Background Oxidative/nitrosative stress and endothelial dysfunction are hypothesized to be central to cancer therapeutics-related cardiac dysfunction (CTRCD). However, the relationship between circulating arginine-nitric oxide (NO) metabolites and CTRCD remains unstudied. Objectives To examine the relationship between arginine-NO metabolites and CTRCD in a prospective cohort of 170 breast cancer patients treated with doxorubicin ± trastuzumab. Methods Plasma levels of arginine, citrulline, ornithine, asymmetric dimethylarginine (ADMA), symmetric dimethylarginine (SDMA), and N-monomethylarginine (MMA) were quantified at baseline, 1 month, and 2 months following doxorubicin initiation. Determinants of baseline biomarker levels were identified using multivariable linear regression, and Cox regression defined the association between baseline levels and 1- or 2-month biomarker changes and CTRCD rate in 139 participants with quantitated echocardiograms at all time points. Results Age, hypertension, body mass index, and African American race were independently associated with ≥1 baseline citrulline, ADMA, SDMA, and MMA levels. Decreases in arginine and citrulline, and increases in ADMA were observed at 1 and 2 months (all P<0.05). Overall, 32 participants experienced CTRCD over a maximum follow-up of 5.4 years. Hazard ratios for ADMA and MMA at 2 months were 3.33 (95% confidence interval [CI] 1.12, 9.96) and 2.70 (95%CI 1.35, 5.41), respectively, and 0.78 (95%CI 0.64, 0.97) for arginine at 1 month. Conclusions In breast cancer patients undergoing doxorubicin therapy, early alterations in arginine-NO metabolite levels occurred, and early biomarker changes were associated with a greater CTRCD rate. Our findings highlight the potential mechanistic and translational relevance of this pathway to CTRCD.

Recently, JAMA Internal Medicine published a firsthand account of a trauma survivor who had disclosed over a series of years on multiple self-administered screenings that she had experienced trauma, 1 yet none of her health care clinicians had ever followed up with her or provided any support or resources. In reading her account, I wondered how many of her clinicians had even seen the screening questionnaires she completed.Standardized screening questionnaires allow primary care clinicians to learn important information about patients, especially in psychosocial areas (eg, depression, anxiety, substance use) that can be difficult to assess in short appointments. Adding to their efficiency, they can be completed in the waiting room. But for them to be useful, they have to be read, and the appropriate resources must be available.Just as "alarm fatigue" can result in not paying attention to important warnings from electronic health records, use of screening questionnaires performed more often than necessary can deluge clinicians with more information than they can incorporate in a visit, decreasing the efficiency of the visit and leading to cynicism on the part of patients (eg, "Why do they keep asking me if I am depressed, when I keep telling them I am not?") and on the part of primary care clinicians (eg, "Why are my patients repeatedly given these screeners, when I dealt with this issue on the last visit?").In this issue of JAMA Internal Medicine, Simon and colleagues 2 estimated the proportion of standardized screenings performed at 24 federally qualified health centers in 2019 that were excessive, defined as performed when not recommended. Six screeners were evaluated (depression, anxiety, smoking status, passive smoke exposure, health literacy, and preferred learning style), all of which were tied to national performance metrics. The authors found that 34.9% of all screenings performed (2 067 152 of 5 917 382) were excessive.It is likely that excess screenings were driven by fear of missing a targeted metric, combined with challenges in figuring out who was appropriately due for a screening. And while some may think that little harm is done by having patients complete excess questionnaires, patients can hardly be expected to know when their answers matter, and when they will go in a pile of unread papers. If we want patients to respond to sensitive questions, they must know that we are interested in their answers.

When making decisions that involve tradeoffs between the quality and timing of desirable outcomes, people consistently discount the value of future outcomes. A puzzling finding regarding such decisions is the extremely high rate at which people discount future monetary outcomes. Most economists would argue that decision-makers should turn down only rates of return that are lower than those available to them elsewhere. Yet the vast majority of studies find discount rates that are significantly higher than market interest rates (Frederick et al., 2002). Here we ask whether a lack of knowledge about the normative strategy can explain high discount rates. In an initial experiment, nearly half of subjects did not spontaneously cite elements of the normative strategy when asked how people should make intertemporal monetary decisions. In two follow-up experiments, after subjects read a “financial guide” detailing the normative strategy, discount rates declined by up to 85%, but were still higher than market interest rates. This decline persisted, though attenuated, for at least one month. In a final experiment, peer-generated advice influenced discount rates in a similar manner to “expert” advice, and arguments focusing on normative considerations were at least as effective as others. These studies show that part of the explanation for high discount rates is a lack of knowledge regarding the normative strategy, and they quantify how much discount rates are reduced in response to normative arguments. Given the high level of discounting that remains, however, there are other contributing factors to high discount rates that remain to be quantified.

Background. Hypertrophic cardiomyopathy (HCM) in pediatric solid organ transplant recipients has been reported in association with use of calcineurin inhibitors. However, data on the incidence and prevalence of HCM in adult posttransplant patients are limited. We sought to describe the clinical characteristics of solid organ transplant recipients who were diagnosed with HCM from 2011 to 2021 at a single center. Methods. Patients who had undergone solid organ transplant and exhibited left ventricular hypertrophy with left ventricular wall thickness ≥13 mm on transthoracic echocardiography were included. Clinical history, pedigree analysis, clinical genetic testing, transthoracic echocardiography, cardiac magnetic resonance imaging, treatment, and follow-up testing results were collected. Categorical variables were described as n (%). Continuous variables were described with medians and interquartile ranges and compared using the Wilcoxon rank-sum and Kruskal-Wallis tests. A 2-sided P < 0.05 was considered statistically significant. Results. Three lung, 5 kidney, and 4 liver transplant recipients from 12 different families were included. Seven patients (58%) did not carry a preexisting diagnosis of hypertension, and none had a history of aortic or subaortic stenosis. A majority of patients exhibited asymmetric septal hypertrophy (67%; medial septal thickness versus left ventricular posterior wall thickness 17 versus 13 mm; P < 0.001) and dynamic left ventricular outflow tract (LVOT) obstruction (58%). All patients were managed long term with calcineurin inhibitors. Clinical genetic testing in 6 patients identified 2 with disease-causing variants in 2 sarcomere genes, myosin binding protein-C and myosin heavy chain 7. Four patients (33%) underwent successful septal reduction therapy for treatment of symptomatic LVOT obstruction. Conclusions. Symptomatic HCM with dynamic LVOT obstruction can develop in solid organ transplant recipients, and genetic testing can identify individuals with sarcomeric HCM. Medical management and septal reduction therapies are treatment options for severe symptomatic disease.

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