Addressing diversity and inclusion challenges in global neuro-psychiatric and behavioral genomics research.

Advancements in neuro-psychiatric and behavioral genomics offer significant opportunities for better understanding the human brain, behavior and associated disorders. Such advancements may help us prevent, manage and/or cure complex conditions. The serious challenge confronted by these disciplines however is diversity. Both fields lack diversity in terms of genomic reference datasets needed for discovery research, engagement of diverse communities in translational research and in terms of diverse and multidisciplinary scientific teams. This is a challenge because diversity is needed on all levels in order to increase representation and inclusion of all populations across the globe as we move research activities forward. The lack of diversity can translate to an inability to use scientific innovations from these fields for the benefit of all people everywhere and signifies a missed opportunity to address pervasive global health inequities. In this commentary we identify three persistent barriers to reaching diversity targets while focusing on discovery and translational science. Additionally, we propose four suggestions on how to advance efforts and rapidly move towards achieving diversity and inclusion in neuro-psychiatric and behavioral genomics. Without systematically addressing the diversity gap within these fields, the benefits of the science may not be relevant and accessible to all people.

Social enrichment reverses the isolation-induced deficits of neuronal plasticity in the hippocampus of male rats.

Environmental enrichment is known to improve brain plasticity and protect synaptic function from negative insults. In the present study we used the exposure to social enrichment to ameliorate the negative effect observed in post weaning isolated male rats in which neurotrophic factors, neurogenesis, neuronal dendritic trees and spines were altered markedly in the hippocampus. After the 4 weeks of post-weaning social isolation followed by 4 weeks of reunion, different neuronal growth markers as well as neuronal morphology were evaluated using different experimental approaches. Social enrichment restored the reduction of BDNF, NGF and Arc gene expression in the whole hippocampus of social isolated rats. This effect was paralleled by an increase in density and morphology of dendritic spines, as well as in neuronal tree arborisation in granule cells of the dentate gyrus. These changes were associated with a marked increase in neuronal proliferation and neurogenesis in the same hippocampal subregion that were reduced by social isolation stress. These results further suggest that the exposure to social enrichment, by abolishing the negative effect of social isolation stress on hippocampal plasticity, may improve neuronal resilience with a beneficial effect on cognitive function.

Efficacy and safety of hematopoietic stem cell remobilization with plerixafor+G-CSF in adult patients with germ cell tumors.

Autologous hematopoietic SCT (auto-HSCT) can be curative for patients with germ cell tumors. Poor stem cell mobilization jeopardizes the ability to deliver this therapy. Herein, we describe a retrospective study examining safety and efficacy of plerixafor in combination with G-CSF for patients with germ cell tumors who had previously failed stem cell collection. Overall, 21 patients with germ cell tumors and previous mobilization failure were remobilized with G-CSF (10 µg/kg SC) and plerixafor (0.24 mg/kg SC) beginning the evening of day 4 of G-CSF treatment. Dosing of G-CSF and plerixafor was repeated until collection of ≥ 2 × 10(6) CD34+ cells/kg. Remobilization resulted in a median yield of 3.2 × 10(6) CD34+ cells/kg. A total of 17 (81%) patients collected ≥ 2 × 10(6) and 9 (43%) patients collected ≥ 4 × 10(6) CD34+ cells/kg in a median of 2 (range 1-3) and 3 (range 1-4) days, respectively. In all, 16 (76%) patients proceeded to transplant; 8 (38%) received tandem transplants. There were no serious adverse events. In summary, the majority of patients with germ cell tumors who failed prior mobilization with growth factors ± chemotherapy were remobilized with plerixafor plus G-CSF facilitating at least one auto-HSCT. Use of plerixafor plus G-CSF can increase access of this potentially life-saving procedure to patients with high-risk germ cell tumors.

Plerixafor (Mozobil) for stem cell mobilization in patients with multiple myeloma previously treated with lenalidomide.

Lenalidomide and other new agents have considerable activity in multiple myeloma (MM) and have changed the landscape of treatment. Data suggest that lenalidomide therapy before autologous hematopoietic stem cell transplantation has a detrimental effect on stem cell mobilization. This retrospective study examined the efficacy of plerixafor in combination with G-CSF among patients with MM previously treated with lenalidomide (median, 4 cycles; range, 1-20 cycles). Data were analyzed for 60 patients who received plerixafor plus G-CSF for frontline mobilization in a phase 3 clinical trial or an expanded access program (n=20) or for remobilization in a compassionate use program (n=40). The overall median number of CD34+ cells collected was 5.6 × 10(6) per kg (range, 0.45 × 10(6)-37.2 × 10(6)). The minimum number of CD34+ cells (2 × 10(6) per kg) was collected from 86.7% of patients in a median of 1 day. This minimum was collected from 100% of patients who underwent frontline mobilization and 80% of patients who underwent remobilization. These data suggest that CD34+ hematopoietic stem cells can be successfully and predictably collected with combination plerixafor plus G-CSF for primary or secondary mobilization in the majority of patients with MM who have been previously treated with lenalidomide.

Safety and efficacy assessment of plerixafor in patients with multiple myeloma proven or predicted to be poor mobilizers, including assessment of tumor cell mobilization.

This was an open-label, single-center, phase II study of 20 patients with multiple myeloma who were either proven poor mobilizers (n=10; group A) or predicted poor mobilizers (n=10; group B) and were planned for autologous hematopoietic SCT. The aim was to assess the safety and efficacy of plerixafor for stem cell mobilization and tumor cell contamination. The peripheral blood (PB) CD34+ cell count was generally very low pre- plerixafor and increased significantly post-plerixafor administration. Cumulative apheresis yields of > or =2 x 10(6) CD34+ cells/kg were observed in 7 of 10 patients (group A) and 8 of 10 patients (group B). Among the proven poor mobilizers, there was no evidence of tumor cell mobilization in the PB after G-CSF plus plerixafor treatment. Seventeen of 20 (85%) patients underwent transplantation. Neutrophil engraftment occurred at a median of 13 days for all patients. Platelet engraftment occurred at a median of 16 days and 19 days for all proven and predicted poor mobilizers, respectively. At 12 months, 12 of 17 patients had documented durable grafts, 3 of 17 patients died and 2 of 17 patients were lost to follow-up; but they had documented graft durability at the previous 3- and 6-month visit. The safety profile of plerixafor in all patients was consistent with previous reports.

Safety and preliminary efficacy of plerixafor (Mozobil) in combination with chemotherapy and G-CSF: an open-label, multicenter, exploratory trial in patients with multiple myeloma and non-Hodgkin's lymphoma undergoing stem cell mobilization.

Plerixafor, a novel CXCR4 inhibitor, is effective in mobilizing PBSCs particularly when used in conjunction with G-CSF. In four cohorts, this pilot study explored the safety of plerixafor mobilization when incorporated into a conventional stem cell mobilization regimen of chemotherapy and G-CSF. Forty (26 multiple myeloma and 14 non-Hodgkin's lymphoma) patients were treated with plerixafor. Plerixafor was well tolerated and its addition to a chemo-mobilization regimen resulted in an increase in the peripheral blood CD34+ cells. The mean rate of increase in the peripheral blood CD34+ cells was 2.8 cells/microl/h pre- and 13.3 cells/microl/h post-plerixafor administration. Engraftment parameters were acceptable after myeloblative chemotherapy, with the median day for neutrophil and plt engraftment being day 11 (range 8-20 days) and day 13 (range 7-77 days), respectively. The data obtained from the analysis of the cohorts suggest that plerixafor can safely be added to chemotherapy-based mobilization regimens and may accelerate the rate of increase in CD34+ cells on the second day of apheresis. Further studies are warranted to evaluate the effect of plerixafor in combination with chemomobilization on stem cell mobilization and collection on the first and subsequent days of apheresis, and its impact on resource utilization.

Mobilization of peripheral blood stem cells for autologous transplant in non-Hodgkin's lymphoma and multiple myeloma patients by plerixafor and G-CSF and detection of tumor cell mobilization by PCR in multiple myeloma patients.

This report describes the first investigational use of plerixafor in Europe and the determination of tumor cell mobilization by polymerase chain-reaction after plerixafor treatment in a subset of patients with multiple myeloma (MM). Thirty-five patients (31 MM and 4 NHL) received granulocyte colony-stimulating factor (G-CSF) (10 microg/kg) each morning for 4 days. Starting the evening of Day 4, patients recieved plerixafor 0.24 mg/kg. Apheresis was initiated 10-11 h later, in the morning of Day 5. This regimen of G-CSF treatment each morning before apheresis and plerixafor treatment in the evening was repeated for up to 5 consecutive days. Mobilization with plerixafor and G-CSF resulted in a median 2.6-fold increase in peripheral blood (PB) CD34+ cell count compared with before plerixafor treatment. All patients collected > or =2 x 10(6) CD34+ cells/kg and 32 of 35 patients collected > or =5 x 10(6) CD34+ cells/kg. After plerixafor treatment, 3 of 7 patients had a small increase and 4 of 7 patients had a small decrease in PB tumor cells. No G-CSF was given post transplant. The median number of days to polymorphonuclear leukocyte and platelet engraftment was 14.0 and 11.0, respectively. There were no reports of graft failure. Plerixafor was generally well tolerated. Mobilization of PB CD34+ cells was consistent with previous clinical trials. The addition of plerixafor did not significantly increase the relative number of PB MM tumor cells.

Rescue from failed growth factor and/or chemotherapy HSC mobilization with G-CSF and plerixafor (AMD3100): an institutional experience.

Auto-SCT has been shown to be a potentially curative treatment for a variety of hematological malignancies. Auto-SCT is dependent on the successful mobilization and collection of hematopoietic stem cells to ensure engraftment. The inability to mobilize sufficient number of hematopoietic stem cells using standard cytokine-assisted mobilization strategies excludes eligible patients from potentially curative auto-SCT. Plerixafor (AMD3100; Mozobil), a novel bicyclam antagonist of the SDF-1alpha/CXCR4 complex, has been reported previously to augment PBSC mobilization in patients undergoing their first planned stem cell mobilization and collection attempt. In our experience, 17 of 20 patients otherwise eligible for auto-SCT who failed previous mobilization attempts had successful mobilization of CD34(+) hematopoietic stem cells with one apheresis procedure, and an additional patient required two aphereses procedures, when treated with the combination of plerixafor and G-CSF on a compassionate use protocol available at our institution.

AMD3100 plus G-CSF can successfully mobilize CD34+ cells from non-Hodgkin's lymphoma, Hodgkin's disease and multiple myeloma patients previously failing mobilization with chemotherapy and/or cytokine treatment: compassionate use data.

AMD3100 given with G-CSF has been shown to mobilize CD34+ cells in non-Hodgkin's lymphoma (NHL), multiple myeloma (MM), and Hodgkin's disease (HD) patients who could not collect sufficient cells for autologous transplant following other mobilization regimens. These poor mobilizers are usually excluded from company-sponsored trials, but have been included in an AMD3100 Single Patient Use protocol, referred to as a Compassionate Use Protocol (CUP). A cohort of 115 data-audited poor mobilizers in CUP was assessed, with the objective being to collect > or =2 x 10(6) CD34+ cells per kg following AMD3100 plus G-CSF mobilization. The rates of successful CD34+ cell collection were similar for patients who previously failed chemotherapy mobilization or cytokine-only mobilization: NHL -- 60.3%, MM -- 71.4% and HD -- 76.5%. Following transplant, median times to neutrophil and PLT engraftment were 11 days and 18 days, respectively. Engraftment was durable. There were no drug-related serious adverse events. Of the adverse events considered related to AMD3100, two (1.6%) were severe (one patient -- headache, one patient -- nightmares). Other AMD3100-related adverse events were mild (84.8%) or moderate (13.6%). The most common AMD3100-related adverse events were gastrointestinal reactions, injection site reactions and paresthesias. AMD3100 plus G-CSF offers a new treatment to collect CD34+ cells for autologous transplant from poor mobilizers, with a high success rate.

[The influence of professional degree on the knowledge of HIV, HBV and HCV infections in dentistry practice]. / Influenza dei percorsi formativi sulle conoscenze di infezioni da HIV, HBV e HCV nella pratica odontoiatrica.

The knowledge and preventive practices toward the risk of infection with HIV, HBV and HCV were evaluated in a sample of 254 dentists and odontostomatologies in Palermo, by answering to an anonymous questionnaire sent by mail. Overall, most of the participants showed a good knowledge of the transmission pattern of blood-borne viruses as well as good practice for personal hygiene (washing of hands, routine use of gloves, etc.). However 80.8% answered to recap needles after use and more than 40% have had at least one needle injury during the last year in their occupational setting. Moreover, nearly 24% of the interviewed declared to have not made vaccination against Hepatitis B virus infection. Statistical analysis showed a significant correlation between better knowledge, safer practice and different teaching training suggesting that odontostomatology degree might be more appropriate for a better training in preventive medicine for blood borne pathogens. Data also suggest the need of continuous worker education to reduce occupational blood exposures in dentistry.

A pharmacokinetic-pharmacodynamic model for the mobilization of CD34+ hematopoietic progenitor cells by AMD3100.

BACKGROUND: AMD3100 is a small-molecule CXCR4 antagonist that has been shown to induce the mobilization of CD34 + hematopoietic progenitor cells from bone marrow to peripheral blood. AMD3100 has also been shown to augment the mobilization of CD34 + cells in cancer patients when administered in combination with granulocyte colony-stimulating factor (G-CSF) (filgrastim). The purpose of this study was to characterize the exposure-response relationship of AMD3100 in mobilizing CD34 + cells when administered as a single agent in healthy volunteers. METHODS: AMD3100 concentrations and CD34 + cell counts obtained from 29 healthy subjects in a single-dose, intensively sampled pharmacokinetic/pharmacodynamic (PK-PD) study were analyzed by use of nonlinear mixed effects regression with the software NONMEM. FOCE (first order conditional estimation) with interaction was the estimation method, and simultaneous PK-PD fitting was adopted. RESULTS: The pharmacokinetics of AMD3100 was described by a 2-compartment model with first-order absorption. The population estimates (+/-SE) for clearance and central volume of distribution were 5.17 +/- 0.49 L/h and 16.9 +/- 3.79 L, respectively. CD34 + cell mobilization was best described by an indirect effect model that stimulates the entry process of CD34 + from bone marrow to peripheral blood in the form of a sigmoid maximum effect model. The population estimates (+/-SE) of maximum effect, concentration causing 50% of maximum response, and equilibration time were 12.6 +/- 4.89, 53.6 +/- 11.9 mug/L, and 5.37 +/- 1.31 hours, respectively. CONCLUSIONS: This study characterizes the exposure-response relationship of AMD3100 in mobilizing CD34 + cells after subcutaneous administration. This PK-PD model will be useful in assessing relevant covariates and for optimizing the use of AMD3100 in various patient populations.

Low thymic output and reduced heterogeneity of alpha/beta, but not gamma/delta, T lymphocytes in infants with ataxia-telangiectasia.

Ataxia-telangiectasia, a genetic disease caused by the homozygous mutation of the ATM gene, is frequently associated to a deficit of humoral and cellular immune functions. A decreased thymic output and skewed T cell and B cell receptor repertoires have been recently described in children over 7 years of age and in adults with this disease and have been proposed as a possible explanation for the immunodeficiency. To understand whether T cell defects arise early in life as a consequence of ATM gene mutations, we analysed the extent of thymic function by measuring the number of naïve T cells and by studying the heterogeneity of T cells by means of heteroduplex analysis, in two children less than 2 years old with a remarkable reduction of T cell count. We found that the thymic output is decreased in babies with ataxia-telangiectasia if compared with that observed in age-matched normal babies. The low production of new T cells is associated to a reduction of the diversity of alpha/beta, but not gamma/delta, T lymphocytes. Our data indicate that ATM mutation limits the generation of a wide alpha/beta T cell repertoire and this feature can be responsible for the immunodeficiency observed in ataxia-telangiectasia babies.

[Necrotizing fasciitis of soft tissues: role of diagnostic imaging and review of the literature]. / La fascite necrotizzante dei tessuti molli: ruolo della diagnostica per immagini e revisione della letteratura.

PURPOSE: We retrospectively reviewed the diagnostic imaging findings (radiography, CT and US) of our cases of necrotizing fascitis of soft tissues looking for signs that could be useful for early and accurate diagnosis. MATERIAL AND METHODS: May 1991 to February 1998 we examined 130 patients with progressive necrotizing soft tissue infections; in 32 of them (22-84 years old) the retrospective pathologic diagnosis was necrotizing fascitis. Involved sites were the limbs (26/32), the cervical region (5/32) and the perineal region (1/32). Nineteen patients were submitted to conventional radiography, also for soft tissue studies. US was performed in an emergency setting in all the 32 cases, by a selected group of US operators particularly skilled in this kind of soft tissue condition. Contrast enhanced CT was performed in 9 cases. RESULTS: B-mode and Doppler US yielded useful and reliable information for prompt and correct diagnosis. Particularly these techniques showed changes in subcutaneous adipose tissue (28/32), fascia (18/32) and muscle (15/32). We found a good correlation between tissue changes as shown at US and histologic findings, but US missed changes in subcutaneous soft tissue and muscle in 11 cases (3/32 and 8/32, respectively) with subsequent histologic confirmation. Contrast enhanced CT better defined the extent of disease and possible complications, especially in sites that are difficult to study with US. DISCUSSION AND CONCLUSIONS: Early diagnosis and proper treatment are the key issues affecting the chances of recovery for patients with necrotizing fascitis. The clinical suspicion of this condition calls for prompt intervention with effective diagnostic protocols. B-mode, and sometimes color Doppler, US and contrast enhanced CT, together with appropriate laboratory tests, can provide useful information for precise diagnosis and proper treatment.

Psychological constructs associated with emotional blood pressure response and white coat phenomenon.

Some hypertensive and non-hypertensive subjects have a striking blood pressure response to a medical environment (white coat phenomenon), although it is unlikely that its presence, degree, and duration can be routinely predicted. Despite the common observation that "anxious" patients may present with this reaction when a physician measures their blood pressure, no psychological variables have thus far been linked to white coat phenomenon in formal analyses. Ambulatory blood pressure monitoring is a useful tool to disclose the phenomenon since it allows precise evaluation of repeated blood pressure measurements outside the medical environment. To investigate the possible relationship between psychological profile and white coat phenomenon, we have planned to administer a series of psychometric tests to 120 subjects undergoing ambulatory blood pressure monitoring. The present data are derived from an analysis of the first set of 70 patients. Thirty-four subjects who presented with white coat phenomenon (defined as office blood pressure elevated by at least 15% over the mean 24-hour ambulatory blood pressure value) and 36 comparable subjects who did not have this reaction underwent a series of psychometric tests evaluating cognitive behavior, hostility, cynicism, anger, anxiety state, coping ability and strategies, and quality of life. Of the various psychometric tests, the scores of three relevant scales (healthcare-related fears, mental efficiency and behavioral disengagement) were significantly higher in the group of patients with white coat phenomenon, while in both groups, emotional instability was higher than the clinical cut-off point. There were no significant differences between the two groups regarding signs and repression of anger (anger-out and anger-in), cynicism, hostility, or anxiety state. Our data seem to indicate that the subjects most likely to show an overt blood pressure increase in the medical environment are those who evidence healthcare-related fears and emotional instability but are not necessarily anxious. They exhibit high coping skills in cognitive resolution of stressing situations (such as blood pressure measurement) but do not combine these strategies with an adequate behavioral response and do not feel that behavioral involvement is necessary for the management of their clinical condition.

Vaccine induced immunologic memory for hepatitis B surface antigen: implications for policy on booster vaccination.

This paper reviews published literature on the long-term persistence of immunologic memory for HBsAg after a course of hepatitis B vaccine and the functional significance this has for policy on booster vaccination. Several studies have shown that vaccine induced antibody (anti-HBs) specific for the surface antigen (HBsAg) of hepatitis B virus (HBV) is protective at a serum concentration of 10 milli-International Units per milliliter (mIU ml-1). When acquired passively (e.g. from hepatitis B immune globulin), susceptibility to infection returns as antibody declines. However, vaccine induces active synthesis of anti-HBs accompanied by immunologic memory for HBsAg that affords ongoing protection independent of antibody. Persistent memory over periods of 5 years or more is evident from large, rapid increases in antibody following booster vaccination, even in subjects who have lost antibody. Complementary studies, using an in vitro enzyme linked immunosorbent assay (spot-ELISA), show that the number of memory B lymphocytes able to produce anti-HBs does not diminish as the level of antibody declines. That immunologic memory provides effective immunity is suggested by serologic studies over periods of 5 years or more of vaccinees frequently exposed to HBV. Although many failed to maintain at least 10 mIU ml-1 of antibody, there have been very few clinically significant breakthrough infections. Thus, it appears unnecessary to give healthy vaccinees a booster vaccination when the level of anti-HBs falls below 10 mIU ml-1. Current studies suggest good retention of immunologic memory in healthy vaccinees over periods of 5-12 years. While additional studies will better define the limits of this phenomenon, routine booster vaccination should not be needed to sustain immunologic memory and protection within 5 years and perhaps longer after the primary vaccination series.

Antibody responses of healthy infants to a recombinant hepatitis B vaccine administered at two, four, and twelve or fifteen months of age.

Hepatitis B vaccine was administered to healthy infants on two investigational schedules that fall within ranges recommended by the U.S. Public Health Service Advisory Committee on Immunization Practices and by the American Academy of Pediatrics Committee on Infectious Diseases. A month after receiving vaccine at 2, 4, and 12 or 15 months of age, 98% and 100% of the children had > 10 mIU antibodies to hepatitis B surface antigen per milliliter, with gemometric mean titers of 1358 mIU/ml and 3424 mIU/mL, respectively.

Safety, tolerability and immunogenicity of a formalin-inactivated hepatitis A vaccine (VAQTA) in rural Kentucky children.

This study evaluated the immunogenicity and safety/tolerability profile of an investigational formalin-inactivated hepatitis A virus vaccine (VAQTA; Merck Research Laboratories) in 150 seronegative healthy children, 4 to 12 years old. The vaccine was derived from virus grown in infected MRC-5 cells in either roller bottles or Nunc cell factories (Nunc, Denmark). Subjects were vaccinated intramuscularly in a two dose regimen initially and at 24 weeks: Group A (n = 50) with a 12-unit dose from a roller bottle lot; Group B (n = 50) with a 25-unit dose from another roller bottle lot; and Group C (n = 50) with a 25-unit dose from a Nunc cell lot. Sera for anti-hepatitis A virus antibodies were drawn 3 weeks before vaccination and 4, 24 and 28 weeks after the first dose. Seroconversion from < 10 mIU/ml to > or = 10 mIU/ml by modified HAVAB (Abbott Laboratories) was observed in 99% of subjects at week 4 and persisted in 100% of subjects at week 28 (4 weeks after the second dose). The ranges of geometric mean titers of anti-HAV for all subjects at weeks 4, 24 and 28 were 31 to 49, 51 to 79 and 7059 to 29,609 mIU/ml, respectively. The 12- and 25-unit dose levels of roller bottle yielded similar geometric mean titers. The rise in geometric mean titers after the booster dose was > 120-fold and was highest in the recipients of the 25-unit Nunc cell lot (P < 0.05 for Group C vs. B).(ABSTRACT TRUNCATED AT 250 WORDS)

Maternal HEL immunization has no lasting effects on the immune response of offspring to immunization with hen egg-white lysozyme.

The effect of prior maternal immunization on the murine offspring response to subsequent immunization with hen egg-white lysozyme was examined. Adult female A/J mice were immunized with 100 micrograms HEL-CFA intraperitoneally 10-27 weeks before conception. The offspring of these experimental female mice were then immunized with HEL-CFA at differing ages. Suppression of the anti-HEL IgG B cell response was observed when the offspring were immunized prior to 3 weeks of age when high levels of maternal antibody were still present. Older offspring, more than 8 weeks of age, were immunized with HEL-CFA to determine if exposure to maternal immunoglobulin early in ontogeny had primed or altered the offspring response to HEL. At this age, suppressive effects of transferred maternal antibody were no longer evident. Priming was not detected in the offspring as judged by the total magnitude of the anti-HEL antibody response or the kinetics of the response when experimental and age-matched control offspring were examined. Furthermore, qualitative differences in the response as evidenced by IgG vs IgM content and fine specificity of the response (primary vs secondary antibody) were not observed. No evidence was found to suggest that exposure to polyclonal maternal anti-HEL antibody had primed the offspring for a more efficient or qualitatively different response to immunization with the protein antigen HEL. After maternal antibody levels decreased, the offspring response was similar to that of controls, suggesting that the response had not been permanently altered by the prior exposure early in ontogeny to polyclonal maternal antibody.