Immunosuppression and outcomes in adult patients with de novo acute myeloid leukemia with normal karyotypes.

Acute myeloid leukemia (AML) patients rarely have long first remissions (LFRs; >5 y) after standard-of-care chemotherapy, unless classified as favorable risk at presentation. Identification of the mechanisms responsible for long vs. more typical, standard remissions may help to define prognostic determinants for chemotherapy responses. Using exome sequencing, RNA-sequencing, and functional immunologic studies, we characterized 28 normal karyotype (NK)-AML patients with >5 y first remissions after chemotherapy (LFRs) and compared them to a well-matched group of 31 NK-AML patients who relapsed within 2 y (standard first remissions [SFRs]). Our combined analyses indicated that genetic-risk profiling at presentation (as defined by European LeukemiaNet [ELN] 2017 criteria) was not sufficient to explain the outcomes of many SFR cases. Single-cell RNA-sequencing studies of 15 AML samples showed that SFR AML cells differentially expressed many genes associated with immune suppression. The bone marrow of SFR cases had significantly fewer CD4+ Th1 cells; these T cells expressed an exhaustion signature and were resistant to activation by T cell receptor stimulation in the presence of autologous AML cells. T cell activation could be restored by removing the AML cells or blocking the inhibitory major histocompatibility complex class II receptor, LAG3. Most LFR cases did not display these features, suggesting that their AML cells were not as immunosuppressive. These findings were confirmed and extended in an independent set of 50 AML cases representing all ELN 2017 risk groups. AML cell-mediated suppression of CD4+ T cell activation at presentation is strongly associated with unfavorable outcomes in AML patients treated with standard chemotherapy.

How Should We Measure Social Deprivation in Orthopaedic Patients?

BACKGROUND: Social deprivation negatively affects a myriad of physical and behavioral health outcomes. Several measures of social deprivation exist, but it is unclear which measure is best suited to describe patients with orthopaedic conditions. QUESTIONS/PURPOSES: (1) Which measure of social deprivation, defined as "limited access to society's resources due to poverty, discrimination, or other disadvantage," is most strongly and consistently correlated with patient-reported physical and behavioral health in patients with orthopaedic conditions? (2) Compared with the use of a single measure alone, how much more variability in patient-reported health does the simultaneous use of multiple social deprivation measures capture? METHODS: Between 2015 and 2017, a total of 79,818 new patient evaluations occurred within the orthopaedic department of a single, large, urban, tertiary-care academic center. Over that period, standardized collection of patient-reported health measures (as described by the Patient-reported Outcomes Measurement Information System [PROMIS]) was implemented in a staged fashion throughout the department. We excluded the 25% (19,926) of patient encounters that did not have associated PROMIS measures reported, which left 75% (59,892) of patient encounters available for analysis in this cross-sectional study of existing medical records. Five markers of social deprivation were collected for each patient: national and state Area Deprivation Index, Medically Underserved Area Status, Rural-Urban Commuting Area code, and insurance classification (private, Medicare, Medicaid, or other). Patient-reported physical and behavioral health was measured via PROMIS computer adaptive test domains, which patients completed as part of standard care before being evaluated by a provider. Adults completed the PROMIS Physical Function version 1.2 or version 2.0, Pain Interference version 1.1, Anxiety version 1.0, and Depression version 1.0. Children ages 5 to 17 years completed the PROMIS Pediatric Mobility version 1.0 or version 2.0, Pain Interference version 1.0 or version 2.0, Upper Extremity version 1.0, and Peer Relationships version 1.0. Age-adjusted partial Pearson correlation coefficients were determined for each social deprivation measure and PROMIS domain. Coefficients of at least 0.1 were considered clinically meaningful for this purpose. Additionally, to determine the percentage of PROMIS score variability that could be attributed to each social deprivation measure, an age-adjusted hierarchical regression analysis was performed for each PROMIS domain, in which social deprivation measures were sequentially added as independent variables. The model coefficients of determination (r2) were compared as social deprivation measures were incrementally added. Improvement of the r2 by at least 10% was considered clinically meaningful. RESULTS: Insurance classification was the social deprivation measure with the largest (absolute value) age-adjusted correlation coefficient for all adult and pediatric PROMIS physical and behavioral health domains (adults: correlation coefficient 0.40 to 0.43 [95% CI 0.39 to 0.44]; pediatrics: correlation coefficient 0.10 to 0.19 [95% CI 0.08 to 0.21]), followed by national Area Deprivation Index (adults: correlation coefficient 0.18 to 0.22 [95% CI 0.17 to 0.23]; pediatrics: correlation coefficient 0.08 to 0.15 [95% CI 0.06 to 0.17]), followed closely by state Area Deprivation Index. The Medically Underserved Area Status and Rural-Urban Commuting Area code each had correlation coefficients of 0.1 or larger for some PROMIS domains but neither had consistently stronger correlation coefficients than the other. Except for the PROMIS Pediatric Upper Extremity domain, consideration of insurance classification and the national Area Deprivation Index together explained more of the variation in age-adjusted PROMIS scores than the use of insurance classification alone (adults: r2 improvement 32% to 189% [95% CI 0.02 to 0.04]; pediatrics: r2 improvement 56% to 110% [95% CI 0.01 to 0.02]). The addition of the Medically Underserved Area Status, Rural-Urban Commuting Area code, and/or state Area Deprivation Index did not further improve the r2 for any of the PROMIS domains. CONCLUSION: To capture the most variability due to social deprivation in orthopaedic patients' self-reported physical and behavioral health, insurance classification (categorized as private, Medicare, Medicaid, or other) and national Area Deprivation Index should be included in statistical analyses. If only one measure of social deprivation is preferred, insurance classification or national Area Deprivation Index are reasonable options. Insurance classification may be more readily available, but the national Area Deprivation Index stratifies patients across a wider distribution of values. When conducting clinical outcomes research with social deprivation as a relevant covariate, we encourage researchers to consider accounting for insurance classification and/or national Area Deprivation Index, both of which are freely available and can be obtained from data that are typically collected during routine clinical care. LEVEL OF EVIDENCE: Level III, therapeutic study.

Exploring perceptions of healthcare technologies enabled by artificial intelligence: an online, scenario-based survey.

BACKGROUND: Healthcare is expected to increasingly integrate technologies enabled by artificial intelligence (AI) into patient care. Understanding perceptions of these tools is essential to successful development and adoption. This exploratory study gauged participants' level of openness, concern, and perceived benefit associated with AI-driven healthcare technologies. We also explored socio-demographic, health-related, and psychosocial correlates of these perceptions. METHODS: We developed a measure depicting six AI-driven technologies that either diagnose, predict, or suggest treatment. We administered the measure via an online survey to adults (N = 936) in the United States using MTurk, a crowdsourcing platform. Participants indicated their level of openness to using the AI technology in the healthcare scenario. Items reflecting potential concerns and benefits associated with each technology accompanied the scenarios. Participants rated the extent that the statements of concerns and benefits influenced their perception of favorability toward the technology. Participants completed measures of socio-demographics, health variables, and psychosocial variables such as trust in the healthcare system and trust in technology. Exploratory and confirmatory factor analyses of the concern and benefit items identified two factors representing overall level of concern and perceived benefit. Descriptive analyses examined levels of openness, concern, and perceived benefit. Correlational analyses explored associations of socio-demographic, health, and psychosocial variables with openness, concern, and benefit scores while multivariable regression models examined these relationships concurrently. RESULTS: Participants were moderately open to AI-driven healthcare technologies (M = 3.1/5.0 ± 0.9), but there was variation depending on the type of application, and the statements of concerns and benefits swayed views. Trust in the healthcare system and trust in technology were the strongest, most consistent correlates of openness, concern, and perceived benefit. Most other socio-demographic, health-related, and psychosocial variables were less strongly, or not, associated, but multivariable models indicated some personality characteristics (e.g., conscientiousness and agreeableness) and socio-demographics (e.g., full-time employment, age, sex, and race) were modestly related to perceptions. CONCLUSIONS: Participants' openness appears tenuous, suggesting early promotion strategies and experiences with novel AI technologies may strongly influence views, especially if implementation of AI technologies increases or undermines trust. The exploratory nature of these findings warrants additional research.

Empowering medicine residents to order labs mindfully to improve patient-centered care.

BACKGROUND: Unnecessary laboratory testing of hospitalized patients is prevalent. OBJECTIVE: We conducted a study focused on "mindful ordering" to decrease unnecessary laboratory ordering within an Internal Medicine residency program. DESIGNS, SETTINGS AND PARTICIPANTS: We collected survey data on resident/faculty perceptions of laboratory ordering as well as order information from the electronic medical record (EMR). INTERVENTION: Interventions focused on resident-identified barriers such as knowledge, EMR, habit and faculty expectations. Interventions were cumulative and included resident/faculty education and EMR optimization. MAIN OUTCOMES AND MEASURES: We assessed basic and complete metabolic panels (BMP, CMP) and complete blood counts with and without differential (CBC w/diff, w/o diff). Primary outcomes included: total labs ordered per week, lab and frequency, and resident perception of ordering practices. Secondary outcomes included: length-of stay (LOS) and venipuncture utilization. RESULTS: Survey data demonstrated increased resident perception of both mindful ordering and team discussion. Total labs ordered per week decreased 20% in the first year (1944 to 1500 labs/week). Residents' use of the "one-time draw" option increased; use of "daily" frequency decreased. Trends showed an increase in BMP relative to CMP, and an increase in CBC w/o diff relative to CBC w/diff. These changes were sustained through 127 weeks. There was an approximately 10% decrease in monthly average of patients undergoing venipuncture each day (86.7% to 74.2%). The shifts in laboratory ordering in conjunction with increased discussion about labs suggest a sustained change in resident lab ordering behavior. This study shows the impact of focusing interventions on resident-identified barriers to mindful ordering to create a sustained decrease laboratory orders.

Digital Mental Health Intervention Plus Usual Care Compared With Usual Care Only and Usual Care Plus In-Person Psychological Counseling for Orthopedic Patients With Symptoms of Depression or Anxiety: Cohort Study.

BACKGROUND: Depression and anxiety frequently coexist with chronic musculoskeletal pain and can negatively impact patients' responses to standard orthopedic treatments. Nevertheless, mental health is not routinely addressed in the orthopedic care setting. If effective, a digital mental health intervention may be a feasible and scalable method of addressing mental health in an orthopedic setting. OBJECTIVE: We aimed to compare 2-month changes in mental and physical health between orthopedic patients who received a digital mental health intervention in addition to usual orthopedic care, those who received usual orthopedic care only (without a specific mental health intervention), and those who received in-person care with a psychologist as part of their orthopedic treatment plan. METHODS: In this single-center retrospective cohort study involving ancillary analysis of a pilot feasibility study, 2-month self-reported health changes were compared between a cohort of orthopedic patients who received access to a digital mental health intervention (Wysa) and 2 convenience sample comparison cohorts (patients who received usual orthopedic care without a specific mental health intervention and patients who received in-person care with a psychologist as part of their orthopedic treatment plan). All patients were 18 years or older and reported elevated symptoms of depression or anxiety at an orthopedic clinic visit (Patient-Reported Outcomes Measurement Information System [PROMIS] Depression or Anxiety score ≥55). The digital intervention was a multi-component mobile app that used chatbot technology and text-based access to human counselors to provide cognitive behavioral therapy, mindfulness training, and sleep tools, among other features, with an emphasis on behavioral activation and pain acceptance. Outcomes of interest were between-cohort differences in the 2-month longitudinal changes in PROMIS Depression and Anxiety scores (primary outcomes) and PROMIS Pain Interference and Physical Function scores (secondary outcomes). RESULTS: Among 153 patients (mean age 55, SD 15 years; 128 [83.7%] female; 51 patients per cohort), patients who received the digital mental health intervention showed clinically meaningful improvements at the 2-month follow-up for all PROMIS measures (mean longitudinal improvement 2.8-3.7 points; P≤.02). After controlling for age and BMI, the improvements in PROMIS Depression, Pain Interference, and Physical Function were meaningfully greater than longitudinal changes shown by patients who received usual orthopedic care (mean between-group difference 2.6-4.8 points; P≤.04). Improvements in PROMIS Physical Function were also meaningfully greater than longitudinal changes shown by patients who received in-person psychological counseling (mean between-group difference 2.4 points; P=.04). CONCLUSIONS: Patients who received a digital mental health intervention as part of orthopedic care reported greater 2-month mean improvements in depression, pain interference, and physical function than patients who received usual orthopedic care. They also reported a greater mean improvement in physical function and comparable improvements in depression, anxiety, and pain interference compared with orthopedic patients who received in-person psychological counseling.

A Digital Mental Health Intervention in an Orthopedic Setting for Patients With Symptoms of Depression and/or Anxiety: Feasibility Prospective Cohort Study.

BACKGROUND: Symptoms of depression and anxiety commonly coexist with chronic musculoskeletal pain, and when this occurs, standard orthopedic treatment is less effective. However, mental health intervention is not yet a routine part of standard orthopedic treatment, in part because of access-related barriers. Digital mental health intervention is a potential scalable resource that could be feasibly incorporated into orthopedic care. OBJECTIVE: This study's primary purpose was to assess the feasibility of introducing a digital mental health intervention (Wysa) in an outpatient orthopedic setting to patients with coexisting symptoms of depression and/or anxiety. The secondary purpose was to perform a preliminary effectiveness analysis of the intervention. METHODS: In this single-arm, prospective cohort study, participants included adult patients (18 years and older) who presented to a nonsurgical orthopedic specialist at a single tertiary care academic center for evaluation of a musculoskeletal condition and who self-reported symptoms of depression and/or anxiety (Patient-Reported Outcomes Measurement Information System [PROMIS] Depression and/or Anxiety score ≥55). Face-to-face enrollment was performed by a research coordinator immediately after the participant's encounter with an orthopedic clinician. Participants were provided 2 months of access to a mobile app called Wysa, which is an established, multicomponent digital mental health intervention that uses chatbot technology and text-based access to human counselors to deliver cognitive behavioral therapy, mindfulness training, and sleep tools, among other features. For this study, Wysa access also included novel, behavioral activation-based features specifically developed for users with chronic pain. Primary feasibility outcomes included the study recruitment rate, retention rate, and engagement rate with Wysa (defined as engagement with a therapeutic Wysa tool at least once during the study period). Secondary effectiveness outcomes were between-group differences in mean longitudinal PROMIS mental and physical health score changes at 2-month follow-up between high and low Wysa users, defined by a median split. RESULTS: The recruitment rate was 29.3% (61/208), retention rate was 84% (51/61), and engagement rate was 72% (44/61). Compared to low users, high users reported greater improvement in PROMIS Anxiety scores (between-group difference -4.2 points, 95% CI -8.1 to -0.2; P=.04) at the 2-month follow-up. Between-group differences in PROMIS Depression (-3.2 points, 95% CI -7.5 to 1.2; P=.15) and Pain Interference scores (-2.3 points, 95% CI -6.3 to 1.7; P=.26) favored high users but did not meet statistical significance. Improvements in PROMIS Physical Function scores were comparable between groups. CONCLUSIONS: Delivery of a digital mental health intervention within the context of orthopedic care is feasible and has the potential to improve mental health and pain-related impairment to a clinically meaningful degree. Participants' engagement rates exceeded industry standards, and additional opportunities to improve recruitment and retention were identified. Further pilot study followed by a definitive, randomized controlled trial is warranted. TRIAL REGISTRATION: ClinicalTrials.gov NCT04640090; https://clinicaltrials.gov/ct2/show/NCT04640090.

Rate of continued conservative management versus progression to surgery at minimum 1-year follow-up in patients with pre-arthritic hip pain.

BACKGROUND: Extensive literature has described surgical outcomes for pre-arthritic hip pain, but the proportion of patients who progress to surgery remains unknown. OBJECTIVE: To determine the proportion of patients who present to a tertiary referral center for pre-arthritic hip pain and progress to surgery at minimum 1-year follow-up. DESIGN: Retrospective cohort study. SETTING: Single tertiary care academic medical center. PATIENTS: Patients ages 13 to 40 years who presented for initial evaluation to a conservative or surgical orthopedic specialist and were diagnosed with pre-arthritic hip pain (n = 713 patients, 830 hips). INTERVENTION: Not applicable. MAIN OUTCOME MEASURES: The primary outcome was the rate of progression to surgery at minimum 1-year follow-up for the entire cohort. Predictors of progression to surgery were determined for the entire cohort and for radiographically defined subgroups using multiple logistic regression. Candidate predictors included baseline demographic, radiographic, clinical diagnosis, and patient-reported outcome measures. RESULTS: In a cohort with a mean age of 25.4 (SD 8.1) years, 72.7% female, and mean follow-up of 2.6 (range 1.0-4.8) years, 429 of 830 hips (51.7%, 95% confidence interval [CI] 48.2% to 55.1%) progressed to surgery. Predictors of surgical progression in the entire cohort included younger age (OR 0.95/year, 95% CI 0.93 to 0.98), pain duration longer than 6 months (ORs 1.87-2.03, p ≤ .027), worse physical function (OR 0.96/Patient-Reported Outcomes Measurement Information System [PROMIS] point, 0.92 to 0.99), and a clinical diagnosis of femoroacetabular impingement (FAI) (OR 3.47, 2.05 to 5.89), acetabular dysplasia (OR 2.75, 1.73 to 4.35), and/or labral tear (OR 10.71, 6.98 to 16.47). Radiographic dysplasia (lateral center edge angle <20 degrees) increased the likelihood of surgery in all subgroups (ORs 2.05-8.47, p ≤ .008). Increasing maximum α angle increased the likelihood of surgery in patients with severe cam FAI (α > 63 degrees) (OR 1.03/degree, 1.00 to 1.06). CONCLUSION: Almost half of patients with pre-arthritic hip pain did not progress to surgery at a minimum 1-year follow-up. A trial of conservative management is likely worthwhile in most patients.

Convergent Clonal Evolution of Signaling Gene Mutations Is a Hallmark of Myelodysplastic Syndrome Progression.

Progression from myelodysplastic syndromes (MDS) to secondary acute myeloid leukemia (AML) is associated with the acquisition and expansion of subclones. Our understanding of subclone evolution during progression, including the frequency and preferred order of gene mutation acquisition, remains incomplete. Sequencing of 43 paired MDS and secondary AML samples identified at least one signaling gene mutation in 44% of MDS and 60% of secondary AML samples, often below the level of standard sequencing detection. In addition, 19% of MDS and 47% of secondary AML patients harbored more than one signaling gene mutation, almost always in separate, coexisting subclones. Signaling gene mutations demonstrated diverse patterns of clonal evolution during disease progression, including acquisition, expansion, persistence, and loss of mutations, with multiple patterns often coexisting in the same patient. Multivariate analysis revealed that MDS patients who had a signaling gene mutation had a higher risk of AML progression, potentially providing a biomarker for progression. SIGNIFICANCE: Subclone expansion is a hallmark of progression from MDS to secondary AML. Subclonal signaling gene mutations are common at MDS (often at low levels), show complex and convergent patterns of clonal evolution, and are associated with future progression to secondary AML. See related article by Guess et al., p. 316 (33). See related commentary by Romine and van Galen, p. 270. This article is highlighted in the In This Issue feature, p. 265.

Professional decision-making in medicine: Development of a new measure and preliminary evidence of validity.

INTRODUCTION: This study developed a new Professional Decision-Making in Medicine Measure that assesses the use of effective decision-making strategies: seek help, manage emotions, recognize consequences and rules, and test assumptions and motives. The aim was to develop a content valid measure and obtain initial evidence for construct validity so that the measure could be used in future research or educational assessment. METHODS: Clinical scenario-based items were developed based on a review of the literature and interviews with physicians. For each item, respondents are tasked with selecting two responses (out of six plausible options) that they would choose in that situation. Three of the six options reflect a decision-making strategy; these responses are scored as correct. Data were collected from a sample of 318 fourth-year medical students in the United States. They completed a 16-item version of the measure (Form A) and measures of social desirability, moral disengagement, and professionalism attitudes. Professionalism ratings from clerkships were also obtained. A sub-group (n = 63) completed a second 16-item measure (Form B) to pilot test the instrument, as two test forms are useful for pre-posttest designs. RESULTS: Scores on the new measure indicated that, on average, participants answered 75% of items correctly. Evidence for construct validity included the lack of correlation between scores on the measure and socially desirable responding, negative correlation with moral disengagement, and modest to low correlations with professionalism attitudes. A positive correlation was observed with a clerkship rating focused on professionalism in peer interactions. CONCLUSIONS: These findings demonstrate modest proficiency in the use of decision-making strategies among fourth-year medical students. Additional research using the Professional Decision-Making Measure should explore scores among physicians in various career stages, and the causes and correlates of scores. Educators could utilize the measure to assess courses that teach decision-making strategies.

Relating indices of knowledge structure coherence and accuracy to skill-based performance: Is there utility in using a combination of indices?

The authors examined the relative criterion-related validity of knowledge structure coherence and two accuracy-based indices (closeness and correlation) as well as the utility of using a combination of knowledge structure indices in the prediction of skill acquisition and transfer. Findings from an aggregation of 5 independent samples (N = 958) whose participants underwent training on a complex computer simulation indicated that coherence and the accuracy-based indices yielded comparable zero-order predictive validities. Support for the incremental validity of using a combination of indices was mixed; the most, albeit small, gain came in pairing coherence and closeness when predicting transfer. After controlling for baseline skill, general mental ability, and declarative knowledge, only coherence explained a statistically significant amount of unique variance in transfer. Overall, the results suggested that the different indices largely overlap in their representation of knowledge organization, but that coherence better reflects adaptable aspects of knowledge organization important to skill transfer.

Sequence of same-day upper and lower gastrointestinal endoscopy does not affect total procedure' time or medication use: A randomized trial.

BACKGROUND AND AIM: Same-day double upper and lower gastrointestinal endoscopy is frequently performed due to overlapping indications. However, it is unclear whether an upper-lower (U-L) or lower-upper (L-U) sequence is optimal. We analyzed the effect of sequence on total procedure time and sedation use. METHODS: A total of 100 patients scheduled for same-day double endoscopy were randomized to the U-L or L-U sequence arm. Primary outcomes, mean total procedure time, and sedative dosages were compared using a t-test. We also explored associations of the primary outcomes with patient-related and procedure-related factors. RESULTS: Comparing U-L and L-U sequences, mean total procedure time was 41.9 (16.2) versus 43.0 (14.5) min (P = 0.73), diphenhydramine dose 5.5 (15.4) versus 4.5 (14.0) mg (P = 0.74), fentanyl dose 71.5 (119.3) versus 77.6 (164.02) µg (P = 0.83), midazolam dose 1.6 (2.5) versus 1.4 (2.7) mg (P = 0.69), and propofol dose 437.4 (351.4) versus 444.5 (256.0) mg (P = 0.91), respectively. Total procedure and upper endoscopy times were significantly longer with trainee presence (P = 0.0002) and shorter with conscious sedation (P = 0.003). Upper endoscopy time was longer with higher body mass index (P = 0.001), and lower endoscopy time was longer in patients with cirrhosis or chronic kidney disease (P = 0.002 and 0.009, respectively). Time between procedures was significantly longer in the L-U sequence (7.4 [2.9] vs 5.3 [1.1] min, [P < 0.001]). The study had 80% power to detect an 8 min difference in total procedure time. CONCLUSIONS: The sequence of same-day double gastrointestinal endoscopy does not affect total procedure time or medication use. Longer total procedure and upper endoscopy times were associated with trainee presence and use of conscious sedation.

Learner-controlled practice difficulty in the training of a complex task: cognitive and motivational mechanisms.

An inherent aspect of learner-controlled instructional environments is the ability of learners to affect the degree of difficulty faced during training. However, research has yet to examine how learner-controlled practice difficulty affects learning. Based on the notion of desirable difficulties (Bjork, 1994), this study examined the cognitive and motivational antecedents and outcomes of learner-controlled practice difficulty in relation to learning a complex task. Using a complex videogame involving both strong cognitive and psychomotor demands, 112 young adult males were given control over their practice difficulty, which was reflected in the complexity of the training task. Results show that general mental ability, prior experience, pre-training self-efficacy, and error encouragement were positively related to learner-controlled practice difficulty. In turn, practice difficulty was directly related to task knowledge and post-training performance, and it was related to adaptive performance through the mediating influences of task knowledge and post-training performance. In general, this study supports the notion that training difficulty operationalized in terms of task complexity is positively related to both knowledge and performance outcomes. Results are discussed with respect to the need for more research examining how task complexity and other forms of difficulty could be leveraged to advance learner-controlled instructional practices.