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Comparative effectiveness studies of cancer therapeutics in observational data face confounding by patterns of clinical treatment over time. The validity of survival analysis in longitudinal health records depends on study design choices including index date definition and model specification for covariate adjustment.Overall survival in cancer is a multi-state transition process with mortality and treatment switching as competing risks. Parametric Weibull regression quantifies proportionality of hazards across lines of therapy in real-world cohorts of 12 solid tumor types. Study design assessments compare alternative analytic models in simulations with realistic disproportionality. The multi-state simulation framework is adaptable to alternative treatment effect profiles and exposure patterns.Event-specific hazards of treatment-switching and death are not proportional across lines of therapy in 12 solid tumor types. Study designs that include all eligible lines of therapy per subject showed lower bias and variance than designs that select one line per subject. Confounding by line number was effectively mitigated across a range of simulation scenarios by Cox proportional hazards models with stratified baseline hazards and inverse probability of treatment weighting.Quantitative study design assessment can inform the planning of observational research in clinical oncology by demonstrating the potential impact of model misspecification. Use of empirical parameter estimates in simulation designs adapts analytic recommendations to the clinical population of interest.

ImportanceThe KEYNOTE-177 trial demonstrated that patients with metastatic colorectal cancer (MCRC) with high microsatellite instability (MSI-H) and/or mismatch repair deficiency (DMMR) have better outcomes when receiving first-line immune checkpoint inhibitors (ICIs) compared with chemotherapy. Data on performance of ICIs in patients with MCRC in standard practice settings remain limited, and direct MMR vs MSI outcome association comparisons are lacking.ObjectiveTo validate MSI (determined by next-generation sequencing [NGS]) as a biomarker of ICI effectiveness among patients with MCRC in standard practice settings and examine the association of MSI assessed by NGS, DMMR by immunohistochemistry, and tumor mutational burden (cutoff, 10 mutations/megabase) with ICI outcomes.Design, Setting, and ParticipantsThis comparative effectiveness research study of outcomes in prospectively defined biomarker subgroups used data from a deidentified clinicogenomic database and included patients who received Foundation Medicine testing (FoundationOne or FoundationOne CDx) during routine clinical care at approximately 280 US academic or community-based cancer clinics between March 2014 and December 2021. The population included 1 cohort of patients with MSI-H MCRC who received first-line ICIs or chemotherapy and a second cohort who received ICIs in any line of therapy (LOT) for biomarker examination.ExposuresICI therapy or chemotherapy assigned at physician discretion without randomization.Main Outcomes and MeasuresThe main outcomes were time to next treatment (TTNT), progression-free survival (PFS), and overall survival (OS). Hazard ratios were adjusted for known prognostic imbalances. Comparisons of explanatory power used the likelihood ratio test.ResultsA total of 138 patients (median age, 67.0 years [IQR, 56.2-74.0 years]; 73 [52.9%] female) with MSI-H MCRC received first-line ICIs or chemotherapy. A total of 182 patients (median age, 64.5 years [IQR, 55.2-72.0]; 98 [53.8%] female) received ICIs in any LOT. Patients receiving first-line ICIs vs chemotherapy had longer TTNT (median, not reached [NR] vs 7.23 months [IQR, 6.21-9.72 months]; adjusted hazard ratio [AHR], 0.17; 95% CI, 0.08-0.35; P P P = .02). MSI added to DMMR better anticipated TTNT and PFS in patients receiving ICIs than DMMR alone. The same was not observed when DMMR evaluation was added to MSI.Conclusions and RelevanceIn this comparative effectiveness research study, MSI assessed by NGS robustly identified patients with favorable outcomes on first-line ICIs vs chemotherapy and appeared to better anticipate ICI outcomes compared with DMMR.

BackgroundAlthough childhood adversity is a potent determinant of psychopathology, relatively little is known about how the characteristics of adversity exposure, including its developmental timing or duration, influence subsequent mental health outcomes. This study compared three models from life course theory (recency, accumulation, sensitive period) to determine which one(s) best explained this relationship.MethodsProspective data came from the Avon Longitudinal Study of Parents and Children (n= 7476). Four adversities commonly linked to psychopathology (caregiver physical/emotional abuse; sexual/physical abuse; financial stress; parent legal problems) were measured repeatedly from birth to age 8. Using a statistical modeling approach grounded in least angle regression, we determined the theoretical model(s) explaining the most variability (r2) in psychopathology symptoms measured at age 8 using the Strengths and Difficulties Questionnaire and evaluated the magnitude of each association.ResultsRecencywas the best fitting theoretical model for the effect of physical/sexual abuse (girlsr2= 2.35%; boysr2= 1.68%). Bothrecency(girlsr2= 1.55%) andaccumulation(boysr2= 1.71%) were the best fitting models for caregiver physical/emotional abuse.Sensitive periodmodels were chosen alone (parent legal problems in boysr2= 0.29%) and withaccumulation(financial stress in girlsr2= 3.08%) more rarely. Substantial effect sizes were observed (standardized mean differences = 0.22–1.18).ConclusionsChild psychopathology symptoms are primarily explained by recency and accumulation models. Evidence for sensitive periods did not emerge strongly in these data. These findings underscore the need to measure the characteristics of adversity, which can aid in understanding disease mechanisms and determining how best to reduce the consequences of exposure to adversity.

Background Cryopreservation is often used to store cellular therapies, but little is known about how well CD3+ or CD34+ cells tolerate this process. Study Design and Methods Viable CD34+ cell recoveries were analyzed from related and unrelated donor granulocyte–colony-stimulating factor (G-CSF)–mobilized peripheral blood stem cell (PBSC) products and viable CD3+ cell recoveries from G-CSF–mobilized and nonmobilized apheresis products from related and unrelated donors. All products were cryopreserved with 5% dimethyl sulfoxide and 6% pentastarch using a controlled-rate freezer and were stored in liquid nitrogen. Related donor products were cryopreserved immediately after collection and unrelated donor products greater than 12 hours postcollection. Results The postthaw recovery of CD34+ cells from related donor PBSCs was high (n = 86; 97.5 ± 23.1%) and there was no difference in postthaw CD34+ cell recovery from unrelated donor PBSCs (n = 14; 98.8 ± 37.2%; p = 0.863). In related donor lymphocyte products the postthaw CD3+ cell recovery (n = 48; 90.7 ± 21.4%) was greater than that of unrelated donor products (n = 14; 66.6 ± 35.8%; p = 0.00251). All unrelated donor lymphocyte products were from G-CSF–mobilized products, while most related donor lymphocyte products were from nonmobilized products. A comparison of the CD3+ cell recovery from related donor G-CSF–mobilized products (n = 19; 85.0 ± 29.2%) with that of unrelated donor products found no significant difference (p = 0.137). Conclusions The postthaw recovery of CD34+ cells was high in both related and unrelated donor products, but the recovery of CD3+ cells in unrelated donor G-CSF–mobilized products was lower. G-CSF–mobilized unrelated donor products may contain fewer CD3+ cells than non–G-CSF–exposed products upon thaw and, when indicated, cell doses should be monitored.

Disseminated intravascular coagulation (DIC) is a condition in which hemostasis is altered, resulting in unregulated activation of the coagulation cascade. The hallmarks of DIC are thrombosis (from excess clotting), bleeding (from consumption of the coagulation proteins), and thrombocytopenia and anemia (from mechanical destruction of red cells and platelets by coagulation in the microvasculature). DIC is not an isolated disease, it is a symptom of another illness such as endothelial trauma, sepsis, malignancy, or a complication of pregnancy. Therefore, treatment of the underlying medical condition and supportive care with blood products is the mainstay of therapy for DIC. Measurement of platelet count, prothrombin time/activated partial thromboplastin time (PT/aPTT), fibrinogen, and D-dimer, can help diagnose DIC, but treating with blood components only to correct abnormal laboratory tests may not be efficacious. Replenishing coagulation factors, platelets, and red cells should be attempted cautiously as dictated by the clinical scenario. In this report, we discuss the role of the blood bank in helping to manage DIC in hematologic malignancy. * RBC : red blood cells; PT : prothrombin time; aPTT : activated partial thromboplastin time; DIC : disseminated intravascular coagulation; FFP : fresh frozen plasma; TRALI : transfusion-related acute lung injury; AHF : antihemophilic factor; UK : United Kingdom; APL : acute promyelocytic leukemia ; MCV : mean corpuscular volume; AML : acute myelogenous leukemia; PML : promyelocytic leukemia; RARA : retinoic acid receptor-alpha; FP24 : plasma frozen within 24 hours after phlebotomy; TP : thawed plasma

This study examined the effect of peer interaction and sibling status on cognitive activity of 68 boys and girls from grades 1 to 4 at different levels of cognitive equivalence (C-E) functioning. The children were assigned to solitary or peer-dyad game play (same grade and sex) or no-game groups based on C-E level (perceptual vs. functional) and sibling status (older sibling vs. youngest or only child). Results indicated that playing the game with a peer resulted in significant gains. Children who had younger siblings increased their use of the functional mode after playing the game, but youngest or only children did not. Shifts persisted for two weeks. Shifts for older siblings may have been a function of advantages accrued from teaching younger siblings.

Sixty-seven middle-class boys and girls between three and six years of age viewed videotapes of adults engaged in traditional or cross-sex activities to determine the effects of sex-role modeling o...

(1958). A Science Curriculum to Meet Modern Needs. The Clearing House: A Journal of Educational Strategies, Issues and Ideas: Vol. 33, No. 1, pp. 9-12.

Play experience with three-dimensional (3-D) letters appeared to increase printed letter discriminations of 3- and 4-yr.-olds as effectively as play with two-dimensional (2-D) printed letters. In a second experiment 2-D and 3-D tasks were alternated. Consistently fewer discrimination errors were made on the 3-D task. Three-dimensional task experience apparently reduced errors on the subsequent 2-D task; 2-D task experience did not serve to reduce errors on the subsequent 3-D task. These findings are congruent with others that indicate young children discriminate 3-D forms more accurately than 2-D and that haptic experience may contribute to greater accuracy of visual discrimination of both 2-D and 3-D forms.

46 4-yr.-old children from the United States and 80 from Bangalore, India made fewer discrimination errors when letters were three-rather than two-dimensional. More errors were made on Kannada (Indian) than on English orthographic tasks, but there were relatively fewer errors made by Indian than American children. Younger subjects and boys made relatively more errors than other groups. The findings suggest visually perceived depth may activate the young child's enactive system dominant during the preoperational period and serve to increase accuracy of letter discrimination.

Use of letter and shape cues in visual recognition of 3- and 5-letter nonsense words by 1st- and 3rd-graders, and college students ( ns = 50) was investigated. Shape cues were used less frequently than letters; use of shape cues decreased with increasing educational level of Ss and were more frequently used with longer words.

THE last few years have seen the development in the federal government of a new in-service training program devoted to the improvement of budget administration. This program brings together, in organized series of conferences, selected groups of federal employees engaged in budget work. The conferences cover the two broad phases of budget administration: one series deals with budget formulation, the other with budget execution. The growth and operation of this training program are likely to be of interest not only to readers concerned with budgeting but also to others who need to keep in touch with various kinds of training experience. Perhaps the greatest significance of the program lies in the illustration it offers of the value of a sus