Longitudinal assessment of behaviour in young children undergoing general anaesthesia.

BACKGROUND: Exposure to general anaesthesia in children might increase the risk of long-term behavioural problems. It is unclear if any behavioural changes in the short term after anaesthesia could be associated with long-term problems. The goal of the current study was to evaluate the short-term trajectory of parent-reported behaviour measured by the Behaviour Assessment System for Children, third edition (BASC-3) amongst children aged 2.5-6 yr who underwent general anaesthesia for elective surgery. METHODS: Children who were undergoing general anaesthesia for surgery were recruited for assessment of behaviour on two occasions: preoperatively (from 1 week to 1 day before anaesthesia), and 3 months postoperatively. To assess longitudinal changes in the parent-reported behaviour measured by BASC-3, linear mixed models were built with visit number included as a categorical variable and subject-specific random intercepts. RESULTS: Sixty-eight children (37 girls [54%]) were enrolled in the study and completed both assessments. At 3 months after anaesthesia, statistically significant improvements (decrease in T scores) in internalising problems (-2.7 [95% confidence interval -4.2 to -1.1]), anxiety (-2.5 [-4.4 to -0.5]), and somatisation (-3.0 [-5.2 to -0.9]) were found. There were no significant differences in scores between visits for other composites or scales. The pattern of results did not depend upon prior anaesthesia exposure. CONCLUSIONS: Anaesthesia for elective surgery in young children was associated with a small decrease in internalising problems but no changes in other areas of behavioural problems when assessed at 3 months postoperatively, including in children with prior exposure to anaesthesia.

Longitudinal assessment of cognitive function in young children undergoing general anaesthesia.

BACKGROUND: Exposure to general anaesthesia in children may be related to deficits in certain areas of cognition. It is unclear if these deficits could be measured in the immediate postoperative period in young children. The goal of the current study was to evaluate the trajectory of cognitive function in the domains of processing speed, working memory, and fine motor skills amongst children aged 2.5-6 yr who underwent general anaesthesia for elective surgery. METHODS: Children who were scheduled to receive general anaesthesia for surgery were recruited for assessment of cognitive function at three times: preoperatively, 1-2 weeks postoperatively, and 3 months postoperatively. Assessments included processing speed, working memory, and fine motor skills. To assess longitudinal changes in the cognitive outcomes, linear mixed models were built with visit number included as a categorical variable and subject-specific random intercepts. RESULTS: Sixty-one children (33 girls [54%]) enrolled in the study. Twenty-three children (38%) had received general anaesthesia previously. Significant improvements in picture memory, cancellation, and the processing speed composite were found at Visit 2. The improvement in cancellation and processing speed composite remained significant at Visit 3. Statistically significant improvement in Mullen fine motor score was noticed at Visit 3 compared with Visit 1. The pattern of results did not depend upon prior anaesthesia exposure. CONCLUSIONS: General anaesthesia for elective surgery in young children was not associated with declines in working memory, processing speed, and fine motor skills in the first 3 months postoperatively, including in children with prior exposure to anaesthesia.

Midostaurin after allogeneic stem cell transplant in patients with FLT3-internal tandem duplication-positive acute myeloid leukemia.

We evaluated standard-of-care (SOC) treatment with or without midostaurin to prevent relapse following allogeneic hematopoietic stem cell transplant (alloHSCT) in patients with acute myeloid leukemia (AML) harboring internal tandem duplication (ITD) in FLT3. Adults (aged 18-70 years) who received alloHSCT in first complete remission, had achieved hematologic recovery, and were transfusion independent were randomized to receive SOC with or without midostaurin (50 mg twice daily) continuously in twelve 4-week cycles. The primary endpoint was relapse-free survival (RFS) 18 months post-alloHSCT. Sixty patients were randomized (30/arm); 30 completed all 12 cycles (midostaurin + SOC, n = 16; SOC, n = 14). The estimated 18-month RFS (95% CI) was 89% (69-96%) in the midostaurin arm and 76% (54-88%) in the SOC arm (hazard ratio, 0.46 [95% CI, 0.12-1.86]; P = 0.27); estimated relapse rates were 11% and 24%, respectively. Inhibition of FLT3 phosphorylation to <70% of baseline (achieved by 50% of midostaurin-treated patients) was associated with improved RFS. The most common serious adverse events were diarrhea, nausea, and vomiting. Rates of graft-vs-host disease were similar between both arms (midostaurin + SOC, 70%; SOC, 73%). The addition of midostaurin maintenance therapy following alloHSCT may provide clinical benefit in some patients with FLT3-ITD AML. (ClinicalTrials.gov identifier: NCT01883362).

Exploring the contribution of collective motions to the dynamics of forced-unfolding in tubulin.

Decomposition of the intrinsic dynamics of proteins into collective motions among distant regions of the protein structure provides a physically appealing approach that couples the dynamics of the system with its functional role. The cellular functions of microtubules (an essential component of the cytoskeleton in all eukaryotic cells) depend on their dynamic instability, which is altered by various factors among which applied forces are central. To shed light on the coupling between forces and the dynamic instability of microtubules, we focus on the investigation of the response of the microtubule subunits (tubulin) to applied forces. We address this point by adapting an approach designed to survey correlations for the equilibrium dynamics of proteins to the case of correlations for proteins forced-dynamics. The resulting collective motions in tubulin have a number of functional implications, such as the identification of long-range couplings with a role in blocking the dynamic instability of microtubules. A fundamental implication of our study for the life of a cell is that, to increase the likelihood of unraveling of large cytoskeletal filaments under physiological forces, molecular motors must use a combination of pulling and torsion rather than just pulling.

"It's Not Just About a Paycheck": Perspectives on Employment Preparation of Students With Intellectual Disability in Federally Funded Higher Education Programs.

Students with intellectual disability (ID) are increasingly attending postsecondary education institutions and acquiring work experiences while completing their studies. One of the main motivations for students with ID to seek higher education is to broaden and increase their chance for finding fulfilling, paid employment in their communities. Findings from a qualitative study on staff perspectives regarding career development and employment supports and services provided to students attending Transition and Postsecondary Education Programs for Students With Intellectual Disability (TPSID) model demonstration programs in the United States are presented. Results reflect consensus across program staff regarding the goals and expectations for employment of TPSID students. Programs vary considerably in their institutional context, their partnership with other entities, and the structure of employment services, as well as the emphasis placed on paid versus unpaid employment. Some of the key strategies shared by staff regarding successful student employment practices involved outreach and engagement, visibility on campus, improving access to career services, and cultivating partnerships. As higher education continues to expand its offerings to students with ID, postsecondary education programs need to continue to emphasize and honor the importance of paid employment, and continue to seek the best methods to achieve this outcome for students with ID.

Updated safety of midostaurin plus chemotherapy in newly diagnosed FLT3 mutation-positive acute myeloid leukemia: the RADIUS-X expanded access program.

Approval of midostaurin, a multikinase inhibitor, in combination with chemotherapy for the treatment of adults with newly diagnosed FLT3 mutation-positive acute myeloid leukemia, was based on the phase 3 RATIFY trial results. RADIUS-X (NCT02624570) was an expanded access program providing access to midostaurin during regulatory review and extending the understanding of the safety and tolerability of midostaurin. Patients aged ≥18 years received midostaurin with 1-2 cycles of induction therapy (cytarabine plus daunorubicin or idarubicin) and ≤4 cycles of high-dose cytarabine consolidation chemotherapy or as single-agent maintenance therapy. The study enrolled 103 patients. No new safety events were observed; toxicities were not influenced by age, anthracycline choice, or coadministration of CYP3A4 inhibitors. The most common adverse events (AEs) were febrile neutropenia, nausea, and diarrhea. During maintenance, 46% of patients reported AEs. Midostaurin demonstrated a manageable safety profile and was associated with high transplant and low on-treatment relapse rates.