During cortical synaptic development, thalamic axons must establish synaptic connections despite the presence of the more abundant intracortical projections. How thalamocortical synapses are formed and maintained in this competitive environment is unknown. Here, we show that astrocyte-secreted protein hevin is required for normal thalamocortical synaptic connectivity in the mouse cortex. Absence of hevin results in a profound, long-lasting reduction in thalamocortical synapses accompanied by a transient increase in intracortical excitatory connections. Three-dimensional reconstructions of cortical neurons from serial section electron microscopy (ssEM) revealed that, during early postnatal development, dendritic spines often receive multiple excitatory inputs. Immuno-EM and confocal analyses revealed that majority of the spines with multiple excitatory contacts (SMECs) receive simultaneous thalamic and cortical inputs. Proportion of SMECs diminishes as the brain develops, but SMECs remain abundant in Hevin-null mice. These findings reveal that, through secretion of hevin, astrocytes control an important developmental synaptic refinement process at dendritic spines.DOI: http://dx.doi.org/10.7554/eLife.04047.001

IMPORTANCE Given the increase in opioid addiction and overdose in the United States, reasoned opioid use after outpatient surgery may affect prescription medication abuse.OBJECTIVES To examine patient use of opioids after rhinoplasty and establish an optimal postrhinoplasty pain management regimen. DESIGN, SETTING, AND PARTICIPANTSIn this case series, opioid use was evaluated in 62 patients who underwent rhinoplasty performed by 3 fellowship-trained facial plastic surgeons, 2 in private practice in Texas and 1 in an academic setting in Michigan, from February 2016 to September 2016.MAIN OUTCOMES AND MEASURES Opioid use, pain control, and adverse effects were examined and opioid use was compared across patient demographic and surgical procedure characteristics, including rhinoplasty and septoplasty, open vs closed techniques, revision vs primary operations, reduction of turbinates, and use of osteotomies. Opioid use was self-reported as the number of prescribed tablets containing a combination of hydrocodone bitartrate (5 mg) and acetaminophen (325 mg) that were consumed. RESULTSThe mean (SEM) age of the patients was 38.7 (16.4) years and included 50 female patients (81%). Of the initially prescribed 20 to 30 hydrocodone-acetaminophen combination tablets, the 62 patients included in this study used a mean (SEM) of 8.7 (0.9) tablets, only 40% of those prescribed after rhinoplasty. In addition, 46 patients (74%) consumed 15 or fewer tablets, whereas only 3 patients (5%) required refills of pain medication. Sex, age, concurrent septoplasty or turbinate reduction, use of osteotomy, and history of a rhinoplasty were not associated with the number of tablets used. The most common adverse effects included drowsiness in 22 patients (35%), nausea in 7 (11%), light-headedness in 3 (5%), and constipation in 3 (5%). CONCLUSIONS AND RELEVANCETo mitigate the misuse or diversion of physician-prescribed opioid medications, surgeons must be steadfast in prescribing an appropriate amount of pain medication after surgery. A multifaceted pain control program is proposed to manage postoperative pain and ascertain the balance between controlling pain and avoiding overprescribing narcotics.LEVEL OF EVIDENCE NA.

HLA-haploidentical hematopoietic cell transplantation (Haplo-HCT) using posttransplantation cyclophosphamide (PT-Cy) has improved donor availability. However, a matched sibling donor (MSD) is still considered the optimal donor. Using the Center for International Blood and Marrow Transplant Research database, we compared outcomes after Haplo-HCT vs MSD in patients with acute myeloid leukemia (AML) in first complete remission (CR1). Data from 1205 adult CR1 AML patients (2008-2015) were analyzed. A total of 336 patients underwent PT-Cy–based Haplo-HCT and 869 underwent MSD using calcineurin inhibitor–based graft-versus-host disease (GVHD) prophylaxis. The Haplo-HCT group included more reduced-intensity conditioning (65% vs 30%) and bone marrow grafts (62% vs 7%), consistent with current practice. In multivariable analysis, Haplo-HCT and MSD groups were not different with regard to overall survival (P = .15), leukemia-free survival (P = .50), nonrelapse mortality (P = .16), relapse (P = .90), or grade II-IV acute GVHD (P = .98). However, the Haplo-HCT group had a significantly lower rate of chronic GVHD (hazard ratio, 0.38; 95% confidence interval, 0.30-0.48; P < .001). Results of subgroup analyses by conditioning intensity and graft source suggested that the reduced incidence of chronic GVHD in Haplo-HCT is not limited to a specific graft source or conditioning intensity. Center effect and minimal residual disease–donor type interaction were not predictors of outcome. Our results indicate a lower rate of chronic GVHD after PT-Cy–based Haplo-HCT vs MSD using calcineurin inhibitor–based GVHD prophylaxis, but similar other outcomes, in patients with AML in CR1. Haplo-HCT is a viable alternative to MSD in these patients.

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Traumatic brain injury (TBI), a leading cause of death and disability in the United States, causes potentially preventable damage in part through the dysregulation of neural calcium levels. Calcium dysregulation could affect the activity of the calcium-sensitive phosphatase calcineurin (CaN), with serious implications for neural function. The present study used both an in vitro enzymatic assay and Western blot analyses to characterize the effects of lateral fluid percussion injury on CaN activity and CaN-dependent signaling in the rat forebrain. TBI resulted in an acute alteration of CaN phosphatase activity and long-lasting alterations of its downstream effector, cofilin, an actin-depolymerizing protein. These changes occurred bilaterally in the neocortex and hippocampus, appeared to persist for hours after injury, and coincided with synapse degeneration, as suggested by a loss of the excitatory post-synaptic protein PSD-95. Interestingly, the effect of TBI on cofilin in some brain regions was blocked by a single bolus of the CaN inhibitor FK506, given 1 h post-TBI. Overall, these findings suggest a loss of synapse stability in both hemispheres of the laterally-injured brain, and offer evidence for region-specific, CaN-dependent mechanisms.

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Key Points Disease-free survival is higher with myeloablative regimens for patients in their third to fifth decade. Beyond the fifth decade, low-dose total body irradiation regimens offset mortality associated with transplant procedure.

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