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Summary: Background: Population-based survival studies of adult acute myeloid leukemia (AML) have not simultaneously evaluated age at diagnosis, race and ethnicity, sex, calendar period or AML subtypes/subgroups among chemotherapy-treated patients. Methods: For 28,473 chemotherapy-treated AML patients diagnosed at ages ≥20 years in population-based cancer registry areas of the Surveillance, Epidemiology, and End Results Program (2001–2018, followed through 2019), we evaluated 1-month through 5-year relative survival (RS) and 95% confidence intervals (95% CI) using the actuarial method in the SEER∗Stat Survival Session and overall survival (OS) using multivariable Cox regression to estimate proportional hazard ratios (HR) and 95% CI. Findings: RS decreased with increasing age (20–39, 40–59, 60–74, 75–84, ≥85 years) at AML diagnosis. RS declined substantially within the first month and, except for acute promyelocytic leukemia, decreasing patterns continued thereafter for core binding factor AML, AML with antecedent condition/therapy, and all other AML. For all ages, acute promyelocytic leukemia RS stabilized after the first year. For total AML the hazard of death was significantly increased for non-Hispanic (NH)-Black (HR = 1.18, 95% CI = 1.12–1.24) and NH-Pacific Islander patients (HR = 1.31, 95% CI = 1.11–1.55) compared with NH-White patients. In contrast, NH-Asian and Hispanic patients had similar OS to NH-White patients across all ages and most AML subgroups. Males had significantly inferior survival to females with some exceptions. Compared to 2001–2006, in 2013–2018 OS improved for all age and AML subgroups. Interpretation: Chemotherapy-treated U.S. adults with AML have notable differences in survival by age, race and ethnicity, sex, calendar-year period, and AML subgroup. Despite survival gains over time, our findings highlight the need for improving early outcomes across all AML subgroups, older ages, and Black and Pacific Islander patients and long-term outcomes among most treated groups. Funding: Intramural Research Program of the U.S. National Institutes of Health, National Cancer Institute, Division of Cancer Epidemiology and Genetics, and the U.S. Food and Drug Administration, Center for Drug Evaluation and Research, Office of Surveillance and Epidemiology.

Abstract Background Breast cancer survivors are living longer due to early detection and advances in treatment and are at increased risk for second primary cancers. Comprehensive evaluation of second cancer risk among patients treated in recent decades is lacking. Methods We identified 16,004 females diagnosed with a first primary stage I-III breast cancer between 1990 and 2016 (followed through 2017) and survived ≥ 1 year at Kaiser Permanente (KP) Colorado, Northwest, and Washington. Second cancer was defined as an invasive primary cancer diagnosed ≥ 12 months after the first primary breast cancer. Second cancer risk was evaluated for all cancers (excluding ipsilateral breast cancer) using standardized incidence ratios (SIRs), and a competing risk approach for cumulative incidence and hazard ratios (HRs) adjusted for KP center, treatment, age, and year of first cancer diagnosis. Results Over a median follow-up of 6.2 years, 1,562 women developed second cancer. Breast cancer survivors had a 70% higher risk of any cancer (95%CI = 1.62–1.79) and 45% higher risk of non-breast cancer (95%CI = 1.37–1.54) compared with the general population. SIRs were highest for malignancies of the peritoneum (SIR = 3.44, 95%CI = 1.65–6.33), soft tissue (SIR = 3.32, 95%CI = 2.51–4.30), contralateral breast (SIR = 3.10, 95%CI = 2.82–3.40), and acute myeloid leukemia (SIR = 2.11, 95%CI = 1.18–3.48)/myelodysplastic syndrome (SIR = 3.25, 95%CI = 1.89–5.20). Women also had elevated risks for oral, colon, pancreas, lung, and uterine corpus cancer, melanoma, and non-Hodgkin lymphoma (SIR range = 1.31–1.97). Radiotherapy was associated with increased risk for all second cancers (HR = 1.13, 95%CI = 1.01–1.25) and soft tissue sarcoma (HR = 2.36, 95%CI = 1.17–4.78), chemotherapy with decreased risk for all second cancers (HR = 0.87, 95%CI = 0.78–0.98) and increased myelodysplastic syndrome risk (HR = 3.01, 95%CI = 1.01–8.94), and endocrine therapy with lower contralateral breast cancer risk (HR = 0.48, 95%CI = 0.38–0.60). Approximately 1 in 9 women who survived ≥ 1 year developed second cancer, 1 in 13 developed second non-breast cancer, and 1 in 30 developed contralateral breast cancer by 10 years. Trends in cumulative incidence declined for contralateral breast cancer but not for second non-breast cancers. Conclusions Elevated risks of second cancer among breast cancer survivors treated in recent decades suggests that heightened surveillance is warranted and continued efforts to reduce second cancers are needed.

Summary: Background: Historically, survivors of common lymphoid neoplasms (LNs) had increased risks for therapy-related myelodysplastic syndrome/acute myeloid leukemia (tMDS/AML). Despite major treatment advances in the treatment of LNs over the last two decades, a comprehensive evaluation of tMDS/AML trends following both common and rare LNs treated in this contemporary period is lacking. Methods: In US cancer registries during 2000–2018, we identified 1496 tMDS/AML cases among 186,503 adults who were treated with initial chemo/immunotherapy for first primary LN and survived ≥1 year. We quantified tMDS/AML standardized incidence ratios (SIRs), excess absolute risks (EARs, per 10,000 person-years), and cumulative incidence. Findings: The highest tMDS/AML risks occurred after precursor leukemia/lymphoma (SIR = 39, EAR = 30), Burkitt leukemia/lymphoma (SIR = 20, EAR = 24), peripheral T-cell lymphoma (SIR = 12, EAR = 23), chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL; SIR = 9.0, EAR = 27), and mantle cell lymphoma (SIR = 8.5, EAR = 25). Elevated risks (SIRs = 4.2–6.9, EARs = 4.9–15) also were observed after all other LN subtypes except hairy cell leukemia and mycosis fungoides/Sézary syndrome. Among patients treated more recently, tMDS/AML risks were significantly higher after CLL/SLL (SIR2000-2005 = 4.8, SIR2012-2017 = 10, Ptrend = 0.0043), significantly lower after Hodgkin (SIR2000-2005 = 15, SIR2012-2017 = 6.3, Ptrend = 0.024) and marginal zone (SIR2000-2005 = 7.5, SIR2012-2017 = 2.3, Ptrend = 0.015) lymphomas, and non-significantly lower after mantle cell lymphoma (SIR2000-2005 = 10, SIR2012-2017 = 3.2, Ptrend = 0.054), lymphoplasmacytic lymphoma/Waldenström macroglobulinemia (SIR2000-2005 = 6.9, SIR2012-2017 = 1.0, Ptrend = 0.067), and plasma cell neoplasms (SIR2000-2005 = 5.4, SIR2012-2017 = 3.1, Ptrend = 0.051). EAR and cumulative incidence trends generally were similar to SIR trends. Median survival after tMDS/AML was 8.0 months (interquartile range, 3.0–22.0). Interpretation: Although tMDS/AML risks are significantly elevated after initial chemo/immunotherapy for most LNs, patients treated more recently have lower tMDS/AML risks, except after CLL/SLL. Though rare, the poor prognosis following tMDS/AML emphasizes the importance of continued efforts to reduce treatment-associated toxicity. Funding: This research was supported in part by the Intramural Research Program of the National Cancer Institute, National Institutes of Health. LMM, GMD, REC, and CBS verified the data, and all authors had access to the data and made the decision to submit for publication.

Science, technology, engineering, mathematics, and medicine (STEMM) fields change rapidly and are increasingly interdisciplinary. Commonly, STEMM practitioners use short-format training (SFT) such as workshops and short courses for upskilling and reskilling, but unaddressed challenges limit SFT's effectiveness and inclusiveness. Education researchers, students in SFT courses, and organizations have called for research and strategies that can strengthen SFT in terms of effectiveness, inclusiveness, and accessibility across multiple dimensions. This paper describes the project that resulted in a consensus set of 14 actionable recommendations to systematically strengthen SFT. A diverse international group of 30 experts in education, accessibility, and life sciences came together from 10 countries to develop recommendations that can help strengthen SFT globally. Participants, including representation from some of the largest life science training programs globally, assembled findings in the educational sciences and encompassed the experiences of several of the largest life science SFT programs. The 14 recommendations were derived through a Delphi method, where consensus was achieved in real time as the group completed a series of meetings and tasks designed to elicit specific recommendations. Recommendations cover the breadth of SFT contexts and stakeholder groups and include actions for instructors (e.g., make equity and inclusion an ethical obligation), programs (e.g., centralize infrastructure for assessment and evaluation), as well as organizations and funders (e.g., professionalize training SFT instructors; deploy SFT to counter inequity). Recommendations are aligned with a purpose-built framework-"The Bicycle Principles"-that prioritizes evidenced-based teaching, inclusiveness, and equity, as well as the ability to scale, share, and sustain SFT. We also describe how the Bicycle Principles and recommendations are consistent with educational change theories and can overcome systemic barriers to delivering consistently effective, inclusive, and career-spanning SFT.

The ability of Mycobacterium tuberculosis (Mtb) to adapt to its surrounding environment is critical for the bacterium to successfully colonize its host. Transcriptional changes are a vital mechanism by which Mtb responds to key environmental signals experienced, such as pH, chloride (Cl-), nitric oxide (NO), and hypoxia. However, much remains unknown regarding how Mtb coordinates its response to the disparate signals seen during infection. Utilizing a transcription factor (TF) overexpression plasmid library in combination with a pH/Cl--responsive luciferase reporter, we identified the essential TF, PrrA, part of the PrrAB two-component system, as a TF involved in modulation of Mtb response to pH and Cl-. Further studies revealed that PrrA also affected Mtb response to NO and hypoxia, with prrA overexpression dampening induction of NO and hypoxia-responsive genes. PrrA is phosphorylated not just by its cognate sensor histidine kinase PrrB, but also by serine/threonine protein kinases (STPKs) at a second distinct site. Strikingly, a STPK-phosphoablative PrrA variant was significantly dampened in its response to NO versus wild type Mtb, disrupted in its ability to adaptively enter a non-replicative state upon extended NO exposure, and attenuated for in vivo colonization. Together, our results reveal PrrA as an important regulator of Mtb response to multiple environmental signals, and uncover a critical role of STPK regulation of PrrA in its function.

Post-transplantation cyclophosphamide (PTCy) reduces the incidence and severity of graft-versus-host disease (GVHD), thereby improving the safety and accessibility of allogeneic hematopoietic cell transplantation (HCT). We have shown that PTCy works by inducing functional impairment and suppression of alloreactive T cells. We also have identified that reduced proliferation of alloreactive CD4+ T cells at day +7 and preferential recovery of CD4+CD25+Foxp3+ regulatory T cells (Tregs) at day +21 are potential biomarkers associated with optimal PTCy dosing and timing in our B6C3F1→B6D2F1 MHC-haploidentical murine HCT model. To understand whether the effects of PTCy are unique and also to understand better the biology of GVHD prevention by PTCy, here we tested the relative impact of cyclophosphamide compared with five other optimally dosed chemotherapeutics (methotrexate, bendamustine, paclitaxel, vincristine, and cytarabine) that vary in mechanisms of action and drug resistance. Only cyclophosphamide, methotrexate, and cytarabine were effective in preventing fatal GVHD, but cyclophosphamide was superior in ameliorating both clinical and histopathological GVHD. Flow cytometric analyses of blood and spleens revealed that these three chemotherapeutics were distinct in constraining conventional T-cell numerical recovery and facilitating preferential Treg recovery at day +21. However, cyclophosphamide was unique in consistently reducing proliferation and expression of the activation marker CD25 by alloreactive CD4+Foxp3- conventional T cells at day +7. Furthermore, cyclophosphamide restrained the differentiation of alloreactive CD4+Foxp3- conventional T cells at both days +7 and +21, whereas methotrexate and cytarabine only restrained differentiation at day +7. No chemotherapeutic selectively eliminated alloreactive T cells. These data suggest that constrained alloreactive CD4+Foxp3- conventional T-cell numerical recovery and associated preferential CD4+CD25+Foxp3+ Treg reconstitution at day +21 may be potential biomarkers of effective GVHD prevention. Additionally, these results reveal that PTCy uniquely restrains alloreactive CD4+Foxp3- conventional T-cell proliferation and differentiation, which may explain the superior effects of PTCy in preventing GVHD. Further study is needed to determine whether these findings also hold true in clinical HCT.

Abstract: Infectious agents have been identified in the etiology of certain non-Hodgkin lymphoma (NHL) subtypes and solid tumors. The impact of this shared etiology on risk for second cancers in NHL survivors has not been comprehensively studied. We used US population–based cancer registry data to quantify risk of solid malignancies associated with infectious etiology among 127 044 adult 1-year survivors of the 4 most common NHL subtypes diagnosed during 2000 to 2014 (mean follow-up, 4.5-5.2 years). Compared with the general population, elevated risks for liver, stomach, and anal cancers were observed among diffuse large B-cell lymphoma (DLBCL) survivors (standardized incidence ratio [SIR], 1.85; 95% confidence interval [CI], 1.46-2.31; SIR, 1.51; 95% CI, 1.16-1.94; SIR, 3.71; 95% CI, 2.52-5.27, respectively) and marginal zone lymphoma (MZL; SIR, 1.98; 95% CI, 1.34-2.83; SIR, 2.78; 95% CI, 2.02-3.74; SIR, 2.36; 95% CI, 1.02-4.64, respectively) but not follicular lymphoma or chronic lymphocytic leukemia/small lymphocytic lymphoma. Anal cancer risk was particularly elevated among DLBCL survivors with HIV (SIR, 68.34; 95% CI, 37.36-114.66) vs those without (SIR, 2.09; 95% CI, 1.22-3.34). The observed patterns are consistent with shared associations between these cancers and hepatitis C virus, Helicobacter pylori, and HIV, respectively. In contrast, risks for cervical and oropharyngeal/tonsil cancers were not elevated among survivors of any NHL subtype, possibly because of the lack of NHL association with human papillomavirus or population-wide screening practices (for cervical cancer). In summary, patterns of elevated second cancer risk differed by NHL subtype. Our results suggest shared infectious etiology has implications for subsequent cancer risks among DLBCL and MZL survivors, which may help inform surveillance for these survivors.

AbstractCompared with the general population, hematopoietic cell transplantation (HCT) survivors are at elevated risk for developing solid subsequent neoplasms (SNs). The Center for International Blood and Marrow Transplant Research (CIBMTR) is a key resource for quantifying solid SN incidence following HCT, but the completeness of SN ascertainment is uncertain. Within a cohort of 18 450 CIBMTR patients linked to the California Cancer Registry (CCR), we evaluated the completeness of solid SN data reported to the CIBMTR from 1991 to 2018 to understand the implications of using CIBMTR data alone or combined with CCR data to quantify the burden of solid SNs after HCT. We estimated the cumulative incidence of developing a solid SN, accounting for the competing risk of death. Within the cohort, solid SNs were reported among 724 patients; 15.6% of these patients had an SN reported by CIBMTR only, 36.9% by CCR only, and 47.5% by both. The corresponding cumulative incidence of developing a solid SN at 10 years following a first HCT was 4.0% (95% confidence interval [CI], 3.5-4.4) according to CIBMTR data only, 5.3% (95% CI, 4.9-5.9) according to CCR data only, and 6.3% (95% CI, 5.7-6.8) according to both sources combined. The patterns were similar for allogeneic and autologous HCT recipients. Linking detailed HCT information from CIBMTR with comprehensive SN data from cancer registries provides an opportunity to optimize SN ascertainment for informing follow-up care practices and evaluating risk factors in the growing population of HCT survivors.

Background: Disrupted sleep is common among nursing home patients with dementia and is associated with increased agitation, depression, and cognitive impairment. Detecting and treating sleep problems in this population are therefore of great importance, albeit challenging. Systematic observation and objective recordings of sleep are time-consuming and resource intensive and self-report is often unreliable. Commonly used proxy-rated scales contain few sleep items, which affects the reliability of the raters' reports. The present study aimed to adapt the proxy-rated Sleep Disorder Inventory (SDI) to a nursing home context and validate it against actigraphy.Methods: Cross-sectional study of 69 nursing home patients, 68% women, mean age 83.5 (SD 7.1). Sleep was assessed with the SDI, completed by nursing home staff, and with actigraphy (Actiwatch II, Philips Respironics). The SDI evaluates the frequency, severity, and distress of seven sleep-related behaviors. Internal consistency of the SDI was evaluated by Cronbach's alpha. Spearman correlations were used to evaluate the convergent validity between actigraphy and the SDI. Test performance was assessed by calculating the sensitivity, specificity, and predictive values, and by ROC curve analyses. The Youden's Index was used to determine the most appropriate cut-off against objectively measured sleep disturbance defined as

Abstract Background Depression is highly prevalent yet often poorly detected and treated among cancer patients. In light of the move towards evidence-based healthcare policy, we have developed a simple tool that can assist policy makers, organisations and researchers to logically think through the steps involved in improving patient outcomes, and to help guide decisions about where to allocate resources. Methods The model assumes that a series of filters operate to determine outcomes and cost-effectiveness associated with depression care for cancer patients, including: detection of depression, provider response to detection, patient acceptance of treatment, and effectiveness of treatment provided. To illustrate the utility of the model, hypothetical data for baseline and four scenarios in which filter outcomes were improved by 15% were entered into the model. Results The model provides outcomes including: number of people successfully treated, total costs per scenario, and the incremental cost-effectiveness ratio per scenario compared to baseline. The hypothetical data entered into the model illustrate the relative effectiveness (in terms of the number of additional incremental successes) and relative cost-effectiveness (in terms of cost per successful outcome and total cost) of making changes at each step or filter. Conclusions The model provides a readily accessible tool to assist decision makers to think through the steps involved in improving depression outcomes for cancer patents. It provides transparent guidance about how to best allocate resources, and highlights areas where more reliable data are needed. The filter model presents an opportunity to improve on current practice by ensuring that a logical approach, which takes into account the available evidence, is applied to decision making.

It is common to create courses for the higher education context that accomplish content-driven teaching goals and then develop assessments (quizzes and exams) based on the target content. However, content-driven assessment can tend to support teaching- or teacher-centered instruction. Adult learning and educational psychology theories suggest that instead, assessment should be aligned with learning, not teaching, objectives. To support the alignment of assessments with instruction in higher education, the Assessment Evaluation Rubric (AER) was developed. The AER can be utilized to guide the development and evaluation/revision of assessments that are already used. The AER describes, or permits the evaluation of, four features of an assessment: its general alignment with learning goal(s), whether the assessment is intended to/effective as formative or summative, whether some systematic approach to cognitive complexity is reflected, and whether the assessment (instructions as well as results) itself is clearly interpretable. Each dimension (alignment, utility, complexity, and clarity) has four questions that can be rated as present/absent. Other rating methods can also be conceptualized for the AER’s 16 questions, depending on the user’s intent. Any instructor can use the AER to evaluate their own assessments and ensure that they—or new assessments in development—will promote learning and learner-centered teaching. As instructors shift from face-to-face toward virtual or hybrid teaching models, or as they shift online instruction (back) to face-to-face teaching, it creates an ideal opportunity to ensure that assessment is optimizing learning and is valid for instructional decision-making.

Abstract Background Many children in the remote Fitzroy Valley region of Western Australia have prenatal alcohol exposure (PAE). Individuals with PAE can have neurodevelopmental impairments and be diagnosed with one of several types of Fetal Alcohol Spectrum Disorder (FASD). Fine motor skills can be impaired by PAE, but no studies have developed a comprehensive profile of fine motor skills in a population-based cohort of children with FASD. We aimed to develop a comprehensive profile of fine motor skills in a cohort of Western Australian children; determine whether these differed in children with PAE or FASD; and establish the prevalence of impairment. Methods Children (n = 108, 7 to 9 years) were participants in a population-prevalence study of FASD in Western Australia. Fine motor skills were assessed using the Bruininks-Oseretsky Test of Motor Proficiency, which provided a Fine Motor Composite score, and evaluated Fine Manual Control (Fine Motor Precision; Fine Motor Integration) and Manual Coordination (Manual Dexterity; Upper-Limb Coordination). Descriptive statistics were reported for the overall cohort; and comparisons made between children with and without PAE and/or FASD. The prevalence of severe (≤ 2nd percentile) and moderate (≤16th percentile) impairments was determined. Results Overall, Fine Motor Composite scores were ‘average’ (M = 48.6 ± 7.4), as were Manual Coordination (M = 55.7 ± 7.9) and Fine Manual Control scores (M = 42.5 ± 6.2). Children with FASD had significantly lower Fine Motor Composite (M = 45.2 ± 7.7 p = 0.046) and Manual Coordination scores (M = 51.8 ± 7.3, p = 0.027) than children without PAE (Fine Motor Composite M = 49.8 ± 7.2; Manual Coordination M = 57.0 ± 7.7). Few children had severe impairment, but rates of moderate impairment were very high. Conclusions Different types of fine motor skills should be evaluated in children with PAE or FASD. The high prevalence of fine motor impairment in our cohort, even in children without PAE, highlights the need for therapeutic intervention for many children in remote communities.

Background: Urinary symptoms are common for people with neurogenic lower urinary tract dysfunction (NLUTD). No nonprescription approach has been proven safe and effective for self-management of urinary symptoms. Our objective was to describe the safety and tolerability of Lactobacillus rhamnosus GG ( LGG ®) instilled intravesically for self-management of inflammatory urinary symptoms in adults and children with NLUTD due to spinal cord injury or disease (SCI/D) and who use intermittent catheterization (IC). Methods: A total of 103 individuals with SCI/D enrolled in an 18-month study consisting of three 6-month stages: baseline (weekly observation of urinary symptoms); intervention (self-instilled intravesical LGG ® in response to more cloudy or foul-smelling urine); and washout (weekly observation of urinary symptoms). Urinary symptoms were assessed using the Urinary Symptom Questionnaire for people with neurogenic bladder using intermittent catheters (USQNB-IC). Safety was based on serious adverse events and adverse events (S/AEs) and trends in symptoms. Tolerability was defined as the independence of AE experience and willingness to use/pay for this intervention. Results: A total of 74 (77%) adults and 6 (86%) of children completed the study, of whom 64 instilled LGG ® for a total of 357 instillations (range 1–41 per person). There were 59 S/AEs, 44% (26/59) of which were categorized as infectious genitourinary. There was no statistical relationship between S/AEs and use or dose of the intervention. Conclusions: One or two doses of self-instilled intravesical LGG ® in response to more cloudy or foul-smelling urine was safe and well tolerated among this sample of adults and children with SCI/D who have NLUTD and use IC.

Introduction Caregivers of children with health problems experience poorer health than the caregivers of healthy children. To date, population-based studies on this issue have primarily used survey data. Objectives We demonstrate that administrative health data may be used to study these issues, and explore how non-categorical indicators of child health in administrative data can enable population-level study of caregiver health. Methods Dyads from Population Data British Columbia (BC) databases, encompassing nearly all mothers in BC with children aged 6-10 years in 2006, were grouped using a non-categorical definition based on diagnoses and service use. Regression models examined whether four maternal health outcomes varied according to indicators of child health. Results 162,847 mother-child dyads were grouped according to the following indicators: Child High Service Use (18%) vs. Not (82%), Diagnosis of Major and/or Chronic Condition (12%) vs. Not (88%), and Both High Service Use and Diagnosis (5%) vs. Neither (75%). For all maternal health and service use outcomes (number of physician visits, chronic condition, mood or anxiety disorder, hospitalization), differences were demonstrated by child health indicators. Conclusions Mothers of children with health problems had poorer health themselves, as indicated by administrative data groupings. This work not only demonstrates the research potential of using routinely collected health administrative data to study caregiver and child health, but also the importance of addressing maternal health when treating children with health problems. Keywords Population data, linked data, case-mix, children with special health care needs

Despite strong interest over many years, the usage of quantitative trait loci in plant breeding has often failed to live up to expectations. A key weak point in the utilisation of QTLs is the "quality" of markers used during marker-assisted selection (MAS): unreliable markers result in variable outcomes, leading to a perception that MAS products fail to achieve reliable improvement. Most reports of markers used for MAS focus on markers derived from the mapping population. There are very few studies that examine the reliability of these markers in other genetic backgrounds, and critically, no metrics exist to describe and quantify this reliability. To improve the MAS process, this work proposes five core metrics that fully describe the reliability of a marker. These metrics give a comprehensive and quantitative measure of the ability of a marker to correctly classify germplasm as QTL[+]/[-], particularly against a background of high allelic diversity. Markers that score well on these metrics will have far higher reliability in breeding, and deficiencies in specific metrics give information on circumstances under which a marker may not be reliable. The metrics are applicable across different marker types and platforms, allowing an objective comparison of the performance of different markers irrespective of the platform. Evaluating markers using these metrics demonstrates that trait-specific markers consistently out-perform markers designed for other purposes. These metrics also provide a superb set of criteria for designing superior marker systems for a target QTL, enabling the selection of an optimal marker set before committing to design.

BACKGROUND:Advanced practice registered nursing (APRN) competencies exist, but there is no structure supporting the operationalization of the competencies by APRN educators. The development of a Mastery Rubric (MR) for APRNs provides a developmental trajectory that supports educational institutions, educators, students, and APRNs. A MR describes the explicit knowledge, skills, and abilities as performed by the individual moving from novice (student) through graduation and into the APRN career. METHOD:A curriculum development tool, the Mastery Rubric (MR), was created to structure the curriculum and career of the nurse practitioner (NP), the MR-NP. Cognitive task analysis (CTA) yielded the first of the three required elements for any MR: a list of knowledge, skills, and abilities (KSAs) to be established through the curriculum. The European guild structure and Bloom's taxonomy of cognitive behaviors provided the second element of the MR, the specific developmental stages that are relevant for the curriculum. The Body of Work method of standard setting was used to create the third required element of the MR, performance level descriptors (PLDs) for each KSA at each of these stages. Although the CTA was informed by the competencies, it was still necessary to formally assess the alignment of competencies with the resulting KSAs; this was achieved via Degrees of Freedom Analysis (DoFA). Validity evidence was obtained from this Analysis and from the DoFA of the KSAs' alignment with principles of andragogy, and with learning outcomes assessment criteria. These analyses are the first time the national competencies for the NP have been evaluated in this manner. RESULTS:CTA of the 43 NP Competencies led to seven KSAs that support a developmental trajectory for instruction and documenting achievement towards independent performance on the competencies. The Competencies were objectively evaluable for the first time since their publication due to the psychometric validity attributes of the PLD-derived developmental trajectory. Three qualitatively distinct performance levels for the independent practitioner make the previously implicit developmental requirements of the competencies explicit for the first time. DISCUSSION:The MR-NP provides the first articulated and observable developmental trajectory for the NP competencies, during and beyond the formal curriculum. A focus on psychometric validity was brought to bear on how learners would demonstrate their development, and ultimately their achievement, of the competencies. The MR-NP goes beyond the competencies with trajectories and PLDs that can engage both learner and instructor in this developmental process throughout the career.

As the life sciences have become more data intensive, the pressure to incorporate the requisite training into life-science education and training programs has increased. To facilitate curriculum development, various sets of (bio)informatics competencies have been articulated; however, these have proved difficult to implement in practice. Addressing this issue, we have created a curriculum-design and -evaluation tool to support the development of specific Knowledge, Skills and Abilities (KSAs) that reflect the scientific method and promote both bioinformatics practice and the achievement of competencies. Twelve KSAs were extracted via formal analysis, and stages along a developmental trajectory, from uninitiated student to independent practitioner, were identified. Demonstration of each KSA by a performer at each stage was initially described (Performance Level Descriptors, PLDs), evaluated, and revised at an international workshop. This work was subsequently extended and further refined to yield the Mastery Rubric for Bioinformatics (MR-Bi). The MR-Bi was validated by demonstrating alignment between the KSAs and competencies, and its consistency with principles of adult learning. The MR-Bi tool provides a formal framework to support curriculum building, training, and self-directed learning. It prioritizes the development of independence and scientific reasoning, and is structured to allow individuals (regardless of career stage, disciplinary background, or skill level) to locate themselves within the framework. The KSAs and their PLDs promote scientific problem formulation and problem solving, lending the MR-Bi durability and flexibility. With its explicit developmental trajectory, the tool can be used by developing or practicing scientists to direct their (and their team's) acquisition of new, or to deepen existing, bioinformatics KSAs. The MR-Bi is a tool that can contribute to the cultivation of a next generation of bioinformaticians who are able to design reproducible and rigorous research, and to critically analyze results from their own, and others', work.

Background and objectivesHIV-infected patients are at risk for developing chronic kidney disease (CKD), defined by estimated glomerular filtration rate (eGFR) Design, setting, participants and measurementsA retrospective cohort study (2012-2016) was conducted in all HIV-infected patients seen in a federally qualified community health center in Houston, Texas. CKD prevalence and its association with HIV viral load and CD4 count were determined. The association of the change in eGFR over time and comorbidities was assessed using linear mixed models.ResultsOf 3714 HIV-infected patients analyzed, 153 (4.1%) had CKD. The prevalence of CKD in the different racial groups was 5.4% White, 4.0% African American, 2.8% Hispanic/Latino and 3.2% Asian. There was no difference in the rate of decline in kidney function in White vs. African American HIV infected patients with CKD. Compared with non-CKD patients, CKD patients were older, had lived longer with HIV infection, had lower CD4 cell counts, higher proportions of hypertension, hyperlipidemia, and cerebrovascular disease, and had significantly higher rates of eGFR deterioration represented by a median decrease of 26.5% from first to last follow-up eGFR (versus 0% change). Linear mixed modeling identified older age, male gender, White race, longer time with HIV infection, hypertension, history of kidney stones, cerebrovascular disease, autoimmune disease, increased potassium and total cholesterol levels, and being treated with combination ART as associated with a worsening eGFR over time.ConclusionThis study demonstrates a prevalence of CKD in HIV-infected patients of 4.1% and points to an important role for HIV medications and other common comorbidities in the genesis and progression of kidney disease. Importantly, CKD was not more prevalent in African Americans than in Whites, perhaps due to a low prevalence of IV drug abuse as inferred from the lower prevalence of HCV infection in this cohort.

A steward of the discipline was originally defined as “someone who will creatively generate new knowledge, critically conserve valuable and useful ideas, and responsibly transform those understandings through writing, teaching, and application”. This construct was articulated to support and strengthen doctoral education. The purpose of this paper is to expand the construct of stewardship so that it can be applied to both scholars and non-academic practitioners, and can be initiated earlier than doctoral education. To accomplish and justify this, we describe a general developmental trajectory supporting cross-curriculum teaching for stewardship of a discipline as well as of a profession. We argue that the most important features of stewardship, comprising the public trust for the future of their discipline or profession, are obtainable by all practitioners, and are not limited to those who have completed doctoral training. The developmental trajectory is defined using the Mastery Rubric construct, which requires articulating the knowledge, skills, and abilities (KSAs) to be targeted with a curriculum; recognizable stages of performance of these KSAs; and performance level descriptors of each KSA at each stage. Concrete KSAs of stewardship that can be taught and practiced throughout the career (professional or scholarly) were derived directly from the original definition. We used the European guild structure’s stages of Novice, Apprentice, Journeyman, and Master for the trajectory, and through a consensus-based standard setting exercise, created performance level descriptors featuring development of Bloom’s taxonometric cognitive abilities (see Appendix A) for each KSA. Together, these create the Mastery Rubric for Stewardship (MR-S). The MR-S articulates how stewardly behavior can be cultivated and documented for individuals in any disciplinary curriculum, whether research-intensive (preparing “scholars”) or professional (preparing members of a profession or more generally for the work force). We qualitatively assess the validity of the MR-S by examining its applicability to, and concordance with professional practice standards in three diverse disciplinary examples: (1) History; (2) Statistics and Data Science; and (3) Neurosciences. These domains differ dramatically in terms of content and methodologies, but students in each discipline could either continue on to doctoral training and scholarship, or utilize doctoral or pre-doctoral training in other professions. The MR-S is highly aligned with the practice standards of all three of these domains, suggesting that stewardship can be meaningfully cultivated and utilized by those working in or outside of academia, supporting the initiation of stewardship prior to doctoral training and for all students, not only those who will earn PhDs or be scholars first and foremost. The MR-S can be used for curriculum development or revision in order to purposefully promote stewardship at all levels of higher education and beyond. The MR-S renders features of professional stewardship accessible to all practitioners, enabling formal and informal, as well as self-directed, development and refinement of a professional identity.

BACKGROUND:We developed a Urinary Symptom Questionnaire for individuals with neurogenic bladder due to spinal cord injury (SCI) and spina bifida (SB) who manage their bladders with intermittent catheterization, the USQNB-IC. This project followed an approach to patient-centered patient reported outcomes development that we created and published in 2017, specifically to ensure the primacy of the patient's perspective and experience. PARTICIPANTS:Two sets of responses were collected from individuals with neurogenic bladder due to either SCI (n = 336) and SB (patients, n = 179; and caregivers of patients with NB, n = 66), and three sets of "controls", individuals with neurogenic bladder who do not have a history of UTIs (n = 49) individuals with chronic mobility impairments (neither SCI nor SB) and without neurogenic bladder (n = 46), and those with no mobility impairment, no neurogenic bladder, and no history of UTIs (n = 64). METHOD:Data were collected from all respondents to estimate these psychometric or measurement domains characterizing a health related PRO: Reliability (minimization of measurement error; internal consistency or interrelatedness of the items; and maximization of variability that is due to "true" difference between levels of the symptoms across patients), and validity (content, reflection of the construct to be measured; face, recognizability of the contents as representing the construct to be measured; structural, the extent to which the instrument captures recognizable dimensions of the construct to be measured; and criterion, association with a gold standard). RESULTS:Evidence from these five groups of respondents suggest the instrument has face, content, criterion, convergent, and divergent validity, as well as reliability. The items were all more descriptive of our patient (focus) groups and were only weakly endorsed by the control groups. CONCLUSIONS:The instrument is unique in its emphasis on, and origination from, the lived experiences of patients with neurogenic bladder who use intermittent catheterization; this preliminary psychometric evidence suggests the instrument could be useful for research and in the clinic. These results justify further development of the instrument, including formal exploration of the scoring and estimation of responsivity of these items to clinical interventions as well as patient-directed self care.

The objectives of this study were to describe and demonstrate a new model of developing patient reported outcomes (PROs) that are patient-centered, and to test the hypothesis that following this model would result in a qualitatively different PRO than if the typical PRO development model were followed. The typical process of developing PROs begins with an initial list of signs or symptoms originating from clinicians or PRO developers; patient validation of this list ensures that the list (i.e., the new PRO) is interpretable by patients, but not that patient perspectives are central or even represented. The new model begins with elicitation from clinicians and patients independently and separately. These perspectives are formally analyzed qualitatively, and the results are iteratively integrated by researchers, supporting clinical relevance and patient centeredness. We describe the application of this new model to the development of a PRO for urinary signs and symptoms in individuals with neuropathic bladder, and test the hypothesis that the two processes generate qualitatively different instruments using a national validation sample of 300 respondents. Of its 29 items, the new instrument included 13 signs/symptoms derived from existing clinical practice guidelines, with 16 others derived from the patient/focus groups. The three most-endorsed items came from the patients, and the three least-endorsed items came from clinical guidelines. Thematic qualitative analysis of the elicitation process, as well as the results from our national sample, support the conclusion that the new model yields an instrument that is clinically interpretable, but more patient-centered, than the typical model would have done in this context.

Mirrored-self misidentification delusion is the belief that one’s reflection in the mirror is not oneself. This experiment used hypnotic suggestion to impair normal face processing in healthy participants and recreate key aspects of the delusion in the laboratory. From a pool of 439 participants, 22 high hypnotisable participants (highs) and 20 low hypnotisable participants were selected on the basis of their extreme scores on two separately administered measures of hypnotisability. These participants received a hypnotic induction and a suggestion for either impaired (i) self-face recognition or (ii) impaired recognition of all faces. Participants were tested on their ability to recognise themselves in a mirror and other visual media – including a photograph, live video, and handheld mirror – and their ability to recognise other people, including the experimenter and famous faces. Both suggestions produced impaired self-face recognition and recreated key aspects of the delusion in highs. However, only the suggestion for impaired other-face recognition disrupted recognition of other faces, albeit in a minority of highs. The findings confirm that hypnotic suggestion can disrupt face processing and recreate features of mirrored-self misidentification. The variability seen in participants’ responses also corresponds to the heterogeneity seen in clinical patients. An important direction for future research will be to examine sources of this variability within both clinical patients and the hypnotic model.

Interest in sustainable learning has been growing over the past 20 years but it has never been determined whether students—whose learning we are trying to sustain—can perceive either the sustainability of their learning or any of the features of this construct. A four-item survey was developed based on a published definition of “sustainable learning”, and was sent to the 12 graduate students who have completed a new seminar in ethical reasoning. A thematic analysis of the narrative responses was submitted to a degrees-of-freedom analysis to determine the level and type of evidence for student perception of sustainability. Respondents (n = 9) endorsed each of the four dimensions of sustainable learning—and each gave examples for each dimension outside of, and after the end of, the course. One respondent endorsed all dimensions of sustainable learning, but was uncertain whether the course itself led to one particular sustainability dimension. While these results must be considered preliminary because our sample is small and the survey is the first of its kind, they suggest that graduate students can and do perceive each of the four features of sustainability. The survey needs refinement for future/wider use; but this four-dimensional definition could be useful to develop and promote (and assess) sustainable learning in higher education.

Statistical literacy is essential to an informed citizenry; and two emerging trends highlight a growing need for training that achieves this literacy. The first trend is towards “big” data: while automated analyses can exploit massive amounts of data, the interpretation—and possibly more importantly, the replication—of results are challenging without adequate statistical literacy. The second trend is that science and scientific publishing are struggling with insufficient/inappropriate statistical reasoning in writing, reviewing, and editing. This paper describes a model for statistical literacy (SL) and its development that can support modern scientific practice. An established curriculum development and evaluation tool—the Mastery Rubric—is integrated with a new, developmental, model of statistical literacy that reflects the complexity of reasoning and habits of mind that scientists need to cultivate in order to recognize, choose, and interpret statistical methods. This developmental model provides actionable evidence, and explicit opportunities for consequential assessment that serves students, instructors, developers/reviewers/accreditors of a curriculum, and institutions. By supporting the enrichment, rather than increasing the amount, of statistical training in the basic and life sciences, this approach supports curriculum development, evaluation, and delivery to promote statistical literacy for students and a collective quantitative proficiency more broadly.

It is common to create courses for the higher education context that accomplish content-driven teaching goals and then develop assessments (quizzes and exams) based on the target content. However, content-driven assessment can tend to support teaching- or teacher-centered instruction. Adult learning and educational psychology theories suggest that instead, assessment should be aligned with "learning," not teaching, objectives. To support the alignment of assessments with instruction in higher education, the Assessment Evaluation Rubric (AER) was developed. The AER can be utilized to guide the development and evaluation/revision of assessments that are already used. The AER describes, or permits the evaluation of, four features of an assessment: its general alignment with learning goal(s), whether the assessment is intended to/effective as formative or summative, whether some systematic approach to cognitive complexity is reflected, and whether the assessment (instructions as well as results) itself is clearly interpretable. Each dimension (alignment, utility, complexity, and clarity) has four questions that can be rated as present/absent. Other rating methods can also be conceptualized for the AER's 16 questions, depending on the user's intent. Any instructor can use the AER to evaluate their own assessments and ensure that they--or new assessments in development--will promote "learning" and learner-centered teaching. As instructors shift from face-to-face toward virtual or hybrid teaching models, or as they shift online instruction (back) to face-to-face teaching, it creates an ideal opportunity to ensure that assessment is optimizing learning and is valid for instructional decision-making.

We used a Guttman model to represent responses to test items over time as an approximation of what is often referred to as "points lost" in studies of cognitive decline or interventions. To capture this meaning of "point loss", over four successive assessments, we assumed that once an item is incorrect, it cannot be correct at a later visit. If the loss of a point represents actual decline, then failure of an item to fit the Guttman model over time can be considered measurement error. This representation and definition of measurement error also permits testing the hypotheses that measurement error is constant for items in a test, and that error is independent of "true score", which are two key consequences of the definition of "measurement error"--and thereby, reliability--under Classical Test Theory. We tested the hypotheses by fitting our model to, and comparing our results from, four consecutive annual evaluations in three groups of elderly persons: a) cognitively normal (NC, N = 149); b) diagnosed with possible or probable AD (N = 78); and c) cognitively normal initially and a later diagnosis of AD (converters, N = 133). Of 16 items that converged, error-free measurement of "cognitive loss" was observed for 10 items in NC, eight in converters, and two in AD. We found that measurement error, as we defined it, was inconsistent over time and across cognitive functioning levels, violating the theory underlying reliability and other psychometric characteristics, and key regression assumptions.

To explore different definitions of intra-individual variability (IIV) to summarize performance on commonly utilized cognitive tests (Mini Mental State Exam; Clock Drawing Test); compare them and their potential to differentiate clinically-defined populations; and to examine their utility in predicting clinical change in individuals from the Alzheimer's Disease Neuroimaging Initiative (ADNI).Sample statistics were computed from ADNI cohorts with no cognitive diagnosis, a diagnosis of mild cognitive impairment (MCI), and a diagnosis of possible or probable Alzheimer's disease (AD). Nine different definitions of IIV were computed for each sample, and standardized effect sizes (Cohen's d) were computed for each of these definitions in 500 simulated replicates using scores on the Mini Mental State Exam and Clock Drawing Test. IIV was computed based on test items separately ('within test' IIV) and the two tests together ('across test' IIV). The best performing definition was then used to compute IIV for a third test, the Alzheimer's Disease Assessment Scale-Cognitive, and the simulations and effect sizes were again computed. All effect size estimates based on simulated data were compared to those computed based on the total scores in the observed data. Association between total score and IIV summaries of the tests and the Clinician's Dementia Rating were estimated to test the utility of IIV in predicting clinically meaningful changes in the cohorts over 12- and 24-month intervals.ES estimates differed substantially depending on the definition of IIV and the test(s) on which IIV was based. IIV (coefficient of variation) summaries of MMSE and Clock-Drawing performed similarly to their total scores, the ADAS total performed better than its IIV summary.IIV can be computed within (items) or across (totals) items on commonly-utilized cognitive tests, and may provide a useful additional summary measure of neuropsychological test performance.

Objective. To quantify differences in results obtained by immunoassays (IAs) and tandem mass spectrometry (MSMS) for cortisol and free thyroxine (FT4). Design & Patients. Cortisol was measured over 60 minutes following a standard ACTH stimulation test (n=80); FT4 was measured over time in two cohorts of pregnant (n=57), and nonpregnant (n=28) women. Measurements. Samples were analyzed with both IA and MSMS. Results. Results for cortisol by the two methods tended to agree, but agreement weakened over the 60-minute test and was worse for higher (more extreme) concentrations. The results for FT4 depended on the method. IA measurements tended to agree with MSMS measurements when values fell within “normal levels”, but agreement was not constant across trimester in pregnant women and was poorest for the extreme (low/high) concentrations. Correlations between MSMS measurements and the difference between MSMS and IA results were strong and positive (0.411

Executive function (EF) is believed to control or influence the integration and application of cognitive functions such as attention and memory and is an important area of research in cognitive aging. Recent studies and reviews have concluded that there is no single test for EF. Results from first-order latent variable modeling have suggested that little, if any, variability in cognitive performance can be directly (and uniquely) attributed to EF; so instead, we modeled EF, as it is conceptualized, as a higher-order function, using elements of the CERAD neuropsychological battery. Responses to subtests from two large, independent cohorts of nondemented elderly persons were modeled with three theoretically plausible structural models using confirmatory factor analysis. Robust fit statistics, generated for the two cohorts separately, were consistent and support the conceptualization of EF as a higher-order cognitive faculty. Although not specifically designed to assess EF, subtests of the CERAD battery provide theoretically and empirically robust evidence about the nature of EF in elderly adults.

Human immunodeficiency virus (HIV)-associated cognitive disorders (HAND) is characterized by impaired motor and intellectual functions, as well as mood disorders. Brain-derived neurotrophic factor and its receptor TrkB (or NTRK2) mediate the efficacy of antidepressant drugs. Genomic studies of BDNF/TrkB have implicated common single-nucleotide polymorphisms in the pathology of depression. In the current study, we investigated whether single-nucleotide polymorphisms (SNPs) (rs1212171, rs1439050, rs1187352, rs1778933, rs1443445, rs3780645, rs2378672, and rs11140800) in the NTRK2 has a functional impact on depression in HIV-positive subjects. We have utilized the Central Nervous System (CNS) HIV Antiretroviral Therapy Effects Research (CHARTER) cohort. Our methods explored the univariate associations of these SNPs with clinical (current and lifetime) diagnosis of depression via chi-square. The distribution of alleles was significantly different for African-Americans and Caucasians (non-Hispanic) for several SNPs, so our regression analyses included both "statistical controls" for race group and models for each group separately. Finally, we applied a method of simultaneous analysis of associations, estimating the mutually shared information across a system of variables, separately by race group. Our results indicate that there is no significant association between clinical diagnosis of major depression and these SNPs for either race group in any analysis. However, we identified that the SNP associations varied by race group and sex.

A steward of the discipline was originally defined as "someone who will creatively generate new knowledge, critically conserve valuable and useful ideas, and responsibly transform those understandings through writing, teaching, and application". This construct was articulated to support and strengthen doctoral education. The purpose of this paper is to expand the construct of stewardship so that it can be applied to both scholars "and non-academic practitioners", and can be initiated earlier than doctoral education. To accomplish and justify this, we describe a general developmental trajectory supporting cross-curriculum teaching for stewardship of a discipline as well as of a profession. We argue that the most important features of stewardship, comprising the public trust for the future of their discipline or profession, are obtainable by all practitioners, and are not limited to those who have completed doctoral training. The developmental trajectory is defined using the Mastery Rubric construct, which requires articulating the knowledge, skills, and abilities (KSAs) to be targeted with a curriculum; recognizable stages of performance of these KSAs; and performance level descriptors of each KSA at each stage. Concrete KSAs of stewardship that can be taught and practiced throughout the career (professional or scholarly) were derived directly from the original definition. We used the European guild structure's stages of Novice, Apprentice, Journeyman, and Master for the trajectory, and through a consensus-based standard setting exercise, created performance level descriptors featuring development of Bloom's taxonometric cognitive abilities (see Appendix A) for each KSA. Together, these create the Mastery Rubric for Stewardship (MR-S). The MR-S articulates how stewardly behavior can be cultivated and documented for individuals in any disciplinary curriculum, whether research-intensive (preparing "scholars") or professional (preparing members of a profession or more generally for the work force). We qualitatively assess the validity of the MR-S by examining its applicability to, and concordance with professional practice standards in three diverse disciplinary examples: (1) History; (2) Statistics and Data Science; and (3) Neurosciences. These domains differ dramatically in terms of content and methodologies, but students in each discipline could either continue on to doctoral training and scholarship, "or" utilize doctoral or pre-doctoral training in other professions. The MR-S is highly aligned with the practice standards of all three of these domains, suggesting that stewardship can be meaningfully cultivated and utilized by those working in or outside of academia, supporting the initiation of stewardship prior to doctoral training and for "all" students, not only those who will earn PhDs or be scholars first and foremost. The MR-S can be used for curriculum development or revision in order to purposefully promote stewardship at all levels of higher education and beyond. The MR-S renders features of professional stewardship accessible to all practitioners, enabling formal and informal, as well as self-directed, development and refinement of a professional identity.