Promoting Growth in Behavioral Neurology: A Path Forward.

Behavioral neurology & neuropsychiatry (BNNP) is a field that seeks to understand brain-behavior relationships, including fundamental brain organization principles and the many ways that brain structures and connectivity can be disrupted, leading to abnormalities of behavior, cognition, emotion, perception, and social cognition. In North America, BNNP has existed as an integrated subspecialty through the United Council for Neurologic Subspecialties since 2006. Nonetheless, the number of behavioral neurologists across academic medical centers and community settings is not keeping pace with increasing clinical and research demand. In this commentary, we provide a brief history of BNNP followed by an outline of the current challenges and opportunities for BNNP from the behavioral neurologist's perspective across clinical, research, and educational spheres. We provide a practical guide for promoting BNNP and addressing the shortage of behavioral neurologists to facilitate the continued growth and development of the subspecialty. We also urge a greater commitment to recruit trainees from diverse backgrounds so as to dismantle persistent obstacles that hinder inclusivity in BNNP-efforts that will further enhance the growth and impact of the subspecialty. With rapidly expanding diagnostic and therapeutic approaches across a range of conditions at the intersection of neurology and psychiatry, BNNP is well positioned to attract new trainees and expand its reach across clinical, research, and educational activities.

Telemedicine impact on post-stroke outpatient follow-up in an academic healthcare network during the COVID-19 pandemic.

BACKGROUND: The expansion of telemedicine associated with the COVID-19 pandemic has influenced outpatient medical care. The objective of our study was to determine the impact of telemedicine on post-acute stroke clinic follow-up. METHODS: We retrospectively evaluated the impact of telemedicine in Emory Healthcare, an academic healthcare system of comprehensive and primary stroke centers in Atlanta, Georgia, on post-hospital stroke clinic follow-up. We compared the frequency of 90-day follow-up in a centralized subspecialty stroke clinic among patients hospitalized before the local COVID-19 pandemic (January 1, 2019- February 28, 2020), during (March 1- April 30, 2020) and after telemedicine implementation (May 1- December 31, 2020). A comparison was made across hospitals less than 1 mile, 10 miles, and 25 miles from the stroke clinic. RESULTS: Of 1096 ischemic stroke patients discharged home or to a rehab facility during the study period, 342 (31%) had follow-up in the Emory Stroke Clinic (comprehensive stroke center 46%, primary stroke center 10 miles away 18%, primary stroke center 25 miles away 14%). Overall, 90-day follow-up increased from 19% to 41% after telemedicine implementation (p<0.001) with telemedicine appointments amounting for up to 28% of all follow-up visits. In multivariable analysis, factors associated with teleneurology follow-up (vs no follow-up) included discharge from the comprehensive stroke center, thrombectomy treatment, private insurance, private transport to the hospital, NIHSS 0-5 and history of dyslipidemia. CONCLUSIONS: Despite telemedicine implementation at an academic healthcare network successfully increasing post-stroke discharge follow-up in a centralized subspecialty stroke clinic, the majority of patients did not complete 90-day follow-up during the COVID-19 pandemic.

Brain Network Dysfunction in Poststroke Delirium and Spatial Neglect: An fMRI Study.

BACKGROUND AND PURPOSE: Delirium, an acute reduction in cognitive functioning, hinders stroke recovery and contributes to cognitive decline. Right-hemisphere stroke is linked with higher delirium incidence, likely, due to the prevalence of spatial neglect (SN), a right-brain disorder of spatial processing. This study tested if symptoms of delirium and SN after right-hemisphere stroke are associated with abnormal function of the right-dominant neural networks specialized for maintaining attention, orientation, and arousal. METHODS: Twenty-nine participants with right-hemisphere ischemic stroke undergoing acute rehabilitation completed delirium and SN assessments and functional neuroimaging scans. Whole-brain functional connectivity of 4 right-hemisphere seed regions in the cortical-subcortical arousal and attention networks was assessed for its relationship to validated SN and delirium severity measures. RESULTS: Of 29 patients, 6 (21%) met the diagnostic criteria for delirium and 16 (55%) for SN. Decreased connectivity of the right basal forebrain to brain stem and basal ganglia predicted more severe SN. Increased connectivity of the arousal and attention network regions with the parietal, frontal, and temporal structures in the unaffected hemisphere was also found in more severe delirium and SN. CONCLUSIONS: Delirium and SN are associated with decreased arousal network activity and an imbalance of cortico-subcortical hemispheric connectivity. Better understanding of neural correlates of poststroke delirium and SN will lead to improved neuroscience-based treatment development for these disorders. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03349411.

Impact of Delirium on Outcomes After Intracerebral Hemorrhage.

BACKGROUND AND PURPOSE: Delirium portends worse outcomes after intracerebral hemorrhage (ICH), but it is unclear if symptom resolution or postacute care intensity may mitigate its impact. We aimed to explore differences in outcome associated with delirium resolution before hospital discharge, as well as the potential mediating role of postacute discharge site. METHODS: We performed a single-center cohort study on consecutive ICH patients over 2 years. Delirium was diagnosed according to DSM-5 criteria and further classified as persistent or resolved based on delirium status at hospital discharge. We determined the impact of delirium on unfavorable 3-month outcome (modified Rankin Scale score, 4-6) using logistic regression models adjusted for established ICH predictors, then used mediation analysis to examine the indirect effect of delirium via postacute discharge site. RESULTS: Of 590 patients (mean age 70.5±15.5 years, 52% male, 83% White), 59% (n=348) developed delirium during hospitalization. Older age and higher ICH severity were delirium risk factors, but only younger age predicted delirium resolution, which occurred in 75% (161/215) of ICH survivors who had delirium. Delirium was strongly associated with unfavorable outcome, but patients with persistent delirium fared worse (adjusted odds ratio [OR], 7.3 [95% CI, 3.3-16.3]) than those whose delirium resolved (adjusted OR, 3.1 [95% CI, 1.8-5.5]). Patients with delirium were less likely to be discharged to inpatient rehabilitation than skilled nursing facilities (adjusted OR, 0.31 [95% CI, 0.17-0.59]), and postacute care site partially mediated the relationship between delirium and functional outcome in ICH survivors, leading to a 25% reduction in the effect of delirium (without mediator: adjusted OR, 3.0 [95% CI, 1.7-5.6]; with mediator: adjusted OR, 2.3 [95% CI, 1.2-4.3]). CONCLUSIONS: Acute delirium resolves in most patients with ICH by hospital discharge, which was associated with better outcomes than in patients with persistent delirium. The impact of delirium on outcomes may be further mitigated by postacute rehabilitation.

Effect of Missed Items on the Reliability of the Kessler Foundation Neglect Assessment Process.

OBJECTIVE: To determine the maximum permissible number of missed items on the 10-item Catherine Bergego Scale administered after the Kessler Foundation Neglect Assessment Process (KF-NAP). Secondary objectives were to determine the frequency, characteristics, and most commonly cited reasons reported for missed items. DESIGN: Retrospective diagnostic accuracy study. SETTING: Sixteen inpatient rehabilitation facilities in the United States. PARTICIPANTS: A consecutive clinical sample of 4256 patients (N=4256) with stroke or other neurologic deficits who were assessed for spatial neglect with the KF-NAP. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Catherine Bergego Scale via KF-NAP. RESULTS: The majority (69.7%) of patients had at least 1 missed item on their KF-NAP. Among those with missed items, it was most common to have 2 missed items (51.4%), and few had more than 3 missed items (11.3%). The most commonly missed items were Collisions (37.2%), Cleaning After Meals (36.1%), Meals (34.0%), and Navigation (19.7%). The most commonly reported reasons for missed items included time constraints, cognitive or communication deficits, and behavior or refusal of the therapy session. These reasons were reported for nearly all item types. Item-specific reasons were also commonly reported, such as a lack of a needed resource for task completion or low functional status of the patient. Prorated scoring of measures with up to 3 missed items maintained an acceptable level of concordance with complete measures (Lin's Concordance Correlation Coefficient=0.96, 95% CI, 0.9478-0.9626) for the combination of 3 missed items with lowest concordance. CONCLUSIONS: Clinicians should make every effort to capture all items on the KF-NAP. However, missed items occur in the majority of cases because of patient factors and barriers inherent to the inpatient hospital setting. When missed items are necessary, clinicians can confidently interpret a prorated score when 7 or more items are scored.

Spatial neglect treatment: The brain's spatial-motor Aiming systems.

Animal and human literature supports spatial-motor "Aiming" bias, a frontal-subcortical syndrome, as a core deficit in spatial neglect. However, spatial neglect treatment studies rarely assess Aiming errors. Two knowledge gaps result: spatial neglect rehabilitation studies fail to capture the impact on motor-exploratory aspects of functional disability. Also, across spatial neglect treatment studies, discrepant treatment effects may also result from sampling different proportions of patients with Aiming bias. We review behavioural evidence for Aiming spatial neglect, and demonstrate the importance of measuring and targeting Aiming bias for treatment, by reviewing literature on Aiming spatial neglect and prism adaptation treatment, and presenting new preliminary data on bromocriptine treatment. Finally, we review neuroanatomical and network disruption that may give rise to Aiming spatial neglect. Because Aiming spatial neglect predicts prism adaptation treatment response, assessment may broaden the ability of rehabilitation research to capture functionally-relevant disability. Frontal brain lesions predict both the presence of Aiming spatial neglect, and a robust response to some spatial neglect interventions. Research is needed that co-stratifies spatial neglect patients by lesion location and Aiming spatial neglect, to personalize spatial neglect rehabilitation and perhaps even open a path to spatial retraining as a means of promoting better mobility after stroke.

Identification of novel HLA-restricted preferentially expressed antigen in melanoma peptides to facilitate off-the-shelf tumor-associated antigen-specific T-cell therapies.

BACKGROUND AIMS: Preferentially expressed antigen in melanoma (PRAME) is a cancer/testis antigen that is overexpressed in many human malignancies and poorly expressed or absent in healthy tissues, making it a good target for anti-cancer immunotherapy. Development of an effective off-the-shelf adoptive T-cell therapy for patients with relapsed or refractory solid tumors and hematological malignancies expressing PRAME antigen requires the identification of major histocompatibility complex (MHC) class I and II PRAME antigens recognized by the tumor-associated antigen (TAA) T-cell product. The authors therefore set out to extend the repertoire of HLA-restricted PRAME peptide epitopes beyond the few already characterized. METHODS: Peptide libraries of 125 overlapping 15-mer peptides spanning the entire PRAME protein sequence were used to identify HLA class I- and II-restricted epitopes. The authors also determined the HLA restriction of the identified epitopes. RESULTS: PRAME-specific T-cell products were successfully generated from peripheral blood mononuclear cells of 12 healthy donors. Ex vivo-expanded T cells were polyclonal, consisting of both CD4+ and CD8+ T cells, which elicited anti-tumor activity in vitro. Nine MHC class I-restricted PRAME epitopes were identified (seven novel and two previously described). The authors also characterized 16 individual 15-mer peptide sequences confirmed as CD4-restricted epitopes. CONCLUSIONS: TAA T cells derived from healthy donors recognize a broad range of CD4+ and CD8+ HLA-restricted PRAME epitopes, which could be used to select suitable donors for generating off-the-shelf TAA-specific T cells.

Performance in practice; exploring trainer and trainee experiences of user-designed formative assessment tools.

INTRODUCTION: General Practice training in Ireland currently has various methods of formative assessment and feedback delivered to trainees. In 2018 the Irish College of General Practitioners commissioned the generation of two new user-designed formative feedback tools that would allow trainee feedback to drive learning. These tools became known as the Performance in Practice (PiP) tools. AIMS: To explore the experiences of General Practice (GP) trainers and trainees having completed a pilot of using the PiP tools for 4 months. METHODS: An explorative phenomenological approach was taken to understand the experiences of trainers and trainees. One to one interviews were conducted, and the transcripts analysed for themes and sub-theme via Template analysis. RESULTS: User experiences focused on two main areas; educational value and acceptability. In relation to educational value, the PiP tools were seen as an improvement over established forms of formative feedback, as they were centred around the curriculum and therefore reflected the unique multifaceted requirements of an independently practising GP. Acceptability primarily focused around data governance and structures, as well as practical issues such as ease of software use. CONCLUSIONS: Overall, the experience of using the PiP tools was positive for both trainers and trainees. Future plans to further explore implementation of the PiP tools have been significantly informed by this research.

Acute myeloid leukaemia and the immune system: implications for immunotherapy.

The recognition of the curative potential of the graft-versus-leukaemia effect for patients with acute myeloid leukaemia (AML) undergoing stem cell transplantation, and the emergence of immunotherapy as a powerful weapon to treat cancer, has spurred the exploration of the immune landscape of AML to apply immunotherapeutic approaches to curing the disease. While current concepts of cancer immunology and immunotherapy have relevance, there are also unique aspects of immune dysregulation in AML to be considered when designing rational immunotherapy for this leukaemia. This is timely because rapid advances in cancer immunobiology, together with technological developments have opened up the field of immunotherapy for malignant disease. Here the current knowledge of AML immunobiology is summarized together with a description of new immunotherapies to counter immunosuppression and immune evasion by AML. Recent advances in treatment with recombinant antibodies, adoptive cell therapy and vaccines and their future promise in AML treatment are reviewed.

Improved stability of long-duration sitting in spatial neglect after a single session of prism adaptation.

Spatial neglect after right brain stroke affects balance, and improvements in sitting balance after prism adaptation have been demonstrated using short-duration center of pressure (CoP) data. We present long-duration (5 min) CoP and trunk muscles electromyography recordings of a 61-year-old man with left-sided spatial neglect, before and after a single session of prism adaptation. His CoP-derived measures showed improved balance and postural stability in both the anterior-posterior and medial-lateral directions after prism adaptation. Concurrently, asymmetry in neuromuscular activations was reduced. The findings suggest that improved sitting balance may be associated with more symmetrical activation of trunk muscles after prism adaptation.

Fractographic analysis of separated endodontic file designs.

Endodontic rotary files are cutting instruments used to perform root canal procedures within a tooth interior. Focusing on quantitative fractographic analysis increases necessary, clinical performance understanding of file separation failure. This research employed controlled, dynamic testing to failure of commercial rotary files, analyzing the fractographic, forensic characteristics in relation to Weibull reliability determination, considering: (1) design analysis; (2) stress concentrations; (3) times to failure; (4) number of cycles to failure (NCF). Ex vivo testing included three file designs, each having constant tip size (0.035 mm), taper (0.06 mm/mm), and length (25 mm). Files were individually tested using an electric, torque-controlled handpiece, rotating within a standardized, simulated canal until fracture separation occurred. Fractographic analysis, including critical measurements, was conducted using the scanning electron microscope (SEM) (PhenomProX, PhenomWorld, NL). Weibull statistical analysis established reliability factors per design group. Fractographic analysis identified separation fractures, processing inclusions, flexural-fatigue striations, and stress concentrations at flute pitches. Calculated NCF median values (1277-EE; 899-VB; 713-PI) demonstrated significant statistical differences among groups (p < 0.001). Separated apical fragments yielded statistically significant differences (p ≤ 0.05) for varying file design groups. Weibull moduli among groups were statistically equivalent. Fractographic analysis exposed a presence of multiple failure factors in addition to defect distribution, governing cyclic fatigue failure originating at stress concentration points irrespective of file design. Fractographic analysis indicated that a change in file design, specifically at the working edges, in addition to improved surface finish, has the potential of reducing failures by lowering points of stress concentration and reducing fracture initiating surface cracks.

Frontal lesions predict response to prism adaptation treatment in spatial neglect: A randomised controlled study.

Spatial neglect commonly follows right hemisphere stroke. It is defined as impaired contralesional stimulus detection, response, or action, causing functional disability. While prism adaptation treatment is highly promising to promote functional recovery of spatial neglect, not all individuals respond. Consistent with a primary effect of prism adaptation on spatial movements, we previously demonstrated that functional improvement after prism adaptation treatment is linked to frontal lobe lesions. However, that study was a treatment-only study with no randomised control group. The current study randomised individuals with spatial neglect to receive 10 days of prism adaptation treatment or to receive only standard care (control group). Replicating our earlier results, we found that the presence of frontal lesions moderated response to prism adaptation treatment: among prism-treated patients, only those with frontal lesions demonstrated functional improvements in their neglect symptoms. Conversely, among individuals in the standard care control group, the presence of frontal lesions did not modify recovery. These results suggest that further research is needed on how frontal lesions may predict response to prism adaptation treatment. Additionally, the results help elucidate the neural network involved in spatial movement and could be used to aid decisions about treatment.

Forced to move: Patterns and predictors of residential displacement during an era of housing insecurity.

Recent work on residential displacement-being forced out of one's home-hints that its nature and prevalence have changed during the early twenty-first century. We evaluate this supposition against the backdrop of past displacement research. Reason-for-move data from seven waves of the American Housing Survey (2001-2013) are used to construct displacement measures that range from narrow (limited to forced moves prompted by government or private action or disaster loss) to broad (also including eviction and foreclosure). Our analysis shows that, regardless of measure, no consistent upward trend over time is apparent in the small percentage of mobile households experiencing displacement, although as many as 3.6 million individuals may be affected biennially. We also find that longstanding socioeconomic, racial, and other disparities in displacement persist but tend to be of modest magnitude. Such patterns could contribute to a perception of displacement as socially unpredictable, further heightening public concern about the issue.

Over-expression of PD-1 Does Not Predict Leukemic Relapse after Allogeneic Stem Cell Transplantation.

Blockade of the T-cell exhaustion marker PD-1 to re-energize the immune response is emerging as a promising cancer treatment. Relapse of hematologic malignancy after allogeneic stem cell transplantation limits the success of this approach, and PD-1 blockade may hold therapeutic promise. However, PD-1 expression and its relationship with post-transplant relapse is poorly described. Because the donor immunity is activated by alloresponses, PD-1 expression may differ from nontransplanted individuals, and PD-1 blockade could risk graft-versus-host disease. Here we analyzed T-cell exhaustion marker kinetics and their relationship with leukemia relapse in 85 patients undergoing myeloablative T-cell-depleted HLA-matched stem cell transplantation. At a median follow-up of 3.5 years, 35 (44%) patients relapsed. PD-1 expression in CD4 and CD8 T cells was comparably elevated in relapsed and nonrelapsed cohorts. Helios+ regulatory T cells and CD8 effector memory cells at day 30 emerged as independent predictors of relapse. Although leukemia antigen-specific T cells did not overexpress PD-1, single-cell analysis revealed LAG3 and TIM3 overexpression at relapse. These findings indicate that PD-1 is an unreliable marker for leukemia-specific T-cell exhaustion in relapsing patients but implies other exhaustion markers and suppressor cells as relapse biomarkers.

Cytomegalovirus Infection Incidence and Risk Factors Across Diverse Hematopoietic Cell Transplantation Platforms Using a Standardized Monitoring and Treatment Approach: A Comprehensive Evaluation from a Single Institution.

Human cytomegalovirus (CMV) infection and disease remains a significant cause of morbidity and mortality for hematopoietic cell transplantation (HCT) recipients. Disruption of or weak reconstitution of virus-specific cellular immune function, such as with certain HCT approaches, poses significant risk for CMV-related complications. The incidence of and risk factors for CMV infection and the nature of CMV disease were evaluated retrospectively among 356 consecutive HCT recipients transplanted at the National Institutes of Health using all graft sources, including bone marrow, peripheral blood stem cell (PBSC), and umbilical cord blood (UCB), and a range of in vivo and ex vivo approaches for graft-versus-host disease (GVHD) prophylaxis. The cumulative incidence of CMV infection was higher for CMV-seropositive recipients at 33%, regardless of donor CMV serostatus. Patients transplanted with CMV-seropositive donors had a significantly shorter duration of antiviral therapy. Among graft sources UCB was associated with the highest cumulative incidence of CMV infection at 65% and significantly longer treatment duration at a median of 36days, whereas PBSC HCT was associated with the lowest incidence at 26% and the shortest CMV treatment duration at a median of 21days. There were significant differences in the cumulative incidence of CMV infection by T cell manipulation strategy when systemic steroids were included as a risk-modifying event. Over one-third of CMV infections occurred in the setting of systemic steroid administration. CMV disease occurred in 5% of HCT recipients, with 70% of cases in the setting of treatment for GVHD. Although factors related to serostatus, graft source, and GVHD prophylaxis were associated with varied CMV infection incidence, unplanned post-HCT corticosteroid therapy contributed greatly to the incidence of both CMV infection and disease across HCT approaches, highlighting this post-HCT intervention as a key time to potentially tailor the approach to monitoring, preemptive therapy, and even prophylaxis.

T-cell receptor sequencing demonstrates persistence of virus-specific T cells after antiviral immunotherapy.

Viral infections are a serious cause of morbidity and mortality following haematopoietic stem cell transplantation (HSCT). Adoptive cellular therapy with virus-specific T cells (VSTs) has been successful in preventing or treating targeted viruses in prior studies, but the composition of ex vivo expanded VST and the critical cell populations that mediate antiviral activity in vivo are not well defined. We utilized deep sequencing of the T-cell receptor beta chain (TCRB) in order to classify and track VST populations in 12 patients who received VSTs following HSCT to prevent or treat viral infections. TCRB sequencing was performed on sorted VST products and patient peripheral blood mononuclear cells samples. TCRB diversity was gauged using the Shannon entropy index, and repertoire similarity determined using the Morisita-Horn index. Similarity indices reflected an early change in TCRB diversity in eight patients, and TCRB clonotypes corresponding to targeted viral epitopes expanded in eight patients. TCRB repertoire diversity increased in nine patients, and correlated with cytomegalovirus (CMV) viral load following VST infusion (P = 0·0071). These findings demonstrate that allogeneic VSTs can be tracked via TCRB sequencing, and suggests that T-cell receptor repertoire diversity may be critical for the control of CMV reactivation after HSCT.

Cerebral perfusion of the left reading network predicts recovery of reading in subacute to chronic stroke.

Better understanding of cerebral blood flow (CBF) perfusion in stroke recovery can help inform decisions about optimal timing and targets of restorative treatments. In this study, we examined the relationship between cerebral perfusion and recovery from stroke-induced reading deficits. Left stroke patients were tested with a noninvasive CBF measure (arterial spin labeling) <5 weeks post-stroke, and a subset had follow up testing >3 months post-stroke. We measured blood flow perfusion within the left and right sides of the brain, in areas surrounding the lesion, and areas belonging to the reading network. Two hypotheses were tested. The first was that recovery of reading function depends on increased perfusion around the stroke lesion. This hypothesis was not supported by our findings. The second hypothesis was that increased perfusion of intact areas within the reading circuit is tightly coupled with recovery. Our findings are consistent with this hypothesis. Specifically, higher perfusion in the left reading network measured during the subacute stroke period predicted better reading ability and phonology competence in the chronic period. In contrast, higher perfusion of the right homologous regions was associated with decreased reading accuracy and phonology competence in the subacute and chronic periods. These findings suggest that recovery of reading and language competence may rely on improved blood flow in the reading network of the language-dominant hemisphere.

A subset of virus-specific CD161+ T cells selectively express the multidrug transporter MDR1 and are resistant to chemotherapy in AML.

The establishment of long-lived pathogen-specific T cells is a fundamental property of the adaptive immune response. However, the mechanisms underlying long-term persistence of antigen-specific CD4+ T cells are not well-defined. Here we identify a subset of memory CD4+ T cells capable of effluxing cellular toxins, including rhodamine (Rho), through the multidrug efflux protein MDR1 (also known as P-glycoprotein and ABCB1). Drug-effluxing CD4+ T cells were characterized as CD161+CD95+CD45RA-CD127hiCD28+CD25int cells with a distinct chemokine profile and a Th1-polarized pro-inflammatory phenotype. CD4+CD161+Rho-effluxing T cells proliferated vigorously in response to stimulation with anti-CD3/CD28 beads and gave rise to CD161- progeny in vitro. These cells were also capable of self-renewal and maintained their phenotypic and functional characteristics when cultured with homeostatic cytokines. Multidrug-effluxing CD4+CD161+ T cells were enriched within the viral-specific Th1 repertoire of healthy donors and patients with acute myeloid leukemia (AML) and survived exposure to daunorubicin chemotherapy in vitro. Multidrug-effluxing CD4+CD161+ T cells also resisted chemotherapy-induced cytotoxicity in vivo and underwent significant expansion in AML patients rendered lymphopenic after chemotherapy, contributing to the repopulation of anti-CMV immunity. Finally, after influenza vaccination, the proportion of influenza-specific CD4+ T cells coexpressing CD161 was significantly higher after 2 years compared with 4 weeks after immunization, suggesting CD161 is a marker for long-lived antigen-specific memory T cells. These findings suggest that CD4+CD161+ T cells with rapid efflux capacity contribute to the maintenance of viral-specific memory T cells. These data provide novel insights into mechanisms that preserve antiviral immunity in patients undergoing chemotherapy and have implications for the development of novel immunotherapeutic approaches.

Transfusion support for matched sibling allogeneic hematopoietic stem cell transplantation (1993-2010): factors that predict intensity and time to transfusion independence.

BACKGROUND: Patients undergoing allogeneic hematopoietic stem cell transplant require variable, often extensive transfusion support. Identification of factors that predict urgent, intensive, or special needs should improve management of these patients. STUDY DESIGN AND METHODS: This is a retrospective study of red blood cell (RBC) and platelet transfusion support provided for sequential matched sibling donor allogeneic transplants conducted at the Clinical Center, National Institutes of Health, from 1993 through 2010. Factors potentially important for predicting quantity of RBC and platelet transfusions, and time to transfusion independence through Day 200 following hematopoietic stem cell transplantation were evaluated. RESULTS: Subjects (n = 800) received 10,591 RBC and 10,199 platelet transfusions. Multivariable analysis demonstrated that the need for RBC pretransplant, CD34+ dose, transplant year, diagnostic category, and ABO match were significantly independently associated with quantity of RBC transfusions during Days 0 through 30. Only pretransplant need for RBCs, CD34+ dose, and transplant year had significance during Days 0 through 100. Similar analyses for quantity of platelet transfusions demonstrated that for both Days 0 through 30 and 0 through 100 significant factors were need for platelet support before transplant, CD34+ dose, transplant year, and transplant regimen. Of note, long term, during Days 101 through 200, only CD34+ dose remained significant for quantity of RBC and platelet transfusions. Analysis of time to transfusion independence demonstrated that patients with ABO major mismatches required longer to achieve freedom from RBC transfusion support compared to identical matches or those with minor mismatches. CONCLUSION: Patient-specific factors including CD34+ dose and ABO match of the graft should be given particular consideration by transfusion services when planning support of patients receiving allogeneic hematopoietic stem cell transplant.

Prepubertal ovarian inhibition of Light/Dark Box exploration and novel object investigation in juvenile Siberian hamsters.

The overwhelming majority of research on the role of gonadal hormones in behavioral development has focused on perinatal, pubertal, or adult life stages. The juvenile period has been overlooked because it is thought to be a time of gonadal quiescence. In the present study, we tested whether prepubertal gonadectomy impacts the behavior of male and female juvenile hamsters on the Light/Dark Box, Novel Object, and Social Approach tests (Experiment 1) and compared these findings to those obtained after adult gonadectomy (Experiment 2). Prepubertal ovariectomy increased exploration (i.e. time spent in the light zone of the Light/Dark Box) and novel object investigation of juveniles indicating an inhibitory role for the juvenile ovary; social approach was unaffected. In contrast, adult ovariectomy and castration (both prepubertal and adult) had no effect on any behavioral measure. Experiment 3 tested whether rearing hamsters in a short day length (SD), which delays puberty in this species, extends the interval of juvenile ovarian inhibition on exploration and novelty seeking. We also tested whether provision of estradiol reverses the effects of prepubertal ovariectomy. Hormonal manipulations and behavioral tests of Experiment 3 were conducted at ages when long day-reared hamsters are adult (as in Experiment 2), but SD-reared hamsters remain reproductively immature. Ovariectomy again increased exploration in the SD-reared juveniles despite the older age of surgery and testing. Estradiol treatment had no effect. These findings reveal a novel role for the juvenile ovary in exploration and novelty seeking that is unlikely to be mediated exclusively by estradiol.