Background: Per- and polyfluoroalkyl substances (PFAS) emissions from a plastic coating industrial source in southern New Hampshire (NH) have contaminated at least 65 square miles of drinking water. Prior research indicates that high levels of PFAS are associated with a variety of adverse health outcomes, including an increased risk of cancer. Reports indicate that mean blood serum levels of perfluorooctanoic acid (PFOA), one type of PFAS, in residents of the exposed community are more than 2 times greater than the mean blood serum level in the US. Merrimack public water supply customers also have higher average blood levels of perfluorooctane sulfonic acid (PFOS) and perfluorohexane sulfonic acid (PFHxS) than the time—matched US average. A 2018 report concludes that the incidence rate of cancer in Merrimack does not exceed the incidence rate of cancer in NH in general. However, prior reporting on the risk of cancer in Merrimack is compared only to a state-wide metric influenced by the Merrimack cancer incidence. Methods: Our ecological study compared the risk in Merrimack, NH residents for 24 types of cancer between 2005 and 2014, targeted in a previous study, and all-cause cancers, to US national cancer rates and cancer rates in demographically similar towns in New England. Four New England “unexposed towns” were chosen based on demographic similarity to Merrimack, with no documented PFAS exposure in water supplies. We utilized unadjusted logistical regression to approximate risk ratios (RR) and 95% confidence intervals (CI) assessing the risk of cancer in Merrimack NH to each of the 4 comparator communities, the pooled comparator variable, and national average incidence. Results: Residents of Merrimack, NH experienced a significantly higher risk of thyroid cancer (RR = 1.47, 95% CI 1.12-1.93), bladder cancer (RR = 1.45, 95% CI 1.17-1.81), esophageal cancer (RR = 1.71, 95% CI 1.1-2.65), and mesothelioma (RR = 2.41, 95% CI 1.09-5.34), compared to national averages. Our work also suggests that Merrimack residents experienced a significantly higher risk of all-cause cancer (RR = 1.34, 95% CI 1.25-1.43), thyroid cancer (RR = 1.69, 95% CI 1.19-2.39), colon cancer (RR = 1.27, 95% CI 1.02-1.57), and prostate cancer (RR = 1.36, 95% CI 1.15, 1.6) compared with similarly exposed New England communities. Our results indicate that residents of Merrimack may also have a significantly lower risk of some site-specific cancers compared to national averages, including lower risk of prostate cancer (RR = 0.57, 95% CI 0.5-0.66), female breast cancer (RR = 0.60, 95% CI 0.52-0.68), ovarian cancer (RR = 0.52, 95% CI 0.33-0.84) and cervical cancer (RR = 0.29, 95% CI 0.12-0.69). Conclusion: Merrimack residents experienced a significantly higher risk of at least 4 types of cancer over 10 years between 2005 and 2014. Merrimack is a community with documented PFAS contamination of drinking water in public and private water sources. Results indicate that further research is warranted to elucidate if southern NH residents experience increased risk for various types of cancer due to exposure to PFAS contamination.

Alzheimer disease (AD) causes significant economic and social burdens for patients, families, and the health care system. To date, the US Food and Drug Administration (FDA) has approved few treatments for AD, and these temporarily ameliorate symptoms but do not slow, stop, or reverse disease progression. 1 Meanwhile, 99.6% of AD trials conducted between 2002 and 2012 have encountered safety problems or failed to demonstrate benefit. 1 In the face of these challenges, there is global interest to innovate clinical trials that enable more effective outcomes. Adaptive clinical trials for AD treatment could advance understanding of biological mechanisms and clinical progression and access regulatory review avenues such as accelerated approval. Trial innovation could also reinvigorate investment in drug development.Clinical trial failures result from many factors: inadequate understanding of actionable targets and pathways (molecular or biological), inappropriate dosage or treatment duration, and variance owing to heterogeneity of the research population. A major cause of many AD trial failures has been the inability to meet FDArecommended functional and cognitive clinical end points. 1 At a recent FDA patient-centered drugdevelopment meeting, patients and families stressed the need to alleviate cognitive impairment and its disabling consequences. 2 The FDA has indicated that delaying cognitive impairment before the onset of overt dementia may provide sufficient evidence of efficacy for clinical trials in AD. 3 Innovative clinical trial designs have proved successful for other diseases, such as breast cancer, and have enhanced research by identifying relevant outcomes and encouraging financial investment. Since 2008, financing of breast cancer trials has increased while investment in AD trials has declined (Figure ) 4 ; total investment for breast cancer trials far exceeds that for AD. In addition, 34% of breast cancer trials are in later stages of development compared with 13% of AD trials. The decline in investment in AD trials has resulted in a narrow portfolio of drugs currently in development.Alzheimer disease research might emulate the I-SPY (Investigation of Serial Studies to Predict Your Therapeutic Response With Imaging and Molecular Analysis) clinical trial, an adaptive clinical trial platform structured to expedite drug development. I-SPY 2 recruits women with triple-negative breast cancer who are at increased risk for tumor recurrence and death despite standard adjuvant treatment. The trial uses a hybrid umbrella/basket design 5 with the "umbrella" consisting of concurrent testing of up to 12 experimental therapies in patient subgroup "baskets" defined by genetic markers and tumor type. Numerous parties col-VIEWPOINT

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