black people continued to have the highest CVD mortality rates. Mortality rates were second highest for American Indian/Alaskan Native individuals and increased significantly among those aged 25 to 49 years (AAPC: women, 2.1%; men, 1.3%). For white individuals, mortality rates plateaued among women age 25 to 49 years (AAPC, 0.05%). Declines in mortality rates were observed for most major CVD subtypes except for ischemic heart disease, which was stable in white women and increased in American Indian/Alaska Native women, hypertensive heart disease, for which significant increases in rates were observed in most racial/ethnic groups, and endocarditis, for which rates increased in white individuals and American Indian/Alaska Native men. Counties with the highest prevalence of diabetes (quintile 5 vs quintile 1: relative risk range 1.6-1.8 for white individuals and 1.4-1.6 for black individuals) had the most risk of CVD mortality. Conclusions and Relevance: There have been substantial declines in premature CVD mortality in much of the US population. However, increases in CVD mortality before age 50 years among American Indian/Alaska Native individuals, flattening rates in white people, and overall increases in deaths from hypertensive disease suggest that targeted public health interventions are needed to prevent these premature deaths.

Trends in Mortality Due to Cancer in the United States by Age and County-Level Income, 1999-2015.

Disparities in cancer mortality by county-level income have increased. It is unclear whether these widening disparities have affected older and younger adults equally. National death certificate data were utilized to ascertain cancer deaths during 1999-2015. Average annual percent changes in mortality rates and mortality rate ratios (RRs) were estimated by county-level income quintile and age (25-64 vs ≥65 years). Among 25- to 64-year-olds, cancer mortality rates were 30% higher (RR = 1.30, 95% confidence interval [CI] = 1.29 to 1.31) in the lowest-vs the highest-income counties in 1999-2001 and 56% higher (RR = 1.56, 95% CI = 1.55 to 1.57) in 2013-2015; the disparities among those 65 years and older were smaller but also widened over time (RR1999-2001 = 1.04, 95% CI = 1.03 to 1.05; RR2013-2015 = 1.14, 95% CI = 1.13 to 1.14). Widening disparities occurred across cancer sites. If all counties had the mortality rates of the highest-income counties, 21.5% of cancer deaths among 25- to 64-year-olds and 7.3% of cancer deaths in those 65 years and older would have been avoided in 2015. These results highlight an ongoing need for equity-focused interventions, particularly among younger adults.

Premature mortality from all causes and drug poisonings in the USA according to socioeconomic status and rurality: an analysis of death certificate data by county from 2000-15.

BACKGROUND: Increasing premature mortality among some groups of Americans has been largely driven by increases in drug poisoning deaths. However, to our knowledge, a formal descriptive study by race and ethnicity, socioeconomic status, rurality, and geography has not been done. In this study, we examined US trends in premature all-cause and drug poisoning mortality between 2000 and 2015 at the county level among white, black, and Latino people. METHODS: We used US mortality data for the period Jan 1, 2000, to Dec 31, 2015, including underlying cause of death and demographic data, collected from death certificates by the Centers for Disease Control and Prevention National Center for Health Statistics, and ascertained county attributes from the 2011-15 Census American Community Survey. We categorised counties into quintiles on the basis of the percentage of people unemployed, the percentage of people with a bachelor's degree, median income, and rurality. We estimated premature (ie, deaths in those aged 25-64 years) age-standardised mortality for all causes (by race and ethnicity) and drug poisoning, by county, for the periods of 2000-03 and 2012-15. We estimated annual percentage changes in mortality (2000-15) by county-level characteristics. FINDINGS: Premature mortality declined from 2000-03 to 2012-15 among black and Latino people, but increased among white people in many US counties. Drug poisoning mortality increased in counties throughout the country. Significant increases between 2000 and 2015 occurred across low and high socioeconomic status and urban and rural counties among white people aged 25-64 years (annual percentage change range 4·56% per year [95% CI 3·56-5·57] to 11·51% per year [9·41-13·65]), black people aged 50-64 years (2·27% per year [0·42-4·16] to 9·46% per year [7·02-11·96]), Latino women aged 25-49 years (2·43% per year [1·18-3·71] to 5·01% per year [3·80-6·23]), and Latino men aged 50-64 years (2·42% per year [0·53-4·34] to 5·96% per year [3·86-8·11]). Although drug poisoning mortality increased rapidly in counties with the lowest socioeconomic status and in rural counties, most deaths during 2012-15 occurred in the largest metropolitan counties (121 395 [76%] in metropolitan counties with ≥250 000 people vs 2175 [1%] in the most rural counties), reflecting population size. INTERPRETATION: Premature mortality has declined among black and Latino people in the USA, and increased among white people, particularly in less affluent and rural counties. Increasing drug poisoning mortality was not limited to poor white people in rural areas. Rapid increases have occurred in communities throughout the USA regardless of race and ethnicity, socioeconomic status, or rurality. Widespread public health interventions are needed to addess this public health emergency. FUNDING: National Institutes of Health.

Infant and Youth Mortality Trends by Race/Ethnicity and Cause of Death in the United States.

Importance: The United States has higher infant and youth mortality rates than other high-income countries, with striking disparities by racial/ethnic group. Understanding changing trends by age and race/ethnicity for leading causes of death is imperative for focused intervention. Objective: To estimate trends in US infant and youth mortality rates from 1999 to 2015 by age group and race/ethnicity, identify leading causes of death, and compare mortality rates with Canada and England/Wales. Design, Setting, and Participants: This descriptive study analyzed death certificate data from the US National Center for Health Statistics, Statistics Canada, and the UK Office of National Statistics for all deaths among individuals younger than 25 years. The study took place from January 1, 1999, to December 31, 2015, and analyses started in September 2017. Exposures: Race/ethnicity. Main Outcomes and Measures: Average annual percent changes in mortality rates from 1999 to 2015 and absolute rate change between 1999 to 2002 and 2012 to 2015 for each age group, race/ethnicity, and cause of death. Results: Among individuals from birth to age 24 years, 1 169 537 deaths occurred in the United States, 80 540 in Canada, and 121 183 in England/Wales from 1999 to 2015. In the United States, 64% of deaths occurred in male individuals and 52.6% occurred in white individuals (25.1% deaths occurred in black individuals and 17.9% in Latino individuals). All-cause mortality declined for all age groups (infants younger than 1 year [38.5% of deaths], children aged 1-9 years [10.6%], early adolescents aged 10-14 years [5%], late adolescents aged 15-19 years [17.7%], and young adults aged 20-24 years [28.1%]) in the United States, Canada, and England/Wales from 1999 to 2015. However, rates were highest in the United States. Within the United States, annual declines in all-cause mortality rates occurred among all age groups of black, Latino, and white individuals, except for white individuals aged 20 to 24 years, whose rates remained stable. Mortality rates declined across most major causes of death from 1999 to 2002 and 2012 to 2015, with notable declines observed for sudden infant death syndrome, unintentional injury death, and homicides. Among infants, unintentional suffocation and strangulation in bed increased (difference between 2012-2015 and 1999-2002 range, 6.11-29.03 per 100 000). Further, suicide rates among Latino and white individuals aged 10 to 24 years (range, 0.21-2.63 per 100 000) and black individuals aged 10 to 19 years (range, 0.10-0.45 per 100 000) increased, as did unintentional injury deaths in white young adults (0.79 per 100 000). The rise in unintentional injury deaths is attributed to increases in drug poisonings and was also observed in black and Latino young adults. Conclusions and Relevance: Mortality rates in the United States have generally declined for infants and youths from 1999 to 2015 owing to reductions in sudden infant death syndrome, unintentional injury death, and homicides. However, US mortality rates remain higher than Canada and England/Wales, with particularly elevated rates among black and American Indian/Alaskan Native youth. Further, there is a concerning increase in suicide and drug poisoning death rates among US adolescents and young adults.

Policies for biosimilar uptake in Europe: An overview.

BACKGROUND: Across European countries, differences exist in biosimilar policies, leading to variations in uptake of biosimilars and divergences in savings all over Europe. OBJECTIVES: The aim of this article is to provide an overview of different initiatives and policies that may influence the uptake of biosimilars in different European countries. Recommendations will be formulated on how to create sustainable uptake. METHODS: An overview of policies on biosimilars was obtained via a questionnaire, supplemented with relevant articles. Topics were organized in five themes: availability, pricing, reimbursement, demand-side policies, and recommendations to enhance uptake. RESULTS: In all countries studied, biological medicines are available. Restrictions are mainly dependent on local organization of the healthcare system. Countries are willing to include biosimilars for reimbursement, but for commercial reasons they are not always marketed. In two thirds of countries, originator and biosimilar products may be subjected to internal reference pricing systems. Few countries have implemented specific incentives targeting physicians. Several countries are implementing pharmacist substitution; however, the scope and rules governing such substitution tend to vary between these countries. Reported educational policies tend to target primarily physicians, whereas fewer initiatives were reported for patients. Recommendations as proposed by the different country experts ranged from the need for information and communication on biosimilars to competitive pricing, more support for switching and guidance on substitution. CONCLUSIONS: Most countries have put in place specific supply-side policies for promoting access to biosimilars. To supplement these measures, we propose that investments should be made to clearly communicate on biosimilars and educate stakeholders. Especially physicians need to be informed on the entry and use of biosimilars in order to create trust. When physicians are well-informed on the treatment options, further incentives should be offered to prescribe biosimilars. Gainsharing can be used as an incentive to prescribe, dispense or use biosimilars. This approach, in combination with binding quota, may support a sustainable biosimilar market.

Pharmaceutical regulation in 15 European countries review.

In the context of pharmaceutical care, policy-makers repeatedly face the challenge of balancing patient access to effective medicines with affordability and rising costs. With the aim of guiding the health policy discourse towards questions that are important to actual and potential patients, this study investigates a broad range of regulatory measures, spanning marketing authorization to generic substitution and resulting price levels in a sample of 16 European health systems (Austria, Belgium, Denmark, England, Finland, France, Germany, Greece, Ireland, Italy, the Netherlands, Poland, Portugal, Scotland, Spain and Sweden). All countries employ a mix of regulatory mechanisms to contain pharmaceutical expenditure and ensure quality and efficiency in pharmaceutical care, albeit with varying configurations and rigour. This variation also influences the extent of publicly financed pharmaceutical costs. Overall, observed differences in pharmaceutical expenditure should be interpreted in conjunction with the differing volume and composition of consumption and price levels, as well as dispensation practices and their impact on measurement of pharmaceutical costs. No definitive evidence has yet been produced on the effects of different cost-containment measures on patient outcomes. Depending on the foremost policy concerns in each country, different levers will have to be used to enable the delivery of appropriate care at affordable prices.

Closeout of the HALT-PKD trials.

BACKGROUND: The HALT Polycystic Kidney Disease Trials Network consisted of two randomized, double blind, placebo-controlled trials among patients with autosomal dominant polycystic kidney disease. The trials involved 5-8years of participant follow-up with interventions in blood pressure and antihypertensive therapy. We provide a framework for designing and implementing closeout near the end of a trial while ensuring patient safety and maintaining scientific rigor and study morale. METHODS: We discuss issues and resolutions for determining the last visit, tapering medications, and unblinding of participants to study allocation and results. We also discuss closure of clinical sites and Data Coordinating Center responsibilities to ensure timely release of study results and meeting the requirements of regulatory and funding authorities. RESULTS: Just over 90% of full participants had a 6-month study visit prior to their last visit preparing them for trial closeout. Nearly all patients wanted notification of study results (99%) and treatment allocation (99%). All participants were safely tapered off study and open label blood pressure medications. Within 6months, the trials were closed, primary papers published, and 805 letters distributed to participants with results and allocation. DCC obligations for data repository and clinicaltrials.gov reporting were completed within 12months of the last study visit. CONCLUSIONS: Closeout of our trials involved years of planning and significant human and financial resources. We provide questions for investigators to consider when planning closeout of their trials with focus on (1) patient safety, (2) dissemination of study results and (3) compliance with regulatory and funding responsibilities.

Liver involvement in early autosomal-dominant polycystic kidney disease.

BACKGROUND & AIMS: Polycystic liver disease (PLD), the most common extrarenal manifestation of autosomal-dominant polycystic kidney disease (ADPKD), has become more prevalent as a result of increased life expectancy, improved renal survival, reduced cardiovascular mortality, and renal replacement therapy. No studies have fully characterized PLD in large cohorts. We investigated whether liver and cyst volumes are associated with volume of the hepatic parenchyma, results from liver laboratory tests, and patient-reported outcomes. METHODS: We performed a cross-sectional analysis of baseline liver volumes, measured by magnetic resonance imaging, and their association with demographics, results from liver laboratory and other tests, and quality of life. The data were collected from a randomized, placebo-controlled trial underway at 7 tertiary-care medical centers to determine whether the combination of an angiotensin I-converting enzyme inhibitor and angiotensin II-receptor blocker was superior to the inhibitor alone, and whether low blood pressure (<110/75 mm Hg) was superior to standard blood pressure (120-130/70-80 mm Hg), in delaying renal cystic progression in 558 patients with ADPKD, stages 1 and 2 chronic kidney disease, and hypertension (age, 15-49 y). RESULTS: We found hepatomegaly to be common among patients with ADPKD. Cysts and parenchyma contributed to hepatomegaly. Cysts were more common and liver and cyst volumes were greater in women, increasing with age. Patients with advanced disease had a relative loss of liver parenchyma. We observed small abnormalities in results from liver laboratory tests, and that splenomegaly and hypersplenism were associated with PLD severity. Higher liver volumes were associated with a lower quality of life. CONCLUSIONS: Hepatomegaly is common even in early stage ADPKD and is not accounted for by cysts alone. Parenchymal volumes were larger, compared with liver volumes of patients without ADPKD or with those predicted by standardized equations, even among patients without cysts. The severity of PLD was associated with altered biochemical and hematologic features, as well as quality of life. ClinicalTrials.gov identifier: NCT00283686.

Are new models needed to optimize the utilization of new medicines to sustain healthcare systems?

Medicines have made an appreciable contribution to improving health. However, even high-income countries are struggling to fund new premium-priced medicines. This will grow necessitating the development of new models to optimize their use. The objective is to review case histories among health authorities to improve the utilization and expenditure on new medicines. Subsequently, use these to develop exemplar models and outline their implications. A number of issues and challenges were identified from the case histories. These included the low number of new medicines seen as innovative alongside increasing requested prices for their reimbursement, especially for oncology, orphan diseases, diabetes and HCV. Proposed models center on the three pillars of pre-, peri- and post-launch including critical drug evaluation, as well as multi-criteria models for valuing medicines for orphan diseases alongside potentially capping pharmaceutical expenditure. In conclusion, the proposed models involving all key stakeholder groups are critical for the sustainability of healthcare systems or enhancing universal access. The models should help stimulate debate as well as restore trust between key stakeholder groups.

Dabigatran - a continuing exemplar case history demonstrating the need for comprehensive models to optimize the utilization of new drugs.

BACKGROUND: There are potential conflicts between authorities and companies to fund new premium priced drugs especially where there are effectiveness, safety and/or budget concerns. Dabigatran, a new oral anticoagulant for the prevention of stroke in patients with non-valvular atrial fibrillation (AF), exemplifies this issue. Whilst new effective treatments are needed, there are issues in the elderly with dabigatran due to variable drug concentrations, no known antidote and dependence on renal elimination. Published studies showed dabigatran to be cost-effective but there are budget concerns given the prevalence of AF. These concerns resulted in extensive activities pre- to post-launch to manage its introduction. OBJECTIVE: To (i) review authority activities across countries, (ii) use the findings to develop new models to better manage the entry of new drugs, and (iii) review the implications based on post-launch activities. METHODOLOGY: (i) Descriptive review and appraisal of activities regarding dabigatran, (ii) development of guidance for key stakeholder groups through an iterative process, (iii) refining guidance following post launch studies. RESULTS: Plethora of activities to manage dabigatran including extensive pre-launch activities, risk sharing arrangements, prescribing restrictions and monitoring of prescribing post launch. Reimbursement has been denied in some countries due to concerns with its budget impact and/or excessive bleeding. Development of a new model and future guidance is proposed to better manage the entry of new drugs, centering on three pillars of pre-, peri-, and post-launch activities. Post-launch activities include increasing use of patient registries to monitor the safety and effectiveness of new drugs in clinical practice. CONCLUSION: Models for introducing new drugs are essential to optimize their prescribing especially where concerns. Without such models, new drugs may be withdrawn prematurely and/or struggle for funding.