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Infection, autoimmunity, and cancer are the principal human health challenges of the 21st century and major contributors to human death and disease. Often regarded as distinct ends of the immunological spectrum, recent studies have hinted there may be more overlap between these diseases than appears. For example, pathogenic inflammation has been demonstrated as conserved between infection and autoimmune settings. T resident memory (TRM) cells have been highlighted as beneficial for infection and cancer. However, these findings are limited by patient number and disease scope; exact immunological factors shared across disease remain elusive. Here, we integrate large-scale deeply clinically and biologically phenotyped human cohorts of 526 patients with infection, 162 with lupus, and 11,180 with cancer. We identify an NKG2A+ immune bias as associative with protection against disease severity, mortality, and autoimmune and post-acute chronic disease. We reveal that NKG2A+ CD8+ T cells correlate with reduced inflammation, increased humoral immunity, and resemble TRM cells. Our results suggest that an NKG2A+ bias is a pan-disease immunological factor of protection and thus supports recent suggestions that there is immunological overlap between infection, autoimmunity, and cancer. Our findings underscore the promotion of an NKG2A+ biased response as a putative therapeutic strategy.

An ever-growing call for the use of evidence-based practice has come up against the logistical hurdles of a lack of resources and expertise, particularly in rural schools that work with historically underserved students. Although integrated learning systems (ILSs)--stable and likely requiring fewer resources than personnel--do not offer a complete solution to this problem, they may serve as a useful resource, particularly for milder literacy deficits. And yet, there is a surprising lack of empirical research on their effectiveness, particularly for contemporary programs. This study examines the effectiveness and efficiency of two popular ILSs, "Lexia" and "iStation," both of which use a blended model of computer and traditionally delivered instruction, and compares them against business-as-usual (BAU) conditions across a variety of outcomes. Results suggest both programs resulted in meaningful growth across an academic year of implementation, although generally no more so than that observed in the BAU condition. However, "Lexia" yielded the highest level of instructional efficiency. That is, despite comparable growth across conditions, "Lexia" required less staff time to implement per student participant.

Measures of learning speed (i.e., the amount of learning/cumulative time learner spends engaged in an intervention) are rarely included in research designed to evaluate and compare academic interventions. We build a case that includes analyses of learning speed metrics in academic intervention research can provide more useful information for prevention and remediation efforts, deter researchers from drawing misleading data-based conclusions, and promote scientific parsimony. Research is reviewed where the same learning data is analyzed across different metrics (i.e., same amount of learning, different measurement scales) including learning per event, learning speed, and growth. Patterns are analyzed and examples are provided that demonstrate how altering metrics can influence relative effectiveness conclusions and applied recommendations when researchers compare two or more interventions, conduct component analysis or optimization studies, and apply meta-analytic techniques. Opportunity costs for learners, educators, and learning scientists that may be caused by failure to measure learning speed are identified and analyzed. Our review and analyses support the conclusion that, in most instances, researchers can better inform prevention and remediation efforts by including precise measures of learning speed as dependent variables when they evaluate and compare interventions designed to enhance academic skills. Limitations and challenges associated with measuring learning speed are described and directions for future research are provided.

Curriculum-based measurement (CBM) has conventionally included accuracy criteria with recommended fluency thresholds for instructional decision-making. Some scholars have argued for the use of accuracy to directly determine instructional need (e.g., Szadokierski et al., 2017). However, accuracy and fluency have not been directly examined to determine their separate and joint value for decision-making in CBM prior to this study. Instead, there was an assumption that instruction that emphasized accurate responding should be monitored with accuracy data, which evolved into the use of complementing CBM fluency scores with accuracy or using timed assessment to compute percent of responses correct and using accuracy criteria to determine instructional need. The purpose of this article was to examine fluency and accuracy as related but distinct metrics with psychometric properties and associated benefits and limits. Findings suggest that the redundancy between accuracy and fluency causes them to perform comparably overall, but that: (1) fluency is superior to accuracy when accuracy is computed on a timed sample of performance; (2) timed accuracy adds no benefit relative to fluency alone; and (3) accuracy when collected under timed assessment conditions has substantial psychometric limitations that make it unsuitable for the formative instructional decisions which are commonly made using CBM data. The conventional inclusion of accuracy criteria in tandem with fluency criteria for instructional decision-making in CBM should be reconsidered as there may be no added predictive value, but rather additional opportunity for error due to the problems associated with unfixed trials in timed assessment.

Computer-based curriculum-based measurement (CBM) is a relatively common practice, but surprisingly few studies have examined the reliability of computer-based CBM. This study sought to examine the reliability of CBM administered via paper/pencil versus the computer. Twenty-one of 25 students in two third-grade classes (N = 21) participated in two generalizability studies. The primary facet of interest, format of assessment, was examined for two measures, a fact operation (fact family measure) and a more complex operation (multidigit addition). Researchers administered four alternate forms of each measure under both computer and paper/pencil conditions. Results indicated ideal reliability of measurement within all conditions and results were consistent across assessment formats for the fact operation. However, assessment format explained a large proportion of variance for the more complex skill (multidigit addition). Results indicate a need to consider the reliability of transitioning assessment from paper/pencil to computer-based response on a measure-by-measure basis.

BackgroundThe Worldwide Innovative Network (WIN) Consortium has developed the Simplified Interventional Mapping System (SIMS) to better define the cancer molecular milieu based on genomics/transcriptomics from tumor and analogous normal tissue biopsies. SPRING is the first trial to assess a SIMS-based tri-therapy regimen in advanced non-small cell lung cancer (NSCLC).MethodsPatients with advanced NSCLC (no EGFR, ALK, or ROS1 alterations; PD-L1 unrestricted; ≤2 prior therapy lines) received avelumab, axitinib, and palbociclib (3 + 3 dose escalation design).ResultsFifteen patients were treated (five centers, four countries): six at each of dose levels 1 (DL1) and DL2; three at DL3. The most common ≥Grade 3 adverse events were neutropenia, hypertension, and fatigue. The recommended Phase II dose (RP2D) was DL1: avelumab 10 mg/kg IV q2weeks, axitinib 3 mg po bid, and palbociclib 75 mg po daily (7 days off/21 days on). Four patients (27%) achieved a partial response (PR) (progression-free survival [PFS]: 14, 24, 25 and 144+ weeks), including two after progression on pembrolizumab. Four patients attained stable disease (SD) that lasted ≥24 weeks: 24, 27, 29, and 64 weeks. At DL1 (RP2D), four of six patients (66%) achieved stable disease (SD) ≥6 months/PR (2 each). Responders included patients with no detectable PD-L1 expression and low tumor mutational burden.ConclusionsOverall, eight of 15 patients (53%) achieved clinical benefit (SD ≥ 24 weeks/PR) on the avelumab, axitinib, and palbociclib combination. This triplet showed antitumor activity in NSCLC, including in tumors post-pembrolizumab progression, and was active at the RP2D, which was well tolerated. NCT03386929 clinicaltrial.gov.

Bayesian regression has emerged as a viable alternative for the estimation of curriculum-based measurement (CBM) growth slopes. Preliminary findings suggest such methods may yield improved efficiency relative to other linear estimators and can be embedded into data management programs for high-frequency use. However, additional research is needed, as Bayesian estimators require multiple specifications of the prior distributions. The current study evaluates the accuracy of several combinations of prior values, including three distributions of the residuals, two values of the expected growth rate, and three possible values for the precision of slope when using Bayesian simple linear regression to estimate fluency growth slopes for reading CBM. We also included traditional ordinary least squares (OLS) as a baseline contrast. Findings suggest that the prior specification for the residual distribution had, on average, a trivial effect on the accuracy of the slope. However, specifications for growth rate and precision of slope were influential, and virtually all variants of Bayesian regression evaluated were superior to OLS. Converging evidence from both simulated and observed data now suggests Bayesian methods outperform OLS for estimating CBM growth slopes and should be strongly considered in research and practice.

The current availability of research examining the precision of single-skill mathematics (SSM) curriculum-based measurements (CBMs) for progress monitoring is limited. Given the observed variance in administration conditions across current practice and research use, we examined potential differences between student responding and precision of slope when SSM-CBMs were administered individually and in group (classroom) conditions. No differences in student performance or measure precision were observed between conditions, indicating flexibility in the practical and research use of SSM-CBMs across administration conditions. In addition, findings contributed to the literature examining the stability of SSM-CBMs slopes of progress when used for instructional decision-making. Implications for the administration and interpretation of SSM-CBMs in practice are discussed.

Math curriculum-based measurement (CBM) is an essential tool for multi-tiered systems of support decision making, but the reliability of math CBMs has received little research, particularly using more rigorous methods such as generalizability (G) theory. Math CBM is historically organized into two domains: mastery measures and general outcome measures. This paper details 17 concurrent G and dependability studies in a partially crossed design investigating the reliability of mastery measure CBMs for students (N = 263) in Grades K, 1, 3, 5, and 7. This study extends prior research by including novel grade levels and more rigorous math content; using generated rather than static measures; embedding a replication; examining bias by race and sex; and evaluating a simpler scoring method of answers correct as compared to digits correct. Most of the variance in scores was accounted for by student. Probe form effects accounted for less than 5% of the variance for 16 of 17 measures and results replicated across days. G coefficients exceeded 0.75 on the first trial for 14 of 17 measures. G studies were repeated by race, sex, and scoring metric. Overall, 1-4 min of assessment was sufficient to meet reliability thresholds, which exceeds prior findings for general outcome measures. This study supports the reliability of mastery measurement in math CBM and as a precise tool to be used in the screening process.

An adapted alternating treatments design was used to compare the effects of class-wide applications of Taped Problems (TP) and Explicit Timing (ET) interventions on digits correct per minute (DCPM) scores. The study also investigated whether initial fluency scores would differentiate intervention effectiveness between TP and ET procedures. Results showed that both TP and ET resulted in similar DCPM increases, with both approaches significantly outperforming a control condition. Although the interventions showed similar effectiveness at the class-wide level, the interaction between intervention type and initial fluency levels suggested a differential effect. For students with initial fluency scores in the frustrational range ([less than or equal to] 10 DCPM), it was found that TP resulted in a higher growth rate than both ET and the control. For students with initial fluency scores in the instructional range (>10 DCPM), both ET and TP interventions resulted in higher DCPM scores than control but did not differ from one another. The discussion focuses on using skill by treatment interactions to inform intervention selection, explores opportunities and challenges in this research area, and addresses study limitations.

BACKGROUND: RET mutations occur in 70% of medullary thyroid cancers, and RET fusions occur rarely in other thyroid cancers. In patients with RET-altered thyroid cancers, the efficacy and safety of selective RET inhibition are unknown. METHODS: We enrolled patients with RET-mutant medullary thyroid cancer with or without previous vandetanib or cabozantinib treatment, as well as those with previously treated RET fusion-positive thyroid cancer, in a phase 1-2 trial of selpercatinib. The primary end point was an objective response (a complete or partial response), as determined by an independent review committee. Secondary end points included the duration of response, progression-free survival, and safety. RESULTS: In the first 55 consecutively enrolled patients with RET-mutant medullary thyroid cancer who had previously received vandetanib, cabozantinib, or both, the percentage who had a response was 69% (95% confidence interval [CI], 55 to 81), and 1-year progression-free survival was 82% (95% CI, 69 to 90). In 88 patients with RET-mutant medullary thyroid cancer who had not previously received vandetanib or cabozantinib, the percentage who had a response was 73% (95% CI, 62 to 82), and 1-year progression-free survival was 92% (95% CI, 82 to 97). In 19 patients with previously treated RET fusion-positive thyroid cancer, the percentage who had a response was 79% (95% CI, 54 to 94), and 1-year progression-free survival was 64% (95% CI, 37 to 82). The most common adverse events of grade 3 or higher were hypertension (in 21% of the patients), increased alanine aminotransferase level (in 11%), increased aspartate aminotransferase level (in 9%), hyponatremia (in 8%), and diarrhea (in 6%). Of all 531 patients treated, 12 (2%) discontinued selpercatinib owing to drug-related adverse events. CONCLUSIONS: In this phase 1-2 trial, selpercatinib showed durable efficacy with mainly low-grade toxic effects in patients with medullary thyroid cancer with and without previous vandetanib or cabozantinib treatment. (Funded by Loxo Oncology and others; LIBRETTO-001 ClinicalTrials.gov number, NCT03157128.).

BackgroundRET fusions are oncogenic drivers in 1 to 2% of non-small-cell lung cancers (NSCLCs). In patients with RET fusion-positive NSCLC, the efficacy and safety of selective RET inhibition are unknown.MethodsWe enrolled patients with advanced RET fusion-positive NSCLC who had previously received platinum-based chemotherapy and those who were previously untreated separately in a phase 1-2 trial of selpercatinib. The primary end point was an objective response (a complete or partial response) as determined by an independent review committee. Secondary end points included the duration of response, progression-free survival, and safety.ResultsIn the first 105 consecutively enrolled patients with RET fusion-positive NSCLC who had previously received at least platinum-based chemotherapy, the percentage with an objective response was 64% (95% confidence interval [CI], 54 to 73). The median duration of response was 17.5 months (95% CI, 12.0 to could not be evaluated), and 63% of the responses were ongoing at a median follow-up of 12.1 months. Among 39 previously untreated patients, the percentage with an objective response was 85% (95% CI, 70 to 94), and 90% of the responses were ongoing at 6 months. Among 11 patients with measurable central nervous system metastasis at enrollment, the percentage with an objective intracranial response was 91% (95% CI, 59 to 100). The most common adverse events of grade 3 or higher were hypertension (in 14% of the patients), an increased alanine aminotransferase level (in 12%), an increased aspartate aminotransferase level (in 10%), hyponatremia (in 6%), and lymphopenia (in 6%). A total of 12 of 531 patients (2%) discontinued selpercatinib because of a drug-related adverse event.ConclusionsSelpercatinib had durable efficacy, including intracranial activity, with mainly low-grade toxic effects in patients with RET fusion-positive NSCLC who had previously received platinum-based chemotherapy and those who were previously untreated. (Funded by Loxo Oncology and others; LIBRETTO-001 ClinicalTrials.gov number, NCT03157128.).

The duration and nature of immunity generated in response to SARS-CoV-2 infection is unknown. Many public health responses and modeled scenarios for COVID-19 outbreaks caused by SARSCoV-2 assume that infection results in an immune response that protects individuals from future infections or illness for some amount of time. The timescale of protection is a critical determinant of the future impact of the pathogen. The presence or absence of protective immunity due to infection or vaccination (when available) will affect future transmission and illness severity. The dynamics of immunity and nature of protection are relevant to discussions surrounding therapeutic use of convalescent sera as well as efforts to identify individuals with protective immunity. Here, we review the scientific literature on antibody immunity to coronaviruses, including SARS-CoV-2 as well as the related SARS-CoV-1, MERS-CoV and human endemic coronaviruses (HCoVs). We reviewed 1281 abstracts and identified 322 manuscripts relevant to 5 areas of focus: 1) antibody kinetics, 2) correlates of protection, 3) immunopathogenesis, 4) antigenic diversity and cross-reactivity, and 5) population seroprevalence. While studies of SARS-CoV-2 are necessary to determine immune responses to it, evidence from other coronaviruses can provide clues and guide future research.

The study objective was to test the hypothesis that having histocompatible children increases the risk of rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE), possibly by contributing to the persistence of fetal cells acquired during pregnancy. We conducted a case control study using data from the UC San Francisco Mother Child Immunogenetic Study and studies at the Inova Translational Medicine Institute. We imputed human leukocyte antigen (HLA) alleles and minor histocompatibility antigens (mHags). We created a variable of exposure to histocompatible children. We estimated an average sequence similarity matching (SSM) score for each mother based on discordant mother-child alleles as a measure of histocompatibility. We used logistic regression models to estimate odds ratios (ORs) and 95% confidence intervals. A total of 138 RA, 117 SLE, and 913 control mothers were analyzed. Increased risk of RA was associated with having any child compatible at HLA-B (OR 1.9; 1.2-3.1), DPB1 (OR 1.8; 1.2-2.6) or DQB1 (OR 1.8; 1.2-2.7). Compatibility at mHag ZAPHIR was associated with reduced risk of SLE among mothers carrying the HLA-restriction allele B*07:02 (n = 262; OR 0.4; 0.2-0.8). Our findings support the hypothesis that mother-child histocompatibility is associated with risk of RA and SLE.

Many public health responses and modeled scenarios for COVID-19 outbreaks caused by SARS-CoV-2 assume that infection results in an immune response that protects individuals from future infections or illness for some amount of time. The presence or absence of protective immunity due to infection or vaccination (when available) will affect future transmission and illness severity. Here, we review the scientific literature on antibody immunity to coronaviruses, including SARS-CoV-2 as well as the related SARS-CoV, MERS-CoV and endemic human coronaviruses (HCoVs). We reviewed 2,452 abstracts and identified 491 manuscripts relevant to 5 areas of focus: 1) antibody kinetics, 2) correlates of protection, 3) immunopathogenesis, 4) antigenic diversity and cross-reactivity, and 5) population seroprevalence. While further studies of SARS-CoV-2 are necessary to determine immune responses, evidence from other coronaviruses can provide clues and guide future research.