In total, 70% of patients in Cohort 1 received only systemic therapies as their treatment modality for liver metastasis, while 98% of patients in Cohort 2 and Cohort 3 received liver-directed treatment either alone or with systemic therapy. Median Mets-to-Death OS was shortest in Cohort 1 , longer in Cohort 2  and longest in Cohort 3 . Median Eye Tx-to-Death OS was shortest in Cohort 1 , and similar in Cohort 2  and Cohort 3 . It is speculated that this could be due to the shift of treatment modalities from DTIC-based chemotherapy to liver-directed therapies. Combination of liver-directed and newly developed systemic treatments may further improve the survival of these patients.There is no FDA-approved treatment for metastatic uveal melanoma (UM) and overall outcomes are generally poor for those who develop liver metastasis. We performed a retrospective single-institution chart review on consecutive series of UM patients with liver metastasis who were treated at Thomas Jefferson University Hospital between 1971–1993 (Cohort 1,  Although uveal melanoma (UM) is rare, comprising less than 5% of all melanomas, it is the most common primary intraocular malignancy in adults ,2. It isOur Ocular Oncology team at Wills Eye Hospital have previously published several large retrospective reviews evaluating clinical factors predictive of metastasis ,11,12. TCurrently, there is no Food and Drug Administration (FDA) approved treatment for metastatic UM. Chemotherapeutic drugs, commonly used for the treatment of metastatic cutaneous melanoma, rarely induces responses in patients with UM, especially in the setting of metastatic disease to the liver. In particular, dacarbazine (DTIC)-based chemotherapies are reportedly ineffective in the treatment of metastatic UM ,15. Systn = 32) and after  the approval of first-line treatment with immune checkpoint inhibitors (20% with ipilimumab with nivolumab). Median PFS improved from 2.5 months to 3.5 months  that have shown potential survival benefit in metastatic UM ,33, coulThis is a retrospective single-institution chart review on consecutive series of UM patients with liver metastasis who were treated at Thomas Jefferson University Hospital between 1971–1993 , 1998–2007 (Cohort 2), and 2008–2017 (Cohort 3). Cohorts 2 and 3 represent earlier and more recent decades of liver-directed therapy dominant periods. The data on patients in Cohort 1 were obtained from the database created for a previously published retrospective analysis on predictive factors for time-to-metastasis, and served as our historical control . We obtaIn Cohort 1 (1971–1993), patients were mainly treated with DTIC-based chemotherapy like cutaneous melanoma patients at the time. It was during this interval that Dr. Mavligit published his results with chemoembolization . We thenThe following selection criteria were applied to select patients for retrospective analysis: Inclusion Criteria: Histologically confirmed liver metastasis and at least one treatment for liver metastasis ; Exclusion Criteria: Inability to obtain survival information (lost to follow-up). The following information was obtained from medical records: age, date of treatment of the primary UM, clinical features and initial therapy to the primary UM, date and site of systemic recurrence, therapy to the metastasis, and the date of death or last follow up. Liver-directed therapy included chemoembolization, immunoembolization, hepatic perfusion, plain embolization, radioembolization, drug-eluting beads, surgery, radiation, and ablative therapy. Vital status  was confirmed by medical records as well as by reviewing public records, communication with treating physicians or by directly contacting patients or family members. The database was updated for the last time on 28 April 2018.In terms of information on treatment modalities for liver metastasis, the first two treatment modalities after liver metastasis were collected and analyzed as “ever” treatment modalities (Treatment 1 + 2). This is based on the fact that only one patient received a third treatment modality in cohort 1 and the third or later treatment modalities were mostly palliative in nature in cohorts 2 and 3. “Ever” treatment modalities were categorized as (1) “Systemic only”, systemic treatment modalities were given as first and second treatments (if given); (2) “Liver-directed only”, liver-directed treatment modalities were given as first and second treatments (if given); (3) “Liver-directed + Systemic”, liver-directed and systemic treatments were given in consecutive order or in combination. Institutional Review Board (IRB)/Ethics Committee approval was obtained from Thomas Jefferson University [IRB #18D-183]. Our study adhered to the Declaration of Helsinki. Because our study was a retrospective collection of patients’ information, no informed consent was required.The primary endpoints of analysis were overall survival from the initial treatment of primary UM to death (Eye Tx-to-Death OS) and from liver metastasis to death (Mets-to-Death OS). The Kaplan–Meier curves were used to evaluate survival in each cohort. The differences in survival between cohorts was evaluated using the log-rank test adjusted for family-wise type I error of 0.05 in case of paired comparisons. Cox proportional hazards models were used to evaluate the effects of clinical-pathological factors and treatment modalities on OS endpoint in each cohort. The validity of the proportional hazard assumptions was assessed, and covariates that violated the proportional hazard assumption were included in the Cox models either as a strata variables or with the time-varying coefficient using the multiplicative hazard regression model  . The folTo conclude, in this retrospective single center investigation, we demonstrated an improved survival between an earlier cohort and more recent cohorts of UM patients with liver metastasis. We speculate that a major contributing factor for improvement of survival is the shift of treatment modality from DTIC-based systemic chemotherapies to newly developed liver-directed treatments. We also speculate that the addition of immuno-modulatory therapies to liver-directed treatments might have improved the survival of UM patients with liver metastasis. Obviously, further investigation by way of prospective clinical trials is needed to answer these questions.


Recent social movements have highlighted fatal police violence as an enduring public health problem in the United States. To solve it, the public requires basic information, such as understanding where rates of fatal police violence are particularly high, and for which groups. Existing mapping efforts, though critically important, often use inappropriate statistical methods and can produce misleading, unstable rates when denominators are small. To fill this gap, we use inverse-variance-weighted multilevel models to estimate overall and race-stratified rates of fatal police violence for all Metropolitan Statistical Areas (MSAs) in the U.S. (2013–2017), as well as racial inequities in these rates. We analyzed the most recent, reliable data from Fatal Encounters, a citizen science initiative that aggregates and verifies media reports.Rates of police-related fatalities varied dramatically, with the deadliest MSAs exhibiting rates nine times those of the least deadly. Overall rates in Southwestern MSAs were highest, with lower rates in the northern Midwest and Northeast. Yet this pattern was reversed for Black-White inequities, with Northeast and Midwest MSAs exhibiting the highest inequities nationwide. Our main results excluded deaths that could be considered accidents , but sensitivity analyses demonstrated that doing so may underestimate the rate of fatal police violence in some MSAs by 60%. Black-White and Latinx-White inequities were slightly underestimated nationally by excluding reportedly ‘accidental’ deaths, but MSA-specific inequities were sometimes severely under- or over-estimated.Preventing fatal police violence in different areas of the country will likely require unique solutions. Estimates of the severity of these problems  in any given MSA are quite sensitive to which types of deaths are analyzed, and whether race and cause of death are attributed correctly. Monitoring and mapping these rates using appropriate methods is critical for government accountability and successful prevention. Over the last decade, the Black Lives Matter movement has drawn renewed attention to fatal police violence as an urgent public health and racial justice problem, defined here as fatalities in police custody or involving the police that would not have occurred in the absence of police intervention. No national, publicly-funded data system has accurately tracked the number of people who die during contact with police, but these deaths are public health data and can be counted . Police-Geography matters for these deaths. Although rates of police killings are highest in neighborhoods with the greatest concentration of low-income residents and residents of color, Black people were recently found to be at greatest risk in predominantly White neighborhoods . Indeed,Although researchers have begun describing crude differences in rates of fatalities involving police across states and cities ,9, theseWe used multilevel models and 2013–2017 data from Fatal Encounters to estimate rates of fatal police violence for every Metropolitan Statistical Area (MSA), as well as MSA-specific proportional differences in these rates by race/ethnicity, comparing Black and Latinx rates to non-Latinx White rates. This inverse-variance-weighted method allowed us to borrow statistical strength from the full national sample in estimating city-level differences and smooth over volatility in our estimates induced by small populations of certain races or ethnicities in a given area along with rare events. We then calculated confidence intervals for each MSA’s estimate, allowing comparisons between MSAs.Our police-related fatalities data is from Fatal Encounters, a citizen science initiative that systematically identified cases in a prospective manner using online media reports and public records; case coding is triple-checked by paid researchers who verify information across multiple media reports and public records –12. The From the complete Fatal Encounters data for these years, we followed Edwards, Lee, and Esposito  and exclWe geocoded the Fatal Encounters data using ArcGIS version 10.6.1, assigning each police-related fatality to a Metropolitan Statistical Area (MSA) using latitudes and longitudes from Fatal Encounters and MSA shapefiles provided by the 2010 US Census. We chose MSAs as our unit of analysis because (A) of all qualifying fatalities involving police during this period, 6 in 7 occurred within MSAs, and (B) the country’s 382 MSA boundaries are constructed to represent heavily interconnected urban economic zones. MSA boundaries thus reflect the broader geographic areas in which urban Americans live, work, and socialize; police violence is not constrained to the jurisdictional boundaries of police departments in which Americans’ home addresses lie. MSAs may thus better reflect the experience of U.S. urban residents’ daily lives than counties, police departments, or Census tracts would.To calculate rates, we aggregated data on fatal police violence to the MSA level and merged it with race-specific population data from the Census Bureau’s American Community Survey 5-Year Estimates from 2013–2017. Due to the small absolute numbers of fatalities involving police in most MSAs, we used fatalities data from all these years to calculate an average annual rate and increase the stability of our estimates, as per Feldman and colleagues , and becAll racial/ethnic groups’ data were included when calculating overall annual incidence rates of fatal police violence, but from our models estimating racial/ethnic inequities in fatal police violence, we report only Black and Latinx rates compared to White rates. This is because the low total race/ethnicity-specific population and total number of deaths for Native American, Middle Eastern, Asian/Pacific Islander, and people of other races/ethnicities means we lacked sufficient statistical power to estimate meaningful MSA-specific rates for these groups, even aggregated into a single racial/ethnic category. Moreover, Fatal Encounters data do not disaggregate Asian/Pacific Islander people by ethnicity or by the country their family lines originally immigrated to the United States from, making their racial/ethnic group extremely heterogenous in terms of socioeconomic status and police violence risk.We estimated annual incident rates and incident rate ratios (IRR) for police killings in each MSA using multilevel Poisson models with a population offset, assuming normality of the random effects. Importantly, these empirical Bayesian models use inverse-variance-weighting to estimate national rates and ‘borrow strength’ from rates in the rest of the country to stabilize estimation of MSA-specific rates in places where denominators are low  ,22. In eWe estimated two sets of models. The first set estimated the overall annual incident rate for each MSA using random intercepts. These data were organized as years nested within MSAs, with one dataset for the general population and another for each race, in order to calculate more stable annual incidence rates for each subgroup with its corresponding population offset. The second set of models estimated the IRRs of fatal police violence for each MSA, comparing Black, Latinx, and Other Race/Ethnicity incidence rates to White rates. These racial inequity models used data organized as years nested within race nested within MSAS and included random intercepts at the MSA-level, random slopes for each race/ethnicity indicator, and offsets for the MSA-race-specific population. After estimating these models, we used MSA-level random intercepts and slopes to map (A) overall MSA-specific incidence rates and (B) racial inequity incidence rate ratios (IRRs), comparing Black and Latinx rates to the non-Latinx White rate.mepoisson command in Stata MP v. 15.1, which uses a Laplacian approximation as its integration method (the default) [mepoisson to models that use Markov chain Monte Carlo (MCMC) estimation [runmlwin call to the program through Stata [Our main results are calculated using the default) ,25. Givetimation , run wittimation  via the gh Stata . First ogh Stata .Finally, we formally examined whether the MSA-level rates we estimated exhibited spatial autocorrelation using the statistical software GeoDa . We calcOf the included 5494 fatalities involving police from 2013–2017, 2353 (42.83%) of the decedents were White, 1487 (27.07%) were Black, 939 were Latinx (17.09%), and 168 (3.06%) were other race/ethnicities, while 547 lacked data on race/ethnicity. Nationally, from our first set of models, the annual rate of fatal police violence was 0.39 per 100,000 . Yet overall and race-specific rates varied from MSA to MSA: overall rates ranged from 0.13  fatalities per 100,000 in Buffalo-Cheektowaga-Niagara Falls, NY to 1.17/100,000  in Anniston-Oxford-Jacksonville, AL, meaning the most lethal MSA exhibited rates nine times those of the least lethal.Race-specific rates varied less from MSA to MSA for Black people than for their White or Latinx counterparts. While MSA-specific annual rates for Black people ranged from 0.43/100,000  to 2.10 —a ratio of maximum to minimum of 4.9—MSA-specific rates for White people ranged from 0.08  to 1.10 —a maximum/minimum ratio of nearly 14—and for Latinx people ranged from 0.11  to 1.27 —a maximum/minimum ratio of more than 12.On average, there were large racial/ethnic inequities in the rates at which White and Black people were killed during police contact. Across all MSAs, Black people were 3.23 times more likely to be killed compared to White people . Latinx people were 1.05 times more likely, though this IRR was not statically significant .MSA-specific incidence rate ratios also varied. Across all 382 MSAs, Black-White IRRs ranged from 1.81  to 6.51 , a maximum/minimum ratio of 3.6. Latinx-White IRRs varied somewhat less, ranging from 0.71  to 1.50 , a large though statistically insignificant ratio of 2.1.Estimates from the random part of our IRR model suggested that the incidence rates for White and non-White people are related, i.e., MSAs’ random intercepts and random slopes for race were negatively correlated . Given Black people’s much higher overall rate compared to White people, MSAs with high rates of fatal police violence against White people tended to have smaller disparities between White and Black rates; or, equivalently, MSAs with low rates of fatal police violence against White people tended to exhibit more extreme Black-White inequities. Among Latinx people, lower White rates tended to go along with higher, more severe Latinx-White inequities, while MSAs with higher White rates tended to have more equal rates across Latinx and White people, or even exhibit lower Latinx rates than White rates.There were clear spatial patterns to these estimates. Latinx-White IRRs are displayed in Our first sensitivity analysis compared estimates from models analyzing a subset of causes of death (excluding deaths that could be considered accidents) to models analyzing all deaths see . For exaIndeed, IRRs measuring racial/ethnic inequities in fatal police violence were often notably altered in models that included all causes of death compared to the subset included in the main analysis. On average, Black-White IRRs increased by 7% when analyzing all-cause fatalities, but this ranged from an IRR more than two times larger when analyzing all-cause fatalities vs. “accidental” fatalities in Kalamazoo-Portage, MI, to an IRR 0.83 times as large when analyzing all-cause fatalities in Seattle-Tacoma-Bellevue, WA. On average, Latinx-White IRRs increased by only 2% when analyzing all-cause fatalities, but again, geography mattered: the Latinx-White IRR was 39% higher when analyzing all-cause fatalities in Kansas City, MO-KS  but only 0.83 times as large when analyzing all-cause fatalities in Atlanta-Sandy Springs-Roswell, GA .mepoisson, both in terms of point estimates and standard errors.Our second sensitivity analysis used MCMC estimation procedures to calculate MSA-specific rates and compared them with those calculated using Laplacian approximation as the integration method. MCMC model estimates were practically identical to those using Our analysis demonstrates wide geographic variation in the incidence of fatal police violence across the U.S., with the deadliest MSAs exhibiting annual rates 9 times those of the least deadly. These rates varied across the country, with the highest overall rates in the West and Southwest and the lowest overall rates in the Northeast and Midwest. We applied a precision-weighted multilevel modeling strategy to estimate the racial/ethnic inequities in these fatalities across MSAs and identify MSAs with marked Black-White inequities, and demonstrated that areas of the county with low rates overall tended to also exhibit the most severe Black-White inequities. Our findings were robust to two sets of sensitivity analyses: one that included all causes of death and another that used MCMC estimation procedures.Monitoring these incidence rates and their racial/ethnic inequities allows public officials and the communities they represent to track the severity of the problem, devise preventive policies, and evaluate their efficacy. These monitoring efforts also have implications for racial/ethnic inequities in mental health and other health outcomes that are affected by stress from violence by state-sanctioned actors and law enforcement officer impunity ,31. For Our results must be interpreted with the following cautions in mind. First, we have examined variation in fatal police violence across MSAs. Related research suggests this is not the only geographic level that matters: neighborhood context may be critical ,6,7. HowSecond, there is a potential for misclassification of race/ethnicity of the person who died because it is not self-reported, whereby people of color may be classified as White by police and media reports; this would bias racial/ethnic comparisons of the rates of fatalities involving police towards the null . Third, Speaking at the MSA level, however, we found that focusing exclusively on non-“accidental” deaths may yield MSA-specific rates of fatal police violence that are as little as two fifths what they would be if police-related fatalities of all causes were analyzed. MSA-specific racial inequities appeared to be similarly sensitive to the causes of death included in analyses of police-related deaths, such that only including non-“accidental” deaths may deflate estimated Black-White inequities by as much as 50% or inflate them by as much as 15%, depending on the city. How accurately causes of death are reported may thus yield dramatically different assessments of how individual cities are doing at addressing fatal police violence. This is not merely a problem of specificity; it is also a question of which kinds of transformations of policing are required to save lives. Reducing non-“accidental” police-related deaths may require different solutions  than reContinued social epidemiologic research is needed to explain the geographic distribution of fatal police violence, overall and across race/ethnicity. Place-specific policy contexts are likely a major cause of the distribution of overall incidence rates. For example, state and local firearm regulations , levels A historically grounded analysis of racial justice is critical as, across the country, different strategies are being implemented to prevent fatalities involving police and racial/ethnic inequities in these deaths. There is active debate around these methods, including the effectiveness of body cameras –48, commS1 Fig(DOCX)Click here for additional data file.S2 Fig(DOCX)Click here for additional data file.S3 Fig(DOCX)Click here for additional data file.S4 Fig(DOCX)Click here for additional data file.S5 Fig(DOCX)Click here for additional data file.S6 Fig(DOCX)Click here for additional data file.S7 Fig(DOCX)Click here for additional data file.S1 Table(DOCX)Click here for additional data file.S2 Table(DOCX)Click here for additional data file.S3 Table(DOCX)Click here for additional data file.S4 Table(DOCX)Click here for additional data file.S5 Table(DOCX)Click here for additional data file.S6 Table(DOCX)Click here for additional data file.


Is there an association between the use of anti–tumor necrosis factor (TNF) therapy and all-cause mortality in a national cohort of patients with inflammatory bowel disease (IBD)?In this cohort study of 2297 patients, all-cause mortality was 9% over a mean follow-up of of 3.9 years. Anti-TNF therapy was associated with a lower likelihood of mortality for Crohn disease but not ulcerative colitis.This study suggests that anti-TNF therapy may be associated with reduced mortality compared with long-term corticosteroid use among veterans with Crohn disease. Inflammatory bowel disease (IBD) is commonly treated with corticosteroids and anti–tumor necrosis factor (TNF) drugs; however, medications have well-described adverse effects. Prior work suggests that anti-TNF therapy may reduce all-cause mortality compared with prolonged corticosteroid use among Medicare and Medicaid beneficiaries with IBD.To examine the association between use of anti-TNF or corticosteroids and all-cause mortality in a national cohort of veterans with IBD.This cohort study used a well-established Veteran’s Health Administration cohort of 2997 patients with IBD treated with prolonged corticosteroids  and/or new anti-TNF therapy from January 1, 2006, to October 1, 2015. Data were analyzed between July 1, 2019, and December 31, 2020.Use of corticosteroids or anti-TNF.The primary end point was all-cause mortality as defined by the Veterans Health Administration vital status file. Marginal structural modeling was used to compare associations between anti-TNF therapy or corticosteroid use and all-cause mortality.A total of 2997 patients  were included in the final analysis, 1734 (57.9%) with Crohn disease (CD) and 1263 (42.1%) with ulcerative colitis (UC). All-cause mortality was 8.5% (n = 256) over a mean (SD) of 3.9 (2.3) years’ follow-up. At cohort entry, 1836 patients were new anti-TNF therapy users, and 1161 were prolonged corticosteroid users. Anti-TNF therapy use was associated with a lower likelihood of mortality for CD  but not for UC . In a sensitivity analysis adjusting prolonged corticosteroid users to include patients receiving corticosteroids within 90 to 270 days after initiation of anti-TNF therapy, the OR for UC was statistically significant, at 0.33 , and the OR for CD was 0.55 .This study suggests that anti-TNF therapy may be associated with reduced mortality compared with long-term corticosteroid use among veterans with CD, and potentially among those with UC. This cohort study examines the association between use of anti–tumor necrosis factor (TNF) therapy or corticosteroids and all-cause mortality in a national cohort of veterans with inflammatory bowel disease (IBD). However, many patients do not respond to anti-TNF agents or develop recurrent inflammation despite them, prompting reinitiation of corticosteroids.5Inflammatory bowel disease (IBD) is a chronic inflammatory condition associated with disability and reduced quality of life.8 A study of Medicaid and Medicare beneficiaries found a decreased risk of death among patients with Crohn disease (CD) exposed to anti-TNF agents, compared with those taking corticosteroids for a prolonged time.9 Prior registry studies show similar findings for immunomodulators and the anti-TNF medication infliximab, compared with corticosteroids.11 Furthermore, recent data suggest that corticosteroid use is also associated with a 6-fold increased risk of severe coronavirus disease 2019 (COVID-19), wherease anti-TNF agent use is not.12 Despite this, longstanding corticosteroid use among patients with IBD remains common, particularly among the elderly and those with comorbid conditions.14Both corticosteroids and anti-TNF agents have adverse effects, including infections (both), osteoporosis (corticosteroids), and congestive heart failure (both).15 Veterans with IBD frequently have risk factors predisposing them to both corticosteroid and anti-TNF agent adverse effects, including older age, tobacco use, and comorbidities, such as coronary artery disease, hypertension, hyperlipidemia, and diabetes.17 We aimed to examine the hypothesis that anti-TNF therapy is associated with reduced mortality relative to prolonged corticosteroid use in an established cohort of veterans with IBD.The Veterans Health Administration (VHA) is the largest integrated health system in the United States, serving 9 million veterans.International Classification of Diseases, Ninth Revision (ICD-9) codes for CD (555.x) and ulcerative colitis (UC) (556.x). Patients were included if they had 2 or more clinical encounters within the VHA associated with these codes between January 1, 2006, and October 1, 2015, with 1 or more encounter being an outpatient visit.7 This algorithm has demonstrated a positive predictive value of 0.84 for CD and 0.91 for UC.18 Veterans were classified as having undefined IBD if both CD and UC codes were present and were excluded from the final cohort. The Internal Review Board at the VA Ann Arbor Healthcare System Research Services approved this study for a waiver of informed consent for the following reasons: the study involved no more than minimal risk to the participants; the waiver will not adversely affect the rights and welfare of the participants; and the research could not practicably be conducted without the waiver and without access to or use of the PHI. Whenever appropriate, the participants  were provided with additional pertinent information after participation. There was no contact with patients; only existing data were collected, and therefore no participant rights and/or welfare were affected. The research did not impact clinical care decisions or access to clinical care in any way. This report follows the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guideline.Veterans with IBD followed up within VHA were identified using 9 These definitions were based on typical IBD tapering dosages.9 Topical, otic, ophthalmic, and inhaled formulations were excluded. New anti-TNF use was defined as 1 or more filled prescription for adalimumab, certolizumab, or infliximab during the study period, with no anti-TNF prescriptions filled in the preceding 12 months. We did not include golimumab because it was not in the VHA formulary during our study period. Follow-up began when a patient met criteria for either prolonged corticosteroid use or new anti-TNF agent use.Our cohort included patients with incident IBD with prolonged corticosteroid use and/or new anti-TNF use .The primary end point was all-cause mortality as defined by the VHA vital status file.9 Race/ethnicity was classified based on veteran self-report as captured in VHA data. All nondemographic covariates were captured from administrative data, using ICD-9 and Current Procedural Terminology (CPT) codes. We also included year of cohort entry, given evolving trends in use of anti-TNF therapy during the study period. Definitions for all covariates are outlined in eTable 3 in the We evaluated 55 covariates, including demographic characteristics, year at study entry, and additional variables that might be associated with a clinician’s IBD treatment choice, risk of mortality, or treatment complications  for all covariates, with an SMD less than 0.10 indicating a reasonable balance of covariates from baseline propensity models.21 The probability of censoring was estimated in a similar manner. Nine baseline covariates with an SMD of more than 0.10 were identified: comorbidity score, hypertension, coronary disease, hypercholesterolemia, anemia, colonoscopy, computed tomography scan, prior corticosteroid use, and other medication prescriptions  from these models are approximate hazard ratios, derived using a discrete-time approach.t tests, with P < .05 considered statistically significant. Statistical analysis was performed in R, version 3.6.0 .We performed 2 sensitivity analyses to evaluate the association of patients entering the cohort with prolonged corticosteroid use, then starting a new anti-TNF agent. The first sensitivity analysis excluded patients continuing to take corticosteroids 90 to 270 days after initiation of anti-TNF therapy. The second analysis reclassified all follow-up time for these patients as contributing to the prolonged corticosteroid group, instead of reassigning them to the anti-TNF agent group after they filled an anti-TNF agent prescription. In a third analysis, we accounted for duration of anti-TNF agent exposure by censoring all users on the date of their last anti-TNF prescription fill. In a final sensitivity analysis, we restricted our corticosteroid definition to exclude budesonide, given the differences in first-pass metabolism. We tested for differences in medication exposure (anti-TNF agent vs nonbudesonide corticosteroids) using 2-tailed We identified 42 999 patients with a diagnosis of IBD during the study period, among whom 36 728 had available demographic data  started a new anti-TNF agent. Of these 445 patients, 213 received additional corticosteroids within the first 6 months. The mean (SD) age for these patients was 46.4 (16.0) years, and 16 (3.6%) died during the study period. The mean (SD) follow-up time accrued between classification as a prolonged corticosteroid user and initiation of anti-TNF therapy was 2.8 (2.4) years. The highest frequency of new anti-TNF usen in this group occurred in 2014 (19.8% [88 of 445]), and the lowest frequency occurred in 2007 (2.2% [10 of 445]).For both CD and UC, patients entering as prolonged corticosteroid users were older and had poorer health than new anti-TNF users, including higher number of comorbidities, more non–IBD-associated medications, and higher rates of non–IBD-related hospitalizations. They were more likely to use narcotics and to enroll earlier in the study period. Patients using anti-TNF agents had more IBD-related hospital days and electrolyte disorders and were more likely to undergo a colonoscopy. Patients with CD were younger and had fewer comorbidities than those with UC, used more narcotics, and enrolled earlier in the study period. Patients with CD had more serious infections than those with UC, but exposure to immunomodulators and non-IBD medication use overall were similar across groups.Median daily doses of corticosteroids are reported in Overall mortality in the study population was 8.5% (n = 256). Similar rates were seen among patients with CD (8.5% [n = 147]) and patients with UC (8.6% [n = 109]). The mean (SD) follow-up time was 3.9 (2.3) years for patients with CD and patients with UC. Among those who died during follow-up, the mean (SD) age at death was 69.1 (14.0) years overall, 66.7 (15.0) years for those with CD, and 72.2 (11.7) years for those with UC. After controlling for covariates . There are key differences between the populations evaluated in these studies, which may have contributed to the differences in results. First, our study period for both UC and CD encompassed 2006 to 2014, whereas Lewis et al9 incorporated the period from 2001 to 2005 (Medicaid beneficiaries with CD) and from 2006 to 2013 (Medicare beneficiaries with UC and CD). The last 2 decades have shown considerable changes in IBD care, with the increase in the use of corticosteroid-sparing therapy associated with improved disease-related morbidity and shorter duration of cumulative corticosteroid exposure.25 This conjecture is further supported by the appearance of a protective association of anti-TNF therapy with rates of hip fracture and cardiovascular disease in the earlier-enrolling cohort of patients with CD but not the later-enrolling cohort of patients with UC in the study by Lewis et al.9 In addition, 58% of veterans initiating anti-TNF agents in our cohort had no captured corticosteroid exposure. This finding is supported by extremely low rates of corticosteroid use, relative to civilian cohorts, among veterans initiating third-line treatments, such as ustekinumab (13% vs 35%-45%).27 This seeming paradox may be due to corticosteroid prescribing by comanaging civilian gastroenterologists or primary care physicians not captured in VHA claims. Fortunately, any misclassification would bias the findings toward the null.Our work shows trends in the veteran population that are similar to, but more pronounced than, those that Lewis et al29 Our use of a marginal structural model allowed us to adjust for the time-varying association of treatment exposure with our outcome, which is not possible using models such as a Cox proportional hazards regression. Finally, we demonstrated consistent results across different definitions of prolonged corticosteroid use in our 2 sensitivity analyses.Our study has several unique strengths. The study period focuses on the biologic era and thus reflects current patterns of IBD management, with less likelihood of confounding due to prolonged corticosteroid use preceding enrollment. We used a well-established cohort of patients with IBD and were able to follow up with patients in our cohort for a mean (SD) of 3.9 (2.3) years after IBD diagnosis, allowing excellent capture of mortality rates, comorbidities, and medication use.ICD-9 and CPT codes were used to identify patients with IBD, although the algorithm used has been well validated in this cohort.18 Residual confounding by coding errors, disease activity, reason for medication discontinuation, patient and clinician preferences, and system-level issues, such as specialty care access and continuity of care, is possible. Because anti-TNF treatment was initiated, on average, later during the study period, there is also possible unmeasured confounding due to differences in follow-up time between the corticosteroid and anti-TNF treatment groups. Our study population was limited to veterans receiving care within the VHA, and our results may thus not be generalizable to all patients with IBD within the community. We were limited by sample size, which may have contributed to the lack of a significant mortality reduction seen in the group of patients with UC and may have limited our ability to assess factors such as exposure period, dose, and subtype of anti-TNF agent. We also did not include data on smoking owing to unreliable capture within administrative claims.This study has several limitations. As with any administrative data set, We found a robust association between anti-TNF use and reduced mortality among patients with CD in a well-established longitudinal cohort of veterans with IBD, with a nonsignificant mortality reduction among patients with UC. This finding supports prior high-quality studies of Medicaid and Medicare beneficiaries. Given the observation that older patients with more comorbidities do not seem to receive anti-TNF agents to the same degree as their younger, healthier counterparts, there is an urgent need to recognize the benefit associated with anti-TNF therapy vs corticosteroid use in such populations. A multicenter prospective cohort study is warranted to evaluate how factors such as IBD severity, year of diagnosis, and corticosteroid exposure after initiation of anti-TNF agent are associated with risk of mortality and treatment adverse effects.


Merkel cell carcinoma (MCC) is an aggressive cutaneous neuroendocrine neoplasm. Although surgical resection is the first-line treatment for primary MCCs, the characteristics of this disease  generate a considerable number of inoperable cases. Radiation therapy shows potential as a definitive treatment alternative to surgery. In definitive radiation therapy for non-resected MCC, 60-66 Gy administered in 2 Gy per fraction and five fractions per week is recommended. However, such frequent visits to the hospital can be a great burden to elderly patients and family members. In this report, we present the case of an 89-year-old patient with MCC  of the left cheek. The patient was treated with radiation therapy using a mild hypofractionated schedule (57 Gy provided in 3 Gy per fraction and three fractions per week) targeting the gross tumor. The treatment led to complete tumor remission with well-tolerated acute toxicities at three months post-irradiation. This case indicates that a mild hypofractionated irradiation schedule may achieve tumor control in MCC patients who are inoperable and who cannot make frequent hospital visits. Merkel cell carcinoma (MCC) is an aggressive cutaneous neuroendocrine neoplasm ,2. SurgeIn definitive radiation therapy for non-resected MCC, a common schedule is 60-66 Gy administered in 30-33 fractions and five fractions per week . HoweverAn 89-year-old Japanese woman diagnosed with primary MCC of the left cheek was referred to the department of radiation oncology from the department of dermatology for definitive irradiation in April, 2019. Her performance status was 1 assessed by the Eastern Cooperative Oncology Group definition. She had a history of hypertension and valvular disease.In January, 2019, the patient noticed a papule on the left cheek. The lesion was diagnosed as a bacterial infection by the dermatologist. Despite treatment with antibiotics, the lesion showed rapid growth and formed a red dome-like tumor measuring 36 mm in diameter in March, 2019. Immunohistochemical analysis of the biopsied specimen showed positivity for CK20 (with a paranuclear dot-like pattern), chromogranin A, synaptophysin, CD56, and cytokeratin AE1/AE3, and negativity for S-100 and HMB-45. Computed tomography (CT) examination showed a spherical tumor mass in the left cheek Figure  and no lThe patient received radiation therapy with a total dose of 57 Gy administered in 19 fractions . Electrons (12 MeV) were delivered to the gross tumor with a margin of 2-3 cm Figure  using a After one month, the patient developed two lymph node metastases in the left neck (one in level IA and another in level IB regions). The metastatic nodes and elective nodal regions  were treated with additional irradiation  using simultaneous integrated boost intensity-modulated radiation therapy. The treatment led to clinical CR of the irradiated lesion with no evidence of metastasis for another three months. Follow-up by CT every three months up to three years, and every six months thereafter is scheduled to carefully monitor for regional and distant metastases .Here, we present a case of a patient with MCC who selected radiation therapy as an alternative to surgical resection due to advanced age and prevention of cosmetic sequelae. Because frequent hospital visits are a burden for patients and family members, we used a mild hypofractionated schedule . In the conventional schedule of five weekly fractions for definitive radiation therapy for non-resected MCC, 60-66 Gy is administered in 30-33 fractions, showing a BED10  of 72.0-79.2 Gy [Prophylactic irradiation for clinically node-negative cases remains controversial because the treatment (i) increases the risk for lymphedema and (ii) can be performed at a later time point as salvage treatment for locoregional recurrence ,8,9. In We present a case of primary MCC of the head and neck treated with definitive radiation therapy using a mild hypofractionated schedule consisting of 57 Gy administered in 3 Gy per fraction and three fractions per week. The treatment led to complete tumor remission with well-tolerated acute toxicities at three months post-irradiation.


Use of GDMT in octogenarian patients with HF and reduced ejection fraction (EF) were inadequate . However, those on medications had a significant reduction in 6 month mortality. For octogenarians with HF and preserved EF, angiotensin receptor blocker use reduced hospitalizations for HF in men , but not in women (p-interaction = 0.037). HF in octogenarians were found to have different characteristics compared with the non-elderly. However, adequate use of GDMT was still associated with improved survival, and more attention should be given to prescribing medications with clinical benefits.Treatment of heart failure (HF) in the elderly face many difficulties due to lack of robust evidence. We analyzed the outcome of HF in octogenarians using a nationwide HF registry. Among 5625 patients from the Korean Acute Heart Failure (KorAHF) registry, prognosis of octogenarian HF and the association of guideline-directed medical therapy (GDMT) with mortality and readmissions were analyzed. Octogenarian patients  showed a higher mortality, and males were especially at increased risk (HR (hazard ratio) 1.19, 95% CI 1.01–1.40). A J-curve association between blood pressure (BP) and mortality was observed regardless of age, but the nadir value was lower in octogenarians (123.8 vs. 127.9 mmHg for systolic blood pressure (SBP); 67.1 vs. 73.9 mmHg for diastolic blood pressure (DBP),  In recent years, there has been a steep rise in global life expectancy, and more countries are expected to enter “aged” and “super-aged” societal classifications. Although heart failure (HF) can occur in all age groups, it is primarily a disease of the elderly, with increased prevalence in older people. The increasing burden of HF with global aging is a socioeconomic problem worldwide, especially in aged and super-aged societies. Furthermore, advances in the treatment and prevention of ischemic heart disease has also prolonged the lives of patients with heart disease, further contributing to the rise in HF prevalence.Patients with HF are getting older, and physicians need to be delicate in treating these elderly patients, as they are known to have a poor prognosis  and therThe current study aimed to help reduce the gap regarding patient management between clinical trials and real-world practice, as well as to provide evidence for the adequate treatment of elderly HF patients using data from a large-scaled, long-term follow-up acute HF registry.ClinicalTrials.gov (NCT01389843).The Korean Acute Heart Failure (KorAHF) registry is a prospective, multi-center study designed to assess clinical features and outcomes of acute HF in Korea. We enrolled patients hospitalized for acute HF in 10 nationwide centers from March 2011 to February 2019. Detailed information on the design and interim results of the KorAHF registry have been previously published . AccuratPatients were enrolled on admission of an acute HF event, and those surviving to discharge without heart transplantations were included in the current analysis. We defined the elderly as those aged ≥80 years (octogenarians) at time of enrollment. Long-term all-cause mortality was assessed at 5 years, and mortality and readmissions for worsening HF were additionally assessed at 6 months. Outcomes were compared between elderly and non-elderly patients in the total study population, and the association of medications and outcomes were additionally assessed in octogenarians with reduced and preserved ejection fractions (EF). Target doses of GDMT were defined following the 2016 European Society of Cardiology (ESC) Guidelines for the diagnosis and treatment of acute and chronic heart failure .t-test, analysis of variance (ANOVA), or Mann–Whitney U test. Categorical variables are given as numbers and percentages and were compared using the chi-squared test. Blood pressures (BP) were measured at each predefined follow-up visit, and on-treatment BPs were calculated by averaging measurements before the occurrence of an event or end of follow-up [Continuous variables are expressed as mean ± standard deviation or median with interquartile range (IQR), and were compared using the independent ollow-up . RestricPresence of sarcopenia was retrospectively assessed using the skeletal muscle mass index (SMI), a ratio of skeletal muscle to total body mass. Skeletal muscle mass was acquired using a “body-weight and height model” equation as follows:http://www.R-project.org; The R Foundation, Vienna, Austria). All p-values are two-sided, and p-values < 0.05 are considered to be significant. . PreviouAmong the 5625 patients enrolled in the KorAHF registry, 5293 patients survived to discharge after a median of 9 (IQR 6–14) hospital days. Mean patient age was 68.6 ± 14.3 years, 52.8% were male, and 55.2% had an EF of less than 40% at admission. At time of enrollment, 1185 (22.4%) patients were aged ≥80 years, and significant differences were observed in baseline characteristics compared with non-elderly patients. They were more likely to be female, have an ischemic etiology of HF, have preserved left ventricular systolic function, and present with a lower body mass index (BMI) and hemoglobin levels, while levels of natriuretic peptides were increased compared with the non-elderly population. The prevalence of sarcopenia was also higher in octogenarians. The complete baseline demographics of study participants are shown in p < 0.001). Kaplan–Meier survival curves showed continuous divergence of the octogenarian and the non-elderly patients evident from the early follow-up periods (p < 0.001) and readmissions for worsening HF . In octogenarians, male sex was an independent risk of all-cause mortality , whereas diabetes was a significant predictor in the non-elderly. Sarcopenia was a common risk factor both age groups. Multivariate Cox models for mortality and HF readmissions according to age are described in During a median follow-up of 4.3 years (IQR 1.6–5.6 years), elderly patients showed a significantly higher rate of overall mortality compared with the non-elderly  and 69.4 mmHg for diastolic blood pressure . The non-linear association between on-treatment BP and mortality was similar in both elderly and non-elderly patients, but the nadir DBP was lower in octogenarians (69.4 mmHg vs. 83.7 mmHg). The association between DBP and outcome was also more U-shaped in octogenarians, with risk also increasing at higher values compared with non-elderly patients. The risk for mortality according to each BP category is shown in Restricted cubic splines were drawn using significant covariates derived from Cox models described in a previous publication . As showp = 0.041), beta-blockers , and AAs  at discharge were lower in octogenarians (Octogenarian patients with HF and reduced EF (HFrEF) were less likely to receive GDMT compared with non-elderly patients. The prescription rates of RAS inhibitors , but not with readmissions for worsening HF .For octogenarian HFrEF patients, the all-cause mortality rate was significantly lower in those using RAS inhibitors  A. In covp = 0.009), whereas prescription of AAs  and loop diuretics  were increased. For DBP, there were no significant differences except for diuretics, which showed increased use in patients with DBP < 70 mmHg . However, use of RAS inhibitors was also associated with significantly lower mortality rates even at lower systolic and diastolic BP . Beta-blockers were associated with numerically lower, but non-significant, mortality rates at lower BPs . The proportion of patients using RAS inhibitors were lower in patients with SBP < 125 mmHg  in octogenarians. However, after adjusting for early post-discharge mortality and changes in medication, use of beta-blockers was associated with a significantly lower 6 month mortality compared with those without treatment . Beyond 6 months, beta-blocker therapy was still associated with a non-significant, but numerically lower rate of mortality , as shown in Among GDMTs, AAs had the lowest prescription rate in octogenarian patients. In addition, AAs were being used inappropriately in patients with poor renal function. Only 41.6% of octogenarian HFrEF patients who would have benefited from AAs were actually using them, whereas 15.4% of users showed decreased renal function (serum creatinine > 2.5 mg/dL) and/or elevated potassium levels (serum potassium > 5.0 mmol/L). There was no difference in mortality rates according to AA use at discharge , but a sp = 0.035). The difference was mostly driven by the difference in males , whereas only a modest, non-significant difference was observed in female patients . When RAS inhibitor use in males was further divided as use of angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARB), ACE inhibitors showed a non-significant tendency toward lower HF readmissions , whereas the significant benefit persisted with ARBs , as shown in For octogenarians with HF and preserved EF (HFpEF), RAS inhibitor use was associated with a significantly lower rate of HF readmissions at 6 months  . In a stIn our study cohort, octogenarian patients with HFrEF were not receiving adequate GDMT, even though all patients were followed-up by HF specialists. Inadequate use of medications proven to improve clinical outcomes have been reported repeatedly, and this is not a problem that only affects octogenarians. Recent analysis from the CHAMP-HF (Change the Management of Patients with Heart Failure) registry showed that there were significant gaps in use and doses of GDMT in HFrEF patients . Under-tHowever, the nadir point for DBP associated with mortality was lower in octogenarians, suggesting that they might be more tolerable to lower BP than relatively younger patients. Even for patients with SBP < 125 mmHg or DBP < 70 mmHg, use of RAS inhibitors was associated with a significant reduction in mortality. Octogenarian patients may be chronically adapted to lower BP and less prone to perform abrupt postural changes, which reduces the likelihood of postural dizziness or syncope, and makes them more tolerable to medications. Although the mechanism is not clear, the SPRINT subgroup analysis has also reported that older hypertensive patients showed more favorable outcomes with intensive BP-lowering treatments . Even wiFew studies have evaluated the association between GDMT use and prognosis in elderly HF patients, and have produced inconsistent results. Use of RAS inhibitors have shown to improve survival in octogenarians in the EHFS II (EuroHeart Failure Survey II) , and betp = 0.009). This has also been described in the HOPE  study, which suggested that benefits of RAS inhibitors were due in part to a vasculoprotective effect [For HFpEF patients, there are still no definite guideline-recommended medications known to improve survival. Recent studies have advocated the possibility of angiotensin receptor/neprilysin inhibitors (ARNI) or sodium-glucose transport 2 (SGLT2) inhibitors, but further studies are still warranted. In our analysis of octogenarian HFpEF patients, use of RAS inhibitors, and especially ARBs, were associated with a significant reduction in HF readmissions at 6 months. Of further interest is that a sex difference was observed, and that men with HFpEF benefited from using ARBs. A recent report from PARAGON-HF  showed a significant reduction in hospitalizations among women using sacubitril/valsartan . As the e effect . Future Kaplan–Meier curves for mortality according to use of beta-blockers diverged in the early periods for non-elderly patients, but curves for elderly patients saw no such difference up to 30 days post-discharge. The survival benefit of beta blockade was more evident in patients surviving the first month after discharge. This could be explained by the fact that the rate of early mortality is especially high in elderly patients , and thaThe last important observation is that AAs were not being properly used in elderly HF patients. On the basis of the study population in RALES   and EMPHThe limitations of the study are as follows. First, the current study used data from an observational registry. Although efforts were taken to adjust for differences in baseline characteristics, there are limitations that are intrinsic in the design. Second, the prescription of medications was not fixed during follow-up. Patients may have discontinued or initiated certain treatments during follow-up. We tried to assess the changes in medications by performing separate analyses adjusting for changes in medications up to 6 months, but discontinuations and initiations afterwards could have affected results. Third, as mentioned above, increased age is a significant risk for mortality and morbidity, and the effect of hidden factors could have influenced outcomes. As long-term outcomes were more likely to be influenced by old age and frailty, we assessed mid-term outcomes at 6 months, and also performed landmark analysis at 30 days to exclude severely ill patients. Furthermore, although age is a continuous variable, it was dichotomized to emphasize the unique characteristics of elderly patients. Finally, the number of patients used in our analyses might not have provided sufficient power to fully support our findings. Well-designed, prospective randomized controlled trials focusing on elderly HF patients would be needed to fully understand the complexity in treating these patients.HF in octogenarians have different characteristics compared with the non-elderly. However, adequate use of GDMT was still associated with improved survival. Physicians should be more vigilant in prescribing medications with clinical benefits, even in elderly patients with HF.


Serological testing is needed to investigate the extent of transmission of SARS-CoV-2 from front-line essential workers to their household members. However, the requirement for serum/plasma limits serological testing to clinical settings where it is feasible to collect and process venous blood. To address this problem we developed a serological test for SARS-CoV-2 IgG antibodies that requires only a single drop of finger stick capillary whole blood, collected in the home and dried on filter paper . We describe assay performance and demonstrate its utility for remote sampling with results from a community-based study.An ELISA to the receptor binding domain of the SARS-CoV-2 spike protein was optimized to quantify IgG antibodies in DBS. Samples were self-collected from a community sample of 232 participants enriched with health care workers, including 30 known COVID-19 cases and their household members.Among 30 individuals sharing a household with a virus-confirmed case of COVID-19, 80% were seropositive. Of 202 community individuals without prior confirmed acute COVID-19 diagnoses, 36% were seropositive. Of documented convalescent COVID-19 cases from the community, 29 of 30 (97%) were seropositive for IgG antibodies to the receptor binding domain.DBS ELISA provides a minimally-invasive alternative to venous blood collection. Early analysis suggests a high rate of transmission among household members. High rates of seroconversion were also noted following recovery from infection. Serological testing for SARS-CoV-2 IgG antibodies in DBS samples can facilitate seroprevalence assessment in community settings to address epidemiological questions, monitor duration of antibody responses, and assess if antibodies against the spike protein correlate with protection from reinfection. Serological testing for SARS-CoV-2 IgG antibodies identifies prior viral exposure and, potentially, immunity. Recent surveys suggest a range of seroprevalence rates, with relatively low rates in much of the US ,2. OptimA robust and quantitative ELISA was granted Emergency Use Authorization from the FDA; this ELISA measures SARS-CoV-2 antibodies in serum and has been determined to not cross-react with other common coronavirus strains . This saA detailed assay protocol is supplied in the A community-based sample of 232 adults was recruited through electronic communication initiated by the investigators. Participants completed a brief survey of COVID-19 symptoms and diagnosis, and were provided with materials for DBS collection. DBS sample collection occurred between April 18 and May 20, 2020. All participants returned a blood sample of sufficient quantity and quality for analysis. A set of matched serum and DBS samples was collected from 17 individuals in the study. In addition, DBS samples from 23 individuals presumed to be negative based on the pre-pandemic date of sample collection (2018) were used as negative controls for assay validation. Samples were analyzed in duplicate, with the average result reported.Statistical analyses were performed with Prism . An unpaired two-tailed t-test was used to compare negative and confirmed positive samples. Error bars represent ± standard error of the mean (SEM). Passing-Bablok regression and bivariate correlation were used to evaluate patterns of statistical association across matched DBS and serum samples.CR3022, an antibody with defined affinity to the RBD, was used to validate DBS samples in an ELISA. We observed a strong dose-response between CR3022 concentration and optical density (OD) in wells coated with 2.0 μg/mL RBD , with noThere was clear distinction between positive and negative samples . With onWe evaluated IgG levels to RBD protein in 232 DBS samples acquired from the community . Thirty Among the remaining 202 participants, none of whom tested positive for SARS-CoV-2 with PCR, 60% reported some COVID-19-like symptoms with headache, fatigue, or rhinorrhea being most common. Fifteen of these participants were PCR tested and determined viral negative; of these, 9 were determined to be seronegative, 4 were low seropositive, and 2 were seropositive in DBS. Only one participant required hospitalization for dyspnea (0.8%), and this individual tested viral negative and was low seropositive.Follow-up DBS samples were acquired from 28 seronegative and 19 low seropositive participants, approximately 2–3 weeks (range from 13–23 days) after the original DBS sampling date from May 5 through June 4, 2020. IgG to RBD increased in 10 (35%) of the seronegative participants, shifting 1 to seropositive and 4 to low seropositive . FifteenFor the 202 unconfirmed/negative individuals, IgG concentrations ranged from 0–10 μg/ml, with 33 (16%) seropositive, 40 (20%) low seropositive, and 129 (64%) seronegative . In the A number of participants were from a single healthcare facility in which a number of healthcare workers tested positive for virus while others were found to be viral negative between March 24 to April 3, 2020. Those healthcare workers that remained asymptomatic were not tested for active virus. We evaluated the seroconversion of 48 household members from 33 essential healthcare worker households, 40–50 days post the initial exposure date . ParticiCOVID-19 is now widely acknowledged to have high rates of community spread. Strategic testing in community-based settings is critical for tracking spread of SARS-CoV-2 and for identifying the factors that mitigate transmission. We have validated a DBS assay to facilitate large-scale serological testing of SARS-CoV-2 IgG antibodies, and results from our feasibility study document a high rate of household transmission. In addition, based on Hains et al.  and the Because of their potential risks to patients, health care workers and first responders generally had priority for viral PCR testing to ascertain acute infection. However, limited supplies of viral testing materials often restricted access to viral PCR testing during March and April 2020, which likely resulted in under-testing and under-reporting of COVID-19 cases. Serological testing is positioned better to inform viral exposure especially during the interval when viral PCR testing was less available or weeks after symptom onset. Furthermore, improved and reliable serological surveys, combined with close clinical follow up, can elucidate whether serological status predicts immune protection from repeat infection or disease. DBS sampling can aid in these surveys.Advantages of DBS include a low cost and non-invasive approach to blood collection. DBS samples do not require special handling prior to transport and analysis, and IgG antibodies remain stable in DBS for at least 8 weeks at room temperature ,9. WhileWidespread serological testing is needed to more accurately assess viral spread. While our sample is not representative of the general population, the observation of high household seroconversion, using an assay restricted to a small component of the viral spike protein, suggests there may be higher exposure to COVID-19 among some members of the community than previously appreciated.S1 Data(XLSX)Click here for additional data file.S1 File(DOCX)Click here for additional data file.


Adherence to exercise interventions in patients with cancer is often poorly described. Further, it is unclear if self-regulatory behavior change techniques (BCTs) can improve exercise adherence in cancer populations. We aimed to (1) describe exercise adherence in terms of frequency, intensity, time, type (FITT-principles) and dropouts, and (2) determine the effect of specific self-regulatory BCTs on exercise adherence in patients participating in an exercise intervention during curative cancer treatment.with or without self-regulatory BCTs . The exercise program included supervised group-based resistance training and home-based endurance training. Exercise adherence (performed training/prescribed training) was assessed using attendance records, training logs and heart rate monitors, and is presented descriptively. Linear regression and logistic regression were used to assess the effect of self-regulatory BCTs on each FITT-principle and dropout rates, according to intention-to-treat.This study was a secondary analysis using data from a Swedish multicentre RCT. In a 2×2 factorial design, 577 participants recently diagnosed with curable breast, colorectal or prostate cancer were randomized to 6 months of high (HI) or low-to-moderate intensity (LMI) exercise, with vs without self-regulatory BCTs), participants attended on average 52% vs 53% of prescribed sessions, performed 79% vs 76% of prescribed intensity, and 80% vs 77% of prescribed time. They adhered to exercise type in 71% vs 68% of attended sessions. For endurance training (groups with vs without self-regulatory BCTs), participants performed on average 47% vs 51% of prescribed sessions, 57% vs 62% of prescribed intensity, and 71% vs 72% of prescribed time. They adhered to exercise type in 79% vs 78% of performed sessions. Dropout rates (groups with vs without self-regulatory BCTs) were 29% vs 28%. The regression analysis revealed no effect of the self-regulatory BCTs on exercise adherence.For resistance training .NCT02473003 Using this taxonomy, exercise interventions involving patients with cancer often include self-regulatory BCTs such as goal-setting, self-monitoring, action planning, review of behavioral goals and problem solving.1921 Several of these self-regulatory BCTs have been identified as having the potential to increase adherence to exercise interventions in patients with cancer.20 Exercise adherence in this context is defined as the extent to which intervention participants follow the exercise prescription (i.e. perform exercise according to the intervention protocol).23 A detailed description of adherence should include reports of adherence to frequency, intensity, time and type of exercise (FITT-principles).24 Other metrics such as dropout rates should also be included to provide insight into the efficacy and feasibility of exercise interventions.23It is challenging for many patients to be physically active after a cancer diagnosis.2426 but is central to interpret study findings and implement effective exercise programs into clinical practice.27 Furthermore, although self-regulatory BCTs have frequently been used in interventions to facilitate exercise in patients undergoing cancer treatment,21 no clinical trial has directly examined their effect on exercise adherence according to the FITT-principles and dropout rates. This is of particular interest to better understand how to optimize behavioral support in exercise interventions for patients undergoing cancer treatment.To date, adherence to exercise interventions in patients undergoing cancer treatment has been inadequately reportedThe aims of this study were therefore to (1) provide a detailed description of exercise adherence according to the FITT-principles and dropout rates, and (2) determine the effect of specific self-regulatory BCTs on exercise adherence in patients participating in a 6-month exercise intervention during curative cancer treatment. We hypothesized that self-regulatory BCTs would have a beneficial effect on exercise adherence in terms of higher adherence to the FITT-principles and lower dropout rates.28 The Phys-Can study is a multicentre randomized controlled trial (RCT) with a 2×2 factorial design (NCT02473003), approved by the Regional Ethical Review Board in Uppsala (Dnr 2014/249). All participants provided written informed consent to participate.This study was a secondary analysis using data from the Physical Training and Cancer (Phys-Can) study.28 Briefly, the aim of the Phys-Can study was to compare the effects of high (HI) versus low-to-moderate intensity (LMI) exercise with or without self-regulatory BCTs on cancer-related fatigue in patients undergoing curative (i.e. neoadjuvant or adjuvant) cancer treatment. Eligible patients were aged 18 years or over, newly diagnosed with breast, colorectal or prostate cancer and scheduled to undergo curative cancer treatment. Patients were excluded if they suffered from cognitive dysfunction , physical impairments and/or other diseases  that could affect their ability to perform exercise. The recruitment took place at University hospitals in three of the five largest cities in Sweden  between March 2015 and April 2018. The participants were randomized to one of four intervention groups: (1) HI with self-regulatory BCTs, (2) LMI with self-regulatory BCTs, (3) HI without self-regulatory BCTs or (4) LMI without self-regulatory BCTs.The Phys-Can study has previously been described in detail.with or without self-regulatory BCTs.28 The participants initiated the exercise programs during the same period as they started their cancer treatment. An overview of the exercise prescriptions used in the Phys-Can study is presented in 30 Exercise volume (intensity x time) was the same in all groups, with the HI groups exercising twice as intensely as the LMI groups but for half the time.The 6-month intervention started with a 6-week familiarization period and consisted of supervised group-based resistance training and home-based endurance training, The resistance training was offered twice per week in groups of 5 to 10 participants at public gyms and supervised by study coaches . The program consisted of a total of six exercises . To enabThe endurance training was home-based and followed up regularly by a coach at the gym. Participants in the HI groups were instructed to perform HI interval training  twice per week. The total exercise time per week was 40 minutes (including active rest during the sessions) at the beginning of the training period, and was progressively increased up to 80 minutes at the end of the training period. Participants in the LMI groups were instructed to perform 150 minutes per week of LMI continuous training  in bouts of at least 10 minutes . Individwith self-regulatory BCTs were provided with goal-setting, self-monitoring, action planning, review of behavioral goals and problem solving. These BCTs were delivered face-to-face at nine occasions, except for self-monitoring that was performed by the participants after each training session. A detailed description of the specific self-regulatory BCTs used in the Phys-Can study is presented in The groups with and without self-regulatory BCTs), several actions were taken. Before the intervention started, all coaches attended a 3-day mandatory course where they were trained to supervise participants randomized to one condition (i.e. either with or without self-regulatory BCTs). Coaches who provided self-regulatory BCTs supervised only participants randomized to this condition, and the groups trained on different days. Further, the coaches followed a detailed protocol during the intervention and kept a week-by-week checklist for each participant where notes about deviations from the protocol were made. Finally, research staff made repeated visits to the gyms and arranged group meetings (including twice-monthly tele conferences) with the coaches throughout the intervention to ensure that the intervention was delivered as planned.All groups were provided with a certain level of support such as instructions on how to exercise, graded tasks, self-registration of exercise, feedback on exercise behavior as well as social support from coaches and peers. However, to ensure a clear delimitation between the conditions  for resistance training and endurance training was also assessed. Exercise adherence was calculated as performed training divided by prescribed training. A detailed description of how each exercise adherence component was calculated and how adherence data were collected is presented in Data were collected between March 2015 and November 2018. Clinical and demographic information was gathered from medical records and study-specific forms. Exercise adherence, defined as the extent to which the participants followed the exercise prescription according to the intervention protocol,Exercise adherence is reported using descriptive statistics, i.e. mean percentage (SD) or number (%) as appropriate. Multiple linear regression (for resistance and endurance training separately) and logistic regression (for dropout rates) were performed to determine the effect of self-regulatory BCTs on each outcome. Analyses were conducted according to intention-to-treat and models were adjusted for exercise intensity, interaction (exercise intensity × self-regulatory BCTs), study site and cancer diagnosis. Dichotomous variables were generated for nominal variables with two categories . Study site and cancer diagnosis had three categories and were included in models using dummy-coding. The effect of the self-regulatory BCTs on each FITT-principle and dropout rates is presented as unstandardized regression coefficients (B) with 95% Confidence Intervals (95% CI). The regression coefficients can be interpreted as the mean difference in % adherence due to the main effect of the self-regulatory BCTs. All data analyses were performed with the Statistical Package for the Social Sciences .In total, 600 participants were consecutively recruited. Twenty-three participants (4%) withdrew from the study before randomization and 577 (96%) were randomized to one of the four intervention groups. Participants’ mean age was 58.7 years (SD 12). The majority was diagnosed with breast cancer (n = 457), followed by prostate cancer (n = 97) and colorectal cancer (n = 23). Participants reported their previous exercise habits as median 210 minutes (IQR 120-360) of weekly moderate- to high-intensity exercise, and median 0 (IQR 0-1) weekly resistance training session. Participants’ characteristics in the four groups were similar at baseline .with vs without self-regulatory BCTs respectively.Missing data (two training logs in each group) were interpreted as no training sessions were performed (0% adherence). Exercise adherence to resistance and endurance training, as well as dropout rates, are provided for each intervention group in with vs without self-regulatory BCTs), participants performed on average 50% (31) and 51% (31) of the prescribed volume for the entire training period . More specifically, participants attended 52% (31) and 53% (32) of prescribed sessions. When participants attended a session, they performed 79% (37) and 76% (39) of prescribed intensity (weight), and 80% (37) and 77% (39) of prescribed time (set and repetitions). Finally, they adhered to exercise type in 71% (41) and 68% (42) of attended sessions (For supervised group-based resistance training (groups sessions .with vs without self-regulatory BCTs), participants performed on average 48% (37) and 46% (36) of the prescribed volume for the entire training period . More specifically and only for the HI groups, participants performed on average 47% (35) and 51% (35) of prescribed sessions. They performed 57% (34) and 62% (36) of prescribed intensity, and 71% (36) and 72% (38) of prescribed time during the performed sessions. Finally, they adhered to exercise type in 79% (36) and 78% (38) of performed sessions (For home-based endurance training (groups sessions .with vs without self-regulatory BCTs), 29% and 28% of the participants permanently discontinued exercising during the intervention . The regression analysis revealed no effect of the self-regulatory BCTs on any outcome  for adherence to frequency to 3.1  for adherence to time. The main effects for home-based endurance training ranged from −4.5  for adherence to intensity to 1.9  for overall adherence. Finally, the main effect for dropout rates was 0.08 .The delivery of self-regulatory BCTs was similar between the groups allocated to receive this support  and time (sets and repetitions) while undergoing curative cancer treatment. However, the attendance rates were not optimal, which implies that encouraging patients to attend the gym may be the critical challenge for enhancing exercise adherence in future interventions. The difficulty of attending the gym may be explained by cancer-related barriers , which have been previously described as the main reason for lower attendance during treatment.36 Thus, our findings reflect the need to overcome such barriers where possible. A periodized exercise prescription with adjustments for such cancer-related barriers  could be appropriate. Indeed, one explanatory study reported that a “chemotherapy-periodization” of exercise for patients with breast cancer participating in supervised gym-based training resulted in higher attendance rates compared with regular exercise prescription.31 Similar adjustments could be made in future exercise interventions involving patients undergoing other cancer treatments, but research is needed to examine how such individualization could be applied. For home-based endurance training, frequency and intensity for HI training was lower in our study than previously reported in other intervention studies involving similar populations.3739 Nonetheless, those interventions often consisted of supervised endurance training and/or fewer intervals, which could explain the observed differences. The dropout rates within the Phys-Can study were higher than those reported in previous studies involving patients with cancer.40 However, those interventions were usually shorter, conducted after treatment and involved less comprehensive exercise programs, therefore taking part in our intervention was likely more challenging for participants.40 Another possible explanation is that we included in our calculations of dropout rates participants who permanently discontinued exercise before the end of the intervention without leaving the study. Studies usually only include participants who did not complete follow-up assessments.4143 However, we believe that including participants who permanently discontinued exercise gives a more accurate picture of the feasibility of such exercise programs during curative treatment,23 which is valuable information for future interventions.For supervised group-based resistance training, exercise adherence was within the range reported in other exercise interventions involving patient undergoing curative cancer treatment.20 However, it is important to take into account that all groups in the Phys-Can study were provided with evidence-based support such as supervision, instructions on how to exercise, graded tasks, self-registration of exercise, feedback on exercise behavior as well as social support from coaches and peers.21 This was done to ensure that all participants achieved a minimum exercise volume in order to detect possible effects of exercise intensity on the Phys-Can study’s main outcome. It was a precarious balance between being able to evaluate the effects of exercise on the main outcome and evaluating the effect of self-regulatory BCTs on exercise adherence. Thus, the lack of effect of the self-regulatory BCTs could be due to the fact that all groups were provided with enough support to facilitate exercise, and that self-regulatory BCTs as additional support was not sufficient to make a difference. This is consistent with findings published in a previous mixed-methods study, where our participants described that they perceived the support provided to all as more useful than self-regulatory BCTs for performing exercise.44 The lack of effect of the self-regulatory BCTs could also be explained by our participants’ motivation level and exercise habits. All participants agreed to take part in a demanding exercise intervention for 6 months during cancer treatment and so were per definition motivated enough to participate. Further, a majority was already physically active before entering the study. Previous research has demonstrated that baseline motivation and previous exercise habits are strong predictors for exercise adherence after a cancer diagnosis.46 It is thus possible that a more heterogeneous clinical population with lower baseline motivation levels and poorer exercise habits may benefit from these self-regulatory BCTs, but this needs to be further investigated. Finally, another possible explanation is that, despite a high motivation to participate in the study and the use of self-regulatory BCTs, participants did not manage to exercise as prescribed because the prescription may not have been totally in line with their own exercise preferences and needs. Our participants were randomized to one condition and could therefore not choose to perform the exercise mode (resistance vs endurance) and intensity (LMI vs HI) they preferred. Yet it is well established that incorporating patients’ preferences and determining what is important to them is essential for behavioral strategies to be effective.47In the present study, we used a combination of five frequently used self-regulatory BCTs  to facilitate exercise in two of the four intervention groups. The analyses did not reveal any effect of these specific BCTs on any aspect of exercise adherence (FITT-principles and dropout rates). Our results are in contrast with previous studies, where self-regulatory BCTs were found to be associated with higher adherence to exercise interventions in patients with cancer.with and without self-regulatory BCTs). A further strength is the detailed description of the study exercise prescription and adherence, allowing replication of our intervention and highlighting the difficulties that patients may encounter. Limitations include the risk that participants may have under- or over reported endurance training sessions during the 6-month intervention or had technical issues with the heart rate monitors, which could affect the descriptive data. However, by using a combination of data from training logs and heart rate monitors, most of the performed sessions were correctly captured. Furthermore, we could not calculate adherence to frequency, intensity, time, and type for endurance training in the LMI groups. This is because no exercise prescription for frequency was determined by our study protocol. Further, participants in the LMI groups were asked to report or record a maximum of 150 minutes of LMI per week  to minimize burden that a self-registration of exercise for 6 months may imply. We were therefore limited in the possibilities to explore this data in depth. However, the overall adherence rates calculated (corresponding to the exercise volume performed during the entire intervention) still provide valuable information for the LMI groups. Finally, the generalizability of our findings may be limited, considering that our participants were mainly women treated for breast cancer, who were physically active, highly educated and motivated to take part in a comprehensive 6-month intervention. Thus, our results may not be applicable to all patients in clinical settings. However, readers are provided with details regarding the study settings and baseline characteristics of our sample, and should be able to evaluate for which target groups the study provides valuable information.The strengths of our study include using data from a large multicentre RCT to provide detailed information about exercise adherence and effect of self-regulatory BCTs in patients undergoing curative cancer treatment. Intervention integrity was carefully controlled to ensure a clear delimitation between the conditions . Thus, such support may be sufficient for patients motivated enough to exercise during treatment, which is worth considering when aiming to implement exercise interventions in clinical settings. However, a more heterogeneous population with low motivation and exercise levels may benefit from these self-regulatory BCTs, but this needs to be further investigated.


Successful mitotic cell division is critically dependent on the formation of correct attachments between chromosomes and spindle microtubules. Microtubule attachments are mediated by kinetochores, which are large proteinaceous structures assembled on centromeric chromatin of mitotic chromosomes. These attachments must be sufficiently stable to transduce force; however, the strength of these attachments are also tightly regulated to ensure timely, error-free progression through mitosis. The highly conserved, kinetochore-associated NDC80 complex is a core component of the kinetochore-microtubule attachment machinery in eukaryotic cells. A small, disordered region within the Hec1 subunit of the NDC80 complex – the N-terminal “tail” domain – has been actively investigated during the last decade due to its roles in generating and regulating kinetochore-microtubule attachments. In this review, we discuss the role of the NDC80 complex, and specifically the Hec1 tail domain, at the kinetochore-microtubule interface, and how recent studies provide a more unified view of Hec1 tail domain function. Congression of mitotic chromosomes relies on interactions between spindle microtubules and kinetochores, which are comprised of a large number of proteins and multi-protein complexes assembled on regions of centromeric heterochromatin within each sister chromatid . KinetocRING finger, WD repeat, DEAD-like helicase) fold, through which they associate with either the Mis12 complex (bound to CENP-C or CENP-T) or CDK1-phosphorylated CENP-T to anchor the NDC80 complex to the kinetochore  phosphorylation of the tail by the Aurora family of kinases regulates kinetochore-microtubule attachment stability; and (2) the tail contributes to the establishment and maintenance of force-generating kinetochore-microtubule attachments in cells. It is unclear if these two functions of the Hec1 tail are conserved across species, as its contribution to these processes differ between organisms. In the following sections, we will discuss our current understanding of the role of the Hec1 tail domain in phosphoregulation of kinetochore-microtubule attachments, and in generating and maintaining force-transducing attachments during mitosis.At the core of the kinetochore’s force-transducing microtubule binding activity is the NDC80 complex, a heterotetrameric protein complex comprised of Hec1 , Nuf2, Spc24, and Spc25. Extending roughly 60 nm in length, the NDC80 complex is a dumbbell-shaped structure with two globular domains on each end, connected by a central coiled-coil shaft . At one etochore . The N-tetochore . The Hecetochore . At the etochore , a conseetochore . The Hecetochore . In all in vitro . At its in vitro . A largeDuring mitotic progression, a critical function of kinetochores is to adjust the strength with which they bind to spindle microtubules to control kinetochore-microtubule attachment stability. In early mitosis, kinetochore-microtubule attachments are unstable and undergo rapid turnover as a consequence, thus enabling improper attachments to be “reset” until correct, amphitelic attachments are established . As mitoIn vitro kinase assays and mass spectrometry analysis revealed that a recombinantly expressed Hec11–230 fragment was phosphorylated by Aurora B kinase on multiple sites in its far N-terminal domain. Mutagenesis of these target sites to prevent phosphorylation partially recapitulated the microinjection results, suggesting that the injection phenotypes were, at least in part, due to loss of Hec1 tail domain phosphoregulation  or to mimic phosphorylation (by substitution with either aspartic acid or glutamic acid). In these studies, preventing phosphorylation of the Hec1 tail resulted in hyper-stabilization of kinetochore-microtubule attachments, while mimicking phosphorylation led to unstable attachments in cells  bound microtubules with significantly lower affinity than unphosphorylated complexes. Subsequent studies reported similar decreases in binding affinity for microtubules in vitro using purified human NDC80 complexes assembled with mutants of Hec1 containing phospho-mimetic substitutions at Aurora B kinase target sites , in which cells were microinjected with an antibody directed to the N-terminus of Hec1 . Injectegulation . These rin cells . Coincidet sites . Togetheotubules .in vitro  (in vitro by the phosphorylation state of the Hec1 tail domain would shed light on this interesting question.ic acid) . This inic acid) . These ric acid) . A role ic acid) . Reducedic acid) . It is ain vitro assays have allowed investigation into how phosphorylation of the Hec1 tail affects the ability of NDC80 complexes to track with and transduce forces from polymerizing and depolymerizing microtubules. In a recent study, In vitro, NDC80 complexes bind more weakly to depolymerizing microtubule ends than to polymerizing ends, and this has been attributed to a lower affinity of the Hec1 CH domain for curved microtubule protofilaments  that disrupts its centromere localization, but not its microtubule binding activity, has no negative consequence on chromosome bi-orientation or Aurora B-mediated kinetochore-microtubule error correction  out of the kinase’s “reach,” and consequently reducing the extent of their phosphorylation . A numberrection . Collectrrection . Identifrrection . It is nDrosophila S2 cells led to a reduced incidence of experimentally induced syntelic attachments, and depletion of Aurora A from PtK1 cells resulted in a significant increase in spindle pole-associated chromosomes  . While Mrevisiae . Studiesin vitro . The exaC. elegans, preventing PP1 recruitment to its docking site on the kinetochore protein KNL1 delayed formation of load-bearing kinetochore-microtubule attachments; however, cells exhibited no obvious defects in chromosome segregation  destabilized kinetochore-microtubule attachments in cells  from all species tested to date. For example, Bonsai) and demonstrated that tail-less complexes exhibited decreased co-sedimentation with microtubules, with calculated binding affinities of ∼100X lower than wild-type complexes. These results reported for human NDC80Bonsai complexes were later corroborated by C. elegans NDC80 complexes, in which mutants lacking the N-terminal 60 amino acid Hec1/Ndc80 tail domain exhibited severely reduced microtubule binding affinity , while the microtubule surface is enriched in negatively charged residues, many of which are within the unstructured C-terminal acidic tail domains of alpha and beta tubulin, which extend outward from the microtubule surface . As suchin vitro , and remin vitro . Furtherin vitro . Althougin cells . These din cells . An impoin cells .in vitro (The direct tail-microtubule binding model has also been useful for explaining how phosphorylation of the tail domain regulates kinetochore-microtubule attachment stability. In this model, addition of phosphate groups by Aurora kinases, or introduction of phospho-mimetic mutations in the Hec1 tail – both of which reduce the positive charge of the tail – are predicted to decrease NDC80 complex-microtubule binding affinity in vitro . This isin vitro . In factin vitro . While din vitro .Bonsai complex-decorated microtubules that allowed for docking of the solved crystal structures of both tubulin and NDC80Bonsai lacking the Hec1 tail domain. Electron densities were observed between adjacent NDC80 complexes that were not present in the crystal structures, and therefore the authors attributed these densities to the Hec1 tail (Multiple studies have suggested that the Hec1 tail domain promotes NDC80 complex-microtubule binding by affecting oligomerization of NDC80 complexes , 2012. Iec1 tail . Additioec1 tail . In a suec1 tail . Hec1 taec1 tail . Specifiec1 tail . As a coAlthough these studies support the notion that the Hec1 tail domain facilitates high affinity microtubule binding through phosphoregulated oligomerization of NDC80 complexes, several lines of evidence indicate that this may not be the case. For instance, multiple studies have reported that phospho-mimetic substitutions in the Hec1 tail decrease microtubule-binding affinity of single NDC80 complexes independently of their oligomerization . FurtherBonsai complexes recruit “V”-shaped structures to the microtubules that were posited to be Ska complexes based on their size and shape (in vitro (C. elegans and human cells (Bonsai complexes, which are missing most of this internal coiled-coil, are unable to interact with Ska complexes (In a third model, the Hec1 tail may regulate kinetochore-microtubule attachment stability in cells by recruiting additional microtubule-binding proteins to the kinetochore . During nd shape . Mutagennd shape . The autin vitro , and foran cells . Insteadomplexes , presumaomplexes . Thus, aC. elegans embryos resulted in premature and enhanced recruitment of Ska complexes to kinetochores, as well as hyper-stabilized kinetochore-microtubule attachments (The phosphorylation state of the Hec1 tail has also been implicated in regulating recruitment of the Ska complex to kinetochores . Expressachments . The autachments . Howeverachments . Thus, tAs mitosis progresses, dephosphorylation of the Hec1 tail, stabilization of kinetochore-microtubule attachments, and Ska loading onto kinetochores are all largely coincident . This leIn summary, cells likely employ multiple mechanisms, including aspects of the three described above, to ensure precise regulation of kinetochore-microtubule attachments. An important goal for the future will be to determine how Hec1 tail domain phosphorylation functions in concert with other kinetochore-associated microtubule binding proteins to affect kinetochore-microtubule attachment dynamics and stability.The small unstructured Hec1 tail domain clearly plays an important role at the kinetochore-microtubule interface during mitosis. Given the large body of work dissecting the role of phosphorylation of the Hec1 tail in regulating this interface, its role in coordinating temporal regulation of kinetochore function is becoming somewhat clear. Many questions still remain, however, including how the activities of the kinases and phosphatases that act on this domain are spatially and temporally regulated to ensure appropriate kinetochore-microtubule attachment strength.in vitro suggest that the tail domain is not explicitly required for generating kinetochore-microtubule attachments, but instead, plays a more nuanced role in harnessing the forces from dynamic microtubule plus-ends to power chromosome movement and silence the spindle assembly checkpoint. These studies, together with those carried out over the last decade in a number of eukaryotic species, suggest a more conserved role for the Hec1/Ndc80 tail domain across organisms.In contrast to the well-defined role for the tail domain in regulation of kinetochore-microtubule attachments, its role in their establishment and maintenance is still not entirely resolved. Recent studies of human NDC80 complexes in cells and JD and RW researched, wrote, and edited the manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.