Racial, Ethnic, and Socioeconomic Disparities in Treatment Delay Among Patients With Hepatocellular Carcinoma in the United States.

BACKGROUND & AIMS: Failures have been reported across the cancer care continuum in patients with hepatocellular carcinoma (HCC); however, the impact of treatment delays on outcomes has not been well-characterized. We described the prevalence of treatment delays in a racially and ethnically diverse cohort of patients and its association with overall survival. METHODS: Using the Surveillance, Epidemiology, and End Results-Medicare database, we identified patients diagnosed with HCC between 2001 and 2015. We performed multivariable logistic regression analysis to identify factors associated with treatment delay (ie, receipt of HCC-directed therapy >3 months after diagnosis). Cox proportional hazards regression analysis with a 5-month landmark was used to characterize the association between treatment delay and overall survival, accounting for immortal time bias. RESULTS: Of 8450 patients with treatment within 12 months of HCC diagnosis, 1205 (14.3%) experienced treatment delays. The proportion with treatment delays ranged from 6.8% of patients undergoing surgical resection to 21.6% of those undergoing liver transplantation. In multivariable analysis, Black patients (odds ratio, 1.96; 95% confidence interval [CI], 1.21-3.15) and those living in high poverty neighborhoods (odds ratio, 1.55; 95% CI, 1.25-1.92) were more likely to experience treatment delays than white patients and those living in low poverty neighborhoods, respectively. Treatment delay was independently associated with worse survival (hazard ratio 1.15, 95% CI, 1.05-1.25). CONCLUSIONS: Nearly 1 in 7 patients with HCC experience treatment delays, with higher odds in Black patients and those living in high poverty neighborhoods. Treatment delays are associated with worse survival, highlighting a need for interventions to improve time-to-treatment.

Views on increased federal access to state and local National Syndromic Surveillance Program data: a nominal group technique study with state and local epidemiologists.

BACKGROUND: US public health authorities use syndromic surveillance to monitor and detect public health threats, conditions, and trends in near real-time. Nearly all US jurisdictions that conduct syndromic surveillance send their data to the National Syndromic Surveillance Program (NSSP), operated by the US. Centers for Disease Control and Prevention. However, current data sharing agreements limit federal access to state and local NSSP data to only multi-state regional aggregations. This limitation was a significant challenge for the national response to COVID-19. This study seeks to understand state and local epidemiologists' views on increased federal access to state NSSP data and identify policy opportunities for public health data modernization. METHODS: In September 2021, we used a virtual, modified nominal group technique with twenty regionally diverse epidemiologists in leadership positions and three individuals representing national public health organizations. Participants individually generated ideas on benefits, concerns, and policy opportunities relating to increased federal access to state and local NSSP data. In small groups, participants clarified and grouped the ideas into broader themes with the assistance of the research team. An web-based survey was used to evaluate and rank the themes using five-point Likert importance questions, top-3 ranking questions, and open-ended response questions. RESULTS: Participants identified five benefit themes for increased federal access to jurisdictional NSSP data, with the most important being improved cross-jurisdiction collaboration (mean Likert = 4.53) and surveillance practice (4.07). Participants identified nine concern themes, with the most important concerns being federal actors using jurisdictional data without notice (4.60) and misinterpretation of data (4.53). Participants identified eleven policy opportunities, with the most important being involving state and local partners in analysis (4.93) and developing communication protocols (4.53). CONCLUSION: These findings identify barriers and opportunities to federal-state-local collaboration critical to current data modernization efforts. Syndromic surveillance considerations warrant data-sharing caution. However, identified policy opportunities share congruence with existing legal agreements, suggesting that syndromic partners are closer to agreement than they might realize. Moreover, several policy opportunities (i.e., including state and local partners in data analysis and developing communication protocols) received consensus support and provide a promising path forward.

Shifts in Social Determinants of Vitamin A Supplementation Among Children Under Five in Kenya, 2003-2014.

OBJECTIVES: In Africa and Asia, 190 million preschoolers are vitamin A deficient. This study examined the social determinants of intake of vitamin A supplementation (VAS) among children aged 6-59 months during three different time periods in Kenya to identify those most vulnerable to vitamin A deficiency and highlight the varied targeting and outreach efforts; before the onset of a national restructuring and targeted distribution of VAS in children below 5 years through a twice-yearly door-to-door campaign called Child Health Weeks, during the implementation period, and several years later. METHODS: The cross-sectional, national Demographic and Health Surveys were administered in Kenya in 2003, 2008-09, and 2014. Bivariate and multivariable logistic regression analyses were used to assess variables associated with VAS among children (n = 28,239). RESULTS: An overall two-fold increase in VAS was recorded between 2003 (31.8%) and 2014 (67.5%). In 2008-09, children aged 6-11 months were the most likely to receive VAS. In 2003 and 2014, geographical regions and settings, birth order of the child, educational level of the mother, religion, wealth index, number of antenatal visits, and access to a radio were identified as being significantly associated with VAS, in at least one of the years. These determinants were not significant in 2008-09 during the initial Child Health Weeks promotion campaign. The determinants of VAS varied during the three study periods, particularly in 2008-09 when the Child Health Weeks was first implemented. CONCLUSION: As efforts to increase VAS continue, addressing child-specific determinants will be essential to reduce health disparities.

Physician Trust in the News Media and Attitudes toward COVID-19.

CONTEXT: Previous research has established the importance of primary care physicians in communicating public health directives. The implicit assumption is that, because of their expertise, doctors provide accurate and up-to-date information to their patients independent of partisan affiliation or media trust. METHODS: The authors conducted an online survey of 625 primary care physicians and used the results to test (1) whether physician trust in media outlets is consistent with their political partisanship, and (2) whether trust in media outlets influences (a) personal concern that someone in their family will get sick, (b) perceptions about the seriousness of the pandemic as portrayed in the media, and (c) trust in federal government agencies and scientists. FINDINGS: Physicians are better positioned to critically evaluate health-related news, but they are subject to the same biases that influence public opinion. Physicians' partisan commitments influence media trust, and media trust influences concern that a family member will get sick, perceptions regarding the seriousness of the pandemic, and trust in federal government agencies and scientists. CONCLUSIONS: Physician trust in specific media outlets shapes their understanding of the pandemic, and-to the extent that they trust conservative media outlets-it may limit their effectiveness as health policy messengers.

Nonhuman primates learn adjacent dependencies but fail to learn nonadjacent dependencies in a statistical learning task with a salient cue.

There is ample evidence that humans and nonhuman animals can learn complex statistical regularities presented within various types of input. However, humans outperform their nonhuman primate counterparts when it comes to recognizing relationships that exist across one or several intervening stimuli (nonadjacent dependencies). This is especially true when the two elements in the dependency do not share any perceptual similarity (arbitrary associations). In the present study, we investigated whether manipulating the saliency of the predictive stimulus would enhance nonadjacent dependency learning in nonhuman primates. Rhesus macaques and tufted capuchins engaged in a computerized signal detection task that included sequences that were random in nature, included an adjacent dependency, or included a nonadjacent dependency. We manipulated the saliency of the predictive stimulus, such that the predictor jittered in place on the screen in some grammar blocks, as well as the transitional probability (the likelihood of the stimulus preceding the target to accurately predict the target's appearance) from block to block. Some monkeys evidenced learning of adjacent dependencies by faster response times to targets that followed a predictive stimulus compared to targets that were not preceded by a predictor. However, consistent with the body of evidence that indicates that nonhuman animals' statistical learning mechanisms are not at the same level of sophistication as humans', there was no evidence that monkeys learned nonadjacent dependencies of arbitrary associations, even when the salient cue was present.

Community health worker roles and their evolving interprofessional relationships in the United States.

In the United States, growing attention to the cost of care, the social determinants of health, prevention, and population health, signals a refocusing of efforts on value-based care. Just as Accountable Care Organizations and alternative payment models exemplify this shift in attention, so does the increasing integration of Community Health Workers (CHWs) into the US health care system. CHWs are often referred to as "bridge figures," helping clients to navigate what are oftentimes complicated pathways to access a variety of needed services. The integration of CHWs into interprofessional care teams is a process that takes time, and can lead to conflict as traditional care models are disrupted. Through focus groups with CHWs in rural and urban areas of four states, this work identifies and describes three early stages in the evolving interprofessional relationships between CHWs and other care providers. These stages are characterized by: (1) a lack of knowledge and understanding of CHW roles, (2) conflict and competition, and (3) engagement and integration of CHWs into patient care teams. A better understanding of the evolving process of CHW integration is critical to facilitate education and training that will more quickly encourage the development and efficacy of modern models of interprofessional care that include CHWs.

In Vivo Half-Life Extension of BMP1/TLL Metalloproteinase Inhibitors Using Small-Molecule Human Serum Albumin Binders.

Reducing the required frequence of drug dosing can improve the adherence of patients to chronic treatments. Hence, drugs with longer in vivo half-lives are highly desirable. One of the most promising approaches to extend the in vivo half-life of drugs is conjugation to human serum albumin (HSA). In this work, we describe the use of AlbuBinder 1, a small-molecule noncovalent HSA binder, to extend the in vivo half-life and pharmacology of small-molecule BMP1/TLL inhibitors in humanized mice (HSA KI/KI). A series of conjugates of AlbuBinder 1 with BMP1/TLL inhibitors were prepared. In particular, conjugate c showed good solubility and a half-life extension of >20-fold versus the parent molecule in the HSA KI/KI mice, reaching half-lives of >48 h with maintained maximal inhibition of plasma BMP1/TLL. The same conjugate showed a half-life of only 3 h in the wild-type mice, suggesting that the half-life extension was principally due to specific interactions with HSA. It is envisioned that conjugation to AlbuBinder 1 should be applicable to a wide range of small molecule or peptide drugs with short half-lives. In this context, AlbuBinders represent a viable alternative to existing half-life extension technologies.

Predictors of Multiple Emergency Department Utilization Among Frequent Emergency Department Users in 3 States.

BACKGROUND: Research on frequent emergency department (ED) use shows that a subgroup of patients visits multiple EDs. This study characterizes these individuals. OBJECTIVE: The objective of this study was to determine how many frequent ED users seek care at multiple EDs and to identify sociodemographic, clinical, and contextual factors associated with such behavior. RESEARCH DESIGN: We used the 2011-2014 Healthcare Cost and Utilization Project State Emergency Department Databases data on all outpatient ED visits in New York, Massachusetts, and Florida. We studied all adult ED users with ≥5 visits in a year and defined multisite use as visits to ≥3 different sites. We estimated predictors of multisite use with multivariate logistic regressions. RESULTS: Across all 3 states, 1,033,626 frequent users accounted for 7,613,077 ED visits. Of frequent users, 25% were multisite users, accounting for 30% of the visits studied. Frequent users with at least 1 visit for mental health or substance use-related diagnosis were more likely to use multiple sites. Uninsured frequent users and those with public insurance were associated with less use of multiple EDs than those with private coverage while lacking consistent coverage by the same insurance within each year were associated with using multiple sites. CONCLUSIONS: Health policy interventions to reduce duplicative or unnecessary ED use should apply a population health perspective and engage multiple hospitals. Community-level preventive approaches and a stronger infrastructure for mental health and substance use are essential to mitigate multisite ED use.

Violence against healthcare workers and other serious responses to medical disputes in China: surveys of patients at 12 public hospitals.

BACKGROUND: Workplace violence against healthcare workers is a global issue that is on the rise, with Chinese healthcare workers facing growing challenges with hospital violence. Attacks on medical staff have increased in recent years with no clear resolution. Prior research focused on policies to improve the doctor-patient relationship and better protect clinicians, but few studies addressed the patient perspective. This paper examines patients' choices when facing a medical dispute and identifies groups who are more likely to respond to conflict with violence or other serious actions. METHODS: Patient survey responses were collected in 12 leading public hospitals in five Chinese provinces with 5556 participants. The survey asked sociodemographic information, patients' attitudes (e.g., general optimism, trust in their physicians, perceived healthcare quality), and their primary response to a medical dispute. From least to most severe, the options range from "complaining within the family" to "violence." We used t-tests and Chi-square tests to explore the relationships between reactions and patient characteristics. We also performed multivariable logistic regressions to determine the impact of sociodemographics and provider trust on the seriousness of responses. RESULTS: The primary response of a third of respondents was complaining to hospital or health department officials (32.5%). Seeking legal help (26.3%) and direct negotiation with doctors (19.6%) were other frequent responses. More serious responses included 83 stating violence (1.5%), 9.7% expressing a desire to expose the issue to the news media, and 7.4% resorting to seeking third-party assistance. Patients who were more likely to report "violence" were male (OR = 1.81, p < .05), high-income earners (OR = 3.71, p < .05), or reported lower life satisfaction (OR = 1.40, p < .05). Higher trust scores were associated with a lower likelihood of a serious response, including violence (OR = 0.80, p < .01). CONCLUSION: Most respondents reported mild reactions when facing a medical dispute. Among those who reported the intent of serious reactions, some sociodemographic characteristics and the trust of physicians could be predictive. To prevent future hospital violence, this work helps identify the characteristics of patients who are more likely to seek severe approaches to medical dispute resolution, including resorting to violence. From these results, hospitals will be better able to target specific groups for interventions that build patient-provider trust and improve general patient satisfaction.

Immigrant health access in Texas: policy, rhetoric, and fear in the Trump era.

BACKGROUND: Since the 2016 presidential election, reports have suggested that President Trump's rhetoric and his administration's proposed policies could be exacerbating barriers to accessing health care for undocumented as well as lawfully present immigrants and their families in the United States. However, very little empirical work has analyzed this possibility or detailed how these reports and rhetoric have altered the health seeking behavior of mixed immigration status families. METHODS: Using a series of focus groups throughout Texas in both English and Spanish, this qualitative study analyzes changes to health access for immigrants. We consulted Community Health Workers to better understand the barriers encountered by their otherwise hard-to-reach undocumented clients and their families as they interface with the health system, revealing key insights about the changing nature of barriers to access under the Trump administration. RESULTS: We identify four key themes about the changing nature of immigrant health access in the United States: growing fear of interacting with health and social services; that social networks are paradoxically limiting health access in the current political climate; that the administration's rhetoric and proposed policies are impeding health seeking behavior; and that children are encountering new barriers to social program participation. CONCLUSIONS: The Trump administration, its proposed immigration policies, and his rhetoric are posing new and significant barriers to health access for immigrants and their families.

Breaking the link: Distraction from emotional cues reduces the association between trait disinhibition and reactive physical aggression.

Research has implicated biased attention allocation toward emotional cues as a proximal mechanism in the association between trait disinhibition and physical aggression. The current study tested this putative cognitive mechanism by incentivizing a shift of attention from a provoking stimulus to a neutral stimulus during a laboratory aggression paradigm. Participants were 119 undergraduate men. They completed a questionnaire that assessed trait disinhibition, were randomly assigned to a distraction or no-distraction control condition, and completed a shock-based aggression task in which they received low and high provocation from a fictitious opponent. A significant positive association between trait disinhibition and physical aggression was found among non-distracted participants exposed to high, but not low, provocation. Distraction from provoking cues significantly attenuated this association. This study is among the first to provide experimental evidence of (a) the positive relation between trait disinhibition and laboratory-based physical aggression, and (b) a potential method for attenuating this association.

Rhesus monkeys (Macaca mulatta) remember agency information from past events and integrate this knowledge with spatial and temporal features in working memory.

The purpose of the present study was to examine whether rhesus monkeys remember information about their own agency-along with spatial, temporal and contextual properties-from a previously experienced event. In Experiment 1, rhesus monkeys (n = 4) used symbols to reliably indicate whether they had performed or observed an event on a computer screen. In Experiment 2, naïve and experienced monkeys (n = 8) reported agency information when stringent controls for perceptual and proprioceptive cues were included. In Experiment 3, five of the monkeys completed a task in which they reported agency information along with spatial and temporal features of events. Two monkeys performed this agency discrimination when they could not anticipate which memory test they would receive. There was also evidence that these features were integrated in memory. Implications of this research are discussed in relation to working memory, episodic memory and self-awareness in nonhuman animals.

Simians in the Shape School: A comparative study of executive attention.

Executive functions (EF) have been studied extensively in children and adults. However, EF tasks for young children can be difficult to administer and interpret. Espy (1997, Developmental Neuropsychology, 13, 495-499) designed the Shape School task to measure inhibition and switching in preschool-aged children. Shape School presents cartoon-like characters that children must flexibly name by their color, their shape, or both, depending on cues that indicate the appropriate rule. Shape School has been found to be age sensitive as well as predictive of performance on other EF tasks. We presented a computerized analogue of Shape School to seven rhesus macaques. Monkeys were trained to categorize characters by color or shape, or to inhibit this response, depending on whether the characters had eyes open, eyes closed, or wore hats. Monkeys performed above chance on the inhibition and switching components of the task. Long runs of a single classification rule and long runs of noninhibition trials had no significant impact on performance when the rule changed or inhibition was required. This nonverbal adaptation of Shape School can measure EF in nonhuman animals and could be used in conjunction with other EF tasks to provide a clearer picture of both human and nonhuman executive functions.

Effect of the treatment-before-deposit policy on trust in physicians and perceived service quality among patients in 12 hospitals in China.

This study examined effects of the treatment-before-deposit policy on Chinese patients' trust in physicians and perceived service quality. This study included 3313 patients recruited from 12 hospitals in China. The research team used cross-sectional survey to examine Chinese patients' experience with the treatment-before-deposit policy, perceived service quality, and trust in their physicians. Using mediation analysis, we estimated direct and indirect effects of the treatment-before-deposit policy on patients' perceived service quality and trust in their physicians. Patients who benefitted from the treatment-before-deposit policy reported greater service quality and higher trust in their physicians. The impacts of whether patients benefitted from the policy on trust in physicians were fully mediated by perceived service quality with statistically significant indirect effect. The results support the hypothesis that the treatment-before-deposit policy improves patients' perceived service quality and trust in physicians.

Judgments of Monkey's (Macaca mulatta) Facial Expressions by Humans: Does Housing Condition "Affect" Countenance?

The ability to interpret facial expressions of others is one of the more important abilities possessed by humans. However, is it possible for humans to accurately interpret the facial expressions of another species of primate, namely rhesus monkeys (Macaca mulatta)? We investigated this possibility by taking digital photos of four rhesus monkeys housed either singly or socially and allowing thirty-one participants to judge these photographs as representing either a happy, sad, or neutral monkey. Results indicated that the photographs of monkeys that were socially housed were more likely to be rated as happy or neutral than were photographs of singly housed monkeys. We suggest that these results imply important parallels between the perception of human and nonhuman primate facial expressions as well as introduce a potential new method for assessing nonhuman primate well-being.

Do monkeys choose to choose?

Both empirical and anecdotal evidence supports the idea that choice is preferred by humans. Previous research has demonstrated that this preference extends to nonhuman animals, but it remains largely unknown whether animals will actively seek out or prefer opportunities to choose. Here we explored the issue of whether capuchin and rhesus monkeys choose to choose. We used a modified version of the SELECT task-a computer program in which monkeys can choose the order of completion of various psychomotor and cognitive tasks. In the present experiments, each trial began with a choice between two icons, one of which allowed the monkey to select the order of task completion, and the other of which led to the assignment of a task order by the computer. In either case, subjects still had to complete the same number of tasks and the same number of task trials. The tasks were relatively easy, and the monkeys responded correctly on most trials. Thus, global reinforcement rates were approximately equated across conditions. The only difference was whether the monkey chose the task order or it was assigned, thus isolating the act of choosing. Given sufficient experience with the task icons, all monkeys showed a significant preference for choice when the alternative was a randomly assigned order of tasks. To a lesser extent, some of the monkeys maintained a preference for choice over a preferred, but computer-assigned, task order that was yoked to their own previous choice selection. The results indicated that monkeys prefer to choose when all other aspects of the task are equated.

Racial and Ethnic Disparities in Hepatocellular Carcinoma Treatment Receipt in the United States: A Systematic Review and Meta-Analysis.

BACKGROUND: Racial and ethnic disparities in hepatocellular carcinoma (HCC) prognosis exist, partly related to differential failures along the cancer care continuum. We characterized racial and ethnic disparities in treatment receipt among patients with HCC in the United States. METHODS: We searched Medline, Embase, and CINAHL databases to identify studies published between January 2012 and March 2022 reporting HCC treatment receipt among adult patients with HCC, stratified by race or ethnicity. We calculated pooled odds ratios for HCC treatment using random effects models. RESULTS: We identified 15 studies with 320,686 patients (65.8% White, 13.9% Black, 10.4% Asian, and 8.5% Hispanic). Overall, 33.2% of HCC patients underwent any treatment, and 22.7% underwent curative treatment. Compared with White patients, Black patients had lower odds of any treatment (OR 0.67, 95% CI 0.55-0.81) and curative treatment (OR 0.74, 95% CI 0.71-0.78). Similarly, Hispanic patients had lower pooled odds of curative treatment (OR 0.79, 95% CI 0.73-0.84). CONCLUSIONS: There were significant racial and ethnic disparities in HCC treatment receipt, with Black patients having lower odds of receiving any and curative treatment while Hispanic patients having lower odds of curative treatment. IMPACT: Racial and ethnic differences in treatment receipt serve as an intervention target to reduce disparities in HCC prognosis.

The discovery of potent blockers of the canonical transient receptor channels, TRPC3 and TRPC6, based on an anilino-thiazole pharmacophore.

Lead optimization of piperidine amide HTS hits, based on an anilino-thiazole core, led to the identification of analogs which displayed low nanomolar blocking activity at the canonical transient receptor channels 3 and 6 (TRPC3 & 6) based on FLIPR (carbachol stimulated) and electrophysiology (OAG stimulated) assays. In addition, the anilino-thiazole amides displayed good selectivity over other TRP channels (TRPA1, TRPV1, and TRPV4), as well as against cardiac ion channels (CaV1.2, hERG, and NaV1.5). The high oxidation potential of the aliphatic piperidine and aniline groups, as well as the lability of the thiazole amide group contributed to the high clearance observed for this class of compounds. Conversion of an isoquinoline amide to a naphthyridine amide markedly reduced clearance for the bicyclic piperidines, and improved oral bioavailability for this compound series, however TRPC3 and TRPC6 blocking activity was reduced substantially. Although the most potent anilino-thiazole amides ultimately lacked oral exposure in rodents and were not suitable for chronic dosing, analogs such as 14-19, 22, and 23 are potentially valuable in vitro tool compounds for investigating the role of TRPC3 and TRPC6 in cardiovascular disease.

Primary care physicians' strategies for addressing COVID-19 vaccine hesitancy.

OBJECTIVE: To explore the strategies that primary care physicians use to address patient COVID-19 vaccine hesitancy. METHOD: We administered an online survey to 625 primary care physicians from May 14 to May 25, 2021, to assess the messages that primary care physicians use to encourage hesitant patients to get vaccinated against COVID-19.589 physicians from the total pool of 625 provided open-ended responses. We conducted thematic content analysis on the responses based on previous research and themes identified within the data. SETTING: The survey was administered online using the survey research firm Dynata. RESULTS: Eleven primary themes emerged from our analysis, which included, physicians addressing specific concerns about vaccine safety (including costs versus benefits), physicians helping patients understand what it means to remain unvaccinated, or whether physicians try to connect emotionally through the use of guilt, or personal experience, whether physicians use derisive language to communicate with unvaccinated patients. In addition, a small number of physicians indicated they would not attempt to persuade someone who is vaccine hesitant. CONCLUSIONS: Our study shows that while some of the physicians used different strategies to address vaccine hesitancy, some of the physicians used harsh language or did not make any effort to reduce COVID-19 related vaccine hesitancy among their patients. Focused advocacy and training are needed to increase physician engagement in vaccine-related dialogues with their patients. Such efforts will ensure that critical opportunities for patient education and awareness-building are not missed and ensure high levels of vaccination uptake.

Overcoming cognitive set bias requires more than seeing an alternative strategy.

Determining when to switch from one strategy to another is at the heart of adaptive decision-making. Previous research shows that humans exhibit a 'cognitive set' bias, which occurs when a familiar strategy occludes-even much better-alternatives. Here we examined the mechanisms underlying cognitive set by investigating whether better solutions are visually overlooked, or fixated on but disregarded. We analyzed gaze data from 67 American undergraduates (91% female) while they completed the learned strategy-direct strategy (LS-DS) task, which measures their ability to switch from a learned strategy (LS) to a more efficient direct strategy (DS or shortcut). We found that, in the first trial block, participants fixated on the location of the shortcut more when it was available but most (89.6%) did not adopt it. Next, participants watched a video demonstrating either the DS (N = 34 Informed participants) or the familiar LS (N = 33 Controls). In post-video trials, Informed participants used the DS more than pre-video trials and compared to Controls. Notably, 29.4% of Informed participants continued to use the LS despite watching the DS video. We suggest that cognitive set in the LS-DS task does not stem from an inability to see the shortcut but rather a failure to try it.