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PURPOSE Standard cytotoxic induction chemotherapy for acute myeloid leukemia (AML) results in prolonged neutropenia and risk of infection. Romyelocel-L is a universal, allogeneic myeloid progenitor cell product being studied to reduce infection during induction chemotherapy. PATIENTS AND METHODS One hundred sixty-three patients with de novo AML (age ≥ 55 years) receiving induction chemotherapy were randomly assigned on day 0 (d0), of whom 120 were evaluable. Subjects received either romyelocel-L infusion on d9 with granulocyte colony-stimulating factor (G-CSF) starting daily d14 (treatment group) or G-CSF daily alone on d14 (control) until absolute neutrophil count recovery to 500/µL. End points included days in febrile episode, microbiologically defined infections, clinically diagnosed infection, and days in hospital. RESULTS Mean days in febrile episode was shorter in the treatment arm from d15 through d28 (2.36 v 3.90; P = .02). Similarly, a trend toward decreased microbiologically defined infections and clinically diagnosed infection in the treatment arm was observed from d9 to d28 (35.6% v 47.5%; P = .09), reaching a statistically significant difference from d15 to d28 (6.8% v 27.9%; P = .002). Because of this, antibacterial or antifungal use for treatment of an infection was significantly less in the treatment group (d9-d28: 44.1% v 63.9%; P = .01). Significantly fewer patients in the treatment arm received empiric antifungals from d9 tod28 (42.4% v 63.9%; P = .02) and d15-d28 (42.4% v 62.3%; P = .02). Patients in the treatment arm also had 3.2 fewer hospital days compared with control (25.5 v 28.7; P = .001). Remission rates and days to absolute neutrophil count recovery were similar in the two groups. No patients in the romyelocel-L plus G-CSF group died because of infection compared with two patients in the control arm. No graft-versus-host disease was observed. CONCLUSION Subjects receiving romyelocel-L showed a decreased incidence of infections, antimicrobial use, and hospitalization, suggesting that romyelocel-L may provide a new option to reduce infections in patients with AML undergoing induction therapy.

BackgroundHumoral and cellular immune responses to SARS-CoV-2 vaccination among immunosuppressed patients remain poorly defined, as well as variables associated with poor response.MethodsWe performed a retrospective observational cohort study at a large Northern California healthcare system of infection-naïve individuals fully vaccinated against SARS-CoV-2 (mRNA-1273, BNT162b2, or Ad26.COV2.S) with clinical SARS-CoV-2 interferon gamma release assay (IGRA) ordered between January through November 2021. Humoral and cellular immune responses were measured by anti-SARS-CoV-2 S1 IgG ELISA (anti-S1 IgG) and IGRA, respectively, following primary and/or booster vaccination.Results496 immunosuppressed patients (54% female; median age 50 years) were included. 62% (261/419) of patients had positive anti-S1 IgG and 71% (277/389) had positive IGRA after primary vaccination, with 20% of patients having a positive IGRA only. Following booster, 69% (81/118) had positive anti-S1 IgG and 73% (91/124) had positive IGRA. Factors associated with low humoral response rates after primary vaccination included anti-CD20 monoclonal antibodies (P&nbsp

ImportanceData on the humoral and cellular immune response to primary and booster SARS-CoV-2 vaccination in immunosuppressed patients is limited.ObjectiveTo determine humoral and cellular response to primary and booster vaccination in immunosuppressed patients and identify variables associated with poor response.DesignRetrospective observational cohort study.SettingLarge healthcare system in Northern California.ParticipantsThis study included patients fully vaccinated against SARS-CoV-2 (mRNA-1273, BNT162b2, or Ad26.COV2.S) who underwent clinical testing for anti-SARS-SoV-2 S1 IgG ELISA (anti-S1 IgG) and SARS-CoV-2 interferon gamma release assay (IGRA) from January 1, 2021 through November 15, 2021. A cohort of 18 immunocompetent volunteer healthcare workers were included as reference. No participants had a prior diagnosis of SARS-CoV-2 infection.Exposure(s)Immunosuppressive diseases and therapies.Main Outcome(s) and Measure(s)Humoral and cellular SARS-CoV-2 vaccine response as measured by anti-S1 IgG and SARS-CoV-2 IGRA, respectively, after primary and booster vaccination.Results496 patients (54% female; median age 50 years) were included in this study. Among immunosuppressed patients after primary vaccination, 62% (261/419) had positive anti-S1 IgG and 71% (277/389) had positive IGRA. After booster, 69% (81/118) had positive anti-S1 IgG and 73% (91/124) had positive IGRA. Immunosuppressive factors associated with low rates of humoral response after primary vaccination included anti-CD20 monoclonal antibodies (PPP=.002), and B cell lymphoma (P=.004); those associated with low rates of cellular response included S1P receptor modulators (PPP=.009). Only 5% (2/42) of immunosuppressed patients developed a significantly increased cellular response following the booster dose.Conclusions and RelevanceCellular vaccine response rates were higher than humoral response rates in immunosuppressed individuals after primary vaccination, particularly among those undergoing B cell targeting therapies. However, humoral response can be increased with booster vaccination, even in patients on B cell targeting therapies.

Characterization of cell-mediated and humoral immune responses to SARS-CoV2 mRNA vaccine has implications for protective immunity in immunocompromised patients. However, studies have demonstrated poor humoral response to SARS-CoV2 mRNA vaccine in immunocompromised patients and data on cellular immune response are currently lacking. Here we compared immune response after 2-dose vaccination in 100 immunocompromised patients (solid organ transplant recipients, hematologic malignancy, autoimmune condition, and primary immunodeficiency) and 16 immunocompetent healthy healthcare workers. We find that 100% (CI=80.6-100%) of immunocompetent individuals show positive cell-mediated and humoral immune response post vaccination while only 50% (CI=40.4-59.6%) of immunocompromised patients show humoral immune response and 69% (CI=59.4-77.2%) have a positive cell-mediated immune response. 21% of immunocompromised patients have no humoral immune response or cell-mediated immune response and thus are likely vulnerable to SARS-CoV2 infection. Monitoring of immune response in immunocompromised populations, particularly in high-risk immunocompromised patients (solid organ transplant recipients, patients with severe autoimmunity, and those ≥50 years), with clinical IGRA and serological assay after vaccination may identify patients who may benefit from revaccination or prophylactic monoclonal antibody therapy to prevent COVID-19 in this patient population

Introduction Cigarette smoking can have negative consequences in military populations including injury, reduced physical endurance, higher frequency of sick days, and reduced combat readiness. This study used the socioecological model to understand individual, interpersonal, and organizational influences on cigarette smoking among military members. Materials and Methods The sample for this secondary analysis was drawn from personnel at 24 large U.S. military installations, six from each service branch. Analyses included 4,728 personnel who were classified as current cigarette smokers. Generalized linear mixed models were used to estimate the associations among risk and protective factors from multiple ecological levels for smoking intensity and nicotine dependence. Results Smoking to fit in with one’s unit, being in the Army, smoking as a reaction to stress, and work-related stressors were all related to increased intensity of smoking and nicotine dependence. More active coping was associated with lower nicotine dependence and reduced smoking intensity. Conclusion Results based on the socioecological model identify influencing factors and suggest possible interventions for smoking cessation. Reducing tobacco use in the military will require coordinated interventions that address multilevel determinants of use and improve military health. This is important to the strategic alignment of policy and services across the continuum of health care needs.

Antifungal prophylaxis is the standard of care for patients undergoing intensive chemotherapy for haematological malignancy or haematopoietic cell transplantation (HCT). Prophylaxis with azoles reduces invasive fungal infections and may reduce mortality. However, breakthrough infections still occur, and the use of azoles is sometimes complicated by pharmacokinetic variability, drug interactions, adverse events and other issues. Echinocandins are highly active against Candida species, including some organisms resistant to azoles, and have some clinical activity against Aspergillus species as well. Although currently approved echinocandins require daily intravenous administration, the drugs have a favourable safety profile and more predictable pharmacokinetics than mould-active azoles. Clinical data support the efficacy and safety of echinocandins for antifungal prophylaxis in haematology and HCT patients, though data are less robust than for azoles. Notably, sparse evidence exists supporting the use of echinocandins as antifungal prophylaxis for patients with significant graft-versus-host disease (GvHD) after HCT. Two drugs that target (1,3)-β-d-glucan are in development, including an oral glucan synthase inhibitor and an echinocandin with unique pharmacokinetics permitting subcutaneous and weekly administration. Echinocandins are a reasonable alternative to azoles and other agents for antifungal prophylaxis in patients undergoing intensive chemotherapy for haematological malignancy or those receiving HCT, excluding those with significant GvHD.

BACKGROUND: Cytomegalovirus (CMV) infection remains a common complication after allogeneic hematopoietic-cell transplantation. Letermovir is an antiviral drug that inhibits the CMV-terminase complex. METHODS: In this phase 3, double-blind trial, we randomly assigned CMV-seropositive transplant recipients, 18 years of age or older, in a 2:1 ratio to receive letermovir or placebo, administered orally or intravenously, through week 14 after transplantation; randomization was stratified according to trial site and CMV disease risk. Letermovir was administered at a dose of 480 mg per day (or 240 mg per day in patients taking cyclosporine). Patients in whom clinically significant CMV infection (CMV disease or CMV viremia leading to preemptive treatment) developed discontinued the trial regimen and received anti-CMV treatment. The primary end point was the proportion of patients, among patients without detectable CMV DNA at randomization, who had clinically significant CMV infection through week 24 after transplantation. Patients who discontinued the trial or had missing end-point data at week 24 were imputed as having a primary end-point event. Patients were followed through week 48 after transplantation. RESULTS: From June 2014 to March 2016, a total of 565 patients underwent randomization and received letermovir or placebo beginning a median of 9 days after transplantation. Among 495 patients with undetectable CMV DNA at randomization, fewer patients in the letermovir group than in the placebo group had clinically significant CMV infection or were imputed as having a primary end-point event by week 24 after transplantation (122 of 325 patients [37.5%] vs. 103 of 170 [60.6%], P

Objective Starting January 2018 all adult HCT recipients at Stanford University who were at high risk (HR) for CMV disease received Letermovir prophylaxis (LET PPX). HR included: (1) ATG containing regimen, (2) an umbilical cord blood (UBC) graft, or (3) a haplo-identical, (4) unrelated (URD) (5) mismatched-related donor (misM-RD). We performed a retrospective analysis of the impact of LET PPX on the impact of CMV compared to historical controls. Methods 629 adults HCT patients from Jan 2013 - May 2019 were analyzed. 76 of these patients received LET PPX. Plasma CMV PCR was performed weekly through D+100. Prior to 2018, UCB patients received valacyclovir 2000 mg TID. PET was started if viral load (VL) was > 400 copies/ml (2009-2012) or 400 IU/ml (2013-2019). CMV disease was defined by published criteria. Results • LET PPX was well-tolerated without hematopoietic/organ toxicity. • CMV viremia occurred during LET PPX in 71 % of patients which was comparable to 74% in the controls; however, 34% LET PPX (34%) were started on a different CMV-active agent compared to 50% of controls. In 52% of LET PPX patients viremia cleared without change of antiviral or disease. (Table 1) • Although median hospital stays were the same in the LET PPX and control groups, there was a trend to greater number of hospitalizations in the control group. • Median Day post-transplant of first detection of CMV viremia for patients who received PET/change in CMV-active agent was later in the LET PPX group (D+45) than in the controls (D+ 18) • 3 of 76 (3.9%) LET PPX developed disease compared with 48 of 553 controls (8.7%). None of 24 ATG patients on LET PPX developed disease compared to 23/235 controls. (Table 2) Conclusion • Compared to controls, LET prophylaxis decreased the burden of CMV. • Other analyses not shown: hospitalizations, transfusions, infections, GHVD, relapse, survival

Objective CMV continues to have a significant impact on HCT despite preemptive antiviral (PET) strategies. Our objective was to assess the incidence and impact of CMV in HCT recipients. Methods We performed a retrospective analysis of 1109 seropositive adults who underwent HCT at Stanford University from Jan 2009-May 2019 (Fig. 1). Plasma CMV PCR screening was performed weekly through D+100; from 2009-2012, high risk patients received valganciclovir or ganciclovir. Umbilical cord blood (UCB) recipients received valacyclovir 2000 mg thrice daily. PET was instituted if viral load (VL) was > 400 copies/ml (2009-2012) or >400 IU/ml (2013-2019). CMV disease was defined by published criteria. Results Highlights of our observations: • Despite higher frequency of detectable low-level DNAemia and high-risk transplants, CMV disease has decreased over the last decade (Fig. 2). • Between 2009-2012, 41 patients received CMV prophylaxis (22% VGC 9, 73% GCV, 5% FOS; N=3 received PET; N=1 CMV disease); 53% who did not receive prophylaxis received PET. • Following myeloablative regimens, R+/D- were twice as likely to receive PET, regardless of protocol or donor but were not more likely to develop CMV disease (Table 1a). • ATG group had earlier reactivation (median D+11, range 0-68), higher peak VL and increased incidence of disease (8%). 7% of UCB and haplo who reactivated, did so between D+100-180 (vs 2% ATG). • In 19% of patients only low-grade DNAemia ( • Patients for whom CMV therapy was initiated during a hospitalization had higher median total number of admissions and higher number of inpatient days within the first year (Table 1b). Conclusion Despite PET, CMV continues to have a measurable impact on HCT patients. Other analyses include the significance of low grade VL, area under the curve of DNAemia, peak viremia, transfusion requirements, infections, and relapse.

Five rapid methods for detection of antibiotics in milk were compared. The Bacillus stearothermophilus var. calidolactis disc assay was also performed on the same samples. The rapid methods were: Angenics Spot Test, Charm II, Delvotest P, Penzyme Farm, and Penzyme Lab III. Ten antibiotics (penicillin G, cephapirin, cloxacillin, ampicillin, streptomycin, chloramphenicol, erythromycin, novobiocin, tetracycline, and gentamicin) were used individually to spike eight raw milk samples at five levels of antibiotic. Antibiotic levels were chosen that would result in zones of16 mm, 16 mm, and16 mm on the disc assay. Only the disc assay, Charm II and Delvotest P were compared on non-beta-lactam antibiotics. A small percentage of milks with no antibiotic added tested positive with the Charm II and Penzyme Lab III. On combined data for penicillin G, cephapirin, and cloxacillin, for which all methods were compared, the percent correctly categorized as pass (below actionable) for the16 mm zone spiked level, reject or caution at the 16 mm zone level, and reject or caution at the16 mm zone level were: Angenics 79, 83, 100; Charm II 66, 92, 100; Delvotest P 74, 93, 100; Disc Assay 100, 74, 100; Penzyme Farm 93, 61, 92; Penzyme Lab III 81,78, 100 respectively. In most cases, the rapid methods showed greater apparent sensitivity than the disc assay and did not fail to reject milks spiked with antibiotic in excess of the 16 mm zone level.

A survey of commercial milk samples for antibiotic residues, tested by the Sarcina lutea cylinder plate method, revealed a high incidence (72%) of non-specific inhibiton. Penicillin was detected by penicillinase assay in 3.1% of the samples. The method was found to be non-quantitative for residual levels of sanitizers in protein media. Apparently, substances inhibitory to S. lutea develop normally in some milks during marketing.

Summary Background Mucormycosis is an uncommon invasive fungal disease with high mortality and few treatment options. Isavuconazole is a triazole active in vitro and in animal models against moulds of the order Mucorales. We assessed the efficacy and safety of isavuconazole for treatment of mucormycosis and compared its efficacy with amphotericin B in a matched case-control analysis. Methods In a single-arm open-label trial (VITAL study), adult patients (≥18 years) with invasive fungal disease caused by rare fungi, including mucormycosis, were recruited from 34 centres worldwide. Patients were given isavuconazole 200 mg (as its intravenous or oral water-soluble prodrug, isavuconazonium sulfate) three times daily for six doses, followed by 200 mg/day until invasive fungal disease resolution, failure, or for 180 days or more. The primary endpoint was independent data review committee-determined overall response—ie, complete or partial response (treatment success) or stable or progressive disease (treatment failure)—according to prespecified criteria. Mucormycosis cases treated with isavuconazole as primary treatment were matched with controls from the FungiScope Registry, recruited from 17 centres worldwide, who received primary amphotericin B-based treatment, and were analysed for day-42 all-cause mortality. VITAL is registered with ClinicalTrials.gov, number NCT00634049. FungiScope is registered with ClinicalTrials.gov, number NCT01731353. Findings Within the VITAL study, from April 22, 2008, to June 21, 2013, 37 patients with mucormycosis received isavuconazole for a median of 84 days (IQR 19–179, range 2–882). By day 42, four patients (11%) had a partial response, 16 (43%) had stable invasive fungal disease, one (3%) had invasive fungal disease progression, three (8%) had missing assessments, and 13 (35%) had died. 35 patients (95%) had adverse events (28 [76%] serious). Day-42 crude all-cause mortality in seven (33%) of 21 primary-treatment isavuconazole cases was similar to 13 (39%) of 33 amphotericin B-treated matched controls (weighted all-cause mortality: 33% vs 41%; p=0·595). Interpretation Isavuconazole showed activity against mucormycosis with efficacy similar to amphotericin B. Isavuconazole can be used for treatment of mucormycosis and is well tolerated. Funding Astellas Pharma Global Development, Basilea Pharmaceutica International.

Military unit cohesion has been shown to correlate with physical and psychological outcomes. However, little is known about the development of cohesion in the early days of military service during ...

Severe neutropenia induced by chemotherapy or conditioning for hematopoietic cell transplantation often results in morbidity and mortality due to infection by opportunistic pathogens. A system has been developed to generate ex vivo-expanded mouse myeloid progenitor cells (mMPCs) that produce functional neutrophils in vivo upon transplantation in a pathogen challenge model. It has previously been demonstrated that transplantation of large numbers of freshly isolated myeloid progenitors from a single donor provides survival benefit in radiation-induced neutropenic mice. In the present work, an ex vivo-expanded and cryopreserved mMPC product generated from an allogeneic donor pool retains protective activity in vivo in a lethal fungal infection model. Infusion of the allogeneic pooled mMPC product is effective in preventing death from invasive Aspergillus fumigatus in neutropenic animals, and protection is dose dependent. Cell progeny from the mMPC product is detected in the bone marrow, spleen, blood, and liver by flow cytometry 1 week postinfusion but is no longer evident in most animals 4 weeks posttransplant. In this model, the ex vivo-generated pooled allogeneic mMPC product (i) expands and differentiates in vivo; (ii) is functional and prevents death from invasive fungal infection; and (iii) does not permanently engraft or cause allosensitization. These data suggest that an analogous ex vivo-expanded human myeloid progenitor cell product may be an effective off-the-shelf bridging therapy for the infectious complications that develop during hematopoietic recovery following hematopoietic cell transplantation or intensive chemotherapy.

Background: While efficacy of Sudarshan Kriya Yoga (SKY) has been demonstrated in a number of prior studies, little is known about the effects of SKY taught as part of the Your Enlightened Side (YES+) workshop designed for college students and other young adults. Aims: This study aimed to assess the effects of YES+, a yogic breathing-based life skills workshop, on multiple measures of well-being and physiological stress response. Materials and Methods: Two nonrandomized open-trial pilot studies were conducted with a total of 74 young adults (age 25.4 ± 6.6 years; 55% female). Study 1 collected a variety of self-report questionnaires at baseline, postworkshop, and 1-month follow-up. Study 2 collected self-report questionnaires in addition to electrocardiography with a stationary cycling challenge at baseline and 1-month follow-up. Results: Study 1: Improvements in self-reported depression (P's ≤ 0.010), perceived stress (P's ≤ 0.002), life satisfaction (P's ≤ 0.002), social connectedness (P's ≤ 0.004), and gratitude (P's ≤ 0.090) were observed at postworkshop and 1-month after workshop relative to baseline. Study 2: Improvements in self-reported emotion regulation were observed at 1-month follow-up relative to baseline (P = 0.019). Positive and Negative Affect Schedule-Expanded Form positive affect increased (P = 0.021), while fatigue and sadness decreased (P's ≤ 0.005). During the stationary cycling challenge, rate to recovery of electrocardiography inter-beat interval also increased from baseline to 1-month follow-up (P = 0.077). Conclusions: These findings suggest that a life skills workshop integrating yogic breathing techniques may provide self-empowering tools for enhancing well-being in young adults. Future research is indicated to further explore these effects, particularly in regards to vagal tone and other aspects of stress physiology.

Coccidioidomycosis is a fungal infection endemic to the southwestern United States that typically causes a self-limited pulmonary illness. Extrapulmonary dissemination is extremely rare and typically localized to the skin, bone, and meninges. The gastrointestinal system has generally been thought to be spared from this disease. This report describes a patient who was initially diagnosed with pulmonary coccidioidomycosis with mediastinal lymphadenopathy and skin dissemination. Ten months after completion of treatment, he presented with nonspecific abdominal pain and diffuse musculoskeletal and constitutional symptoms. Radiographic imaging revealed near resolution of previously noted thoracic findings but new peritoneal thickening and enhancement suggestive of peritoneal carcinomatosis. Laparoscopic biopsies confirmed Coccidioides immitis by culture and histology without evidence of other abnormalities.This case is unique for several reasons. It is one of a relatively small number of cases that describes a diagnosis of peritoneal coccidioidomycosis and the first case identified in which a healthy patient developed extensive peritoneal disease in spite of near-complete resolution of pulmonary and skin manifestations after appropriate treatment. This case underscores the complexity of this disease and motivates more investigation into pathophysiology and treatment considerations of coccidioidomycosis in the gastrointestinal system. We will review the risk factors associated with dissemination, the interpretation of serologies, the characteristics of patients with peritoneal involvement, and finally, the current treatment guidelines. Abbreviations: AIDS: Acquired Immunodeficiency Syndrome; CF: complement fixation; HIV: Human Immunodeficiency Virus; ID: immunodiffusion; IDCF: quantitative immunodiffusion.

Eremothecium coryli is a dimorphic fungus of the Saccharomycetes class. While species within this class are known to cause human infection, Eremothecium species have previously only been known as phytopathogens and never been isolated from a human sample. Here, we report the first known case of human E. coryli infection.

Hematopoietic cell transplantation can prolong lives; however, as any invasive treatment, it is associated with a variety of infectious and noninfectious complications. Patients experience a variety of viral, bacterial, and fungal infections. Noninfectious complications can affect immunologic, gastrointestinal, cardiovascular, pulmonary, and dermatologic organ systems, among others. Graft-versus-host disease (GVHD) is a common and devastating complication, which involves multiple organs, impairs quality of life, and decreases survival. This chapter discusses various post-HCT complications and their pathophysiology, epidemiology, and treatment.

Background Rezafungin (RZF) is a novel echinocandin in development for prevention of invasive fungal infections caused by Candida, Aspergillus, and Pneumocystis spp. in patients at high risk of infection. RZF has demonstrated in vivo prophylaxis efficacy and low risk of drug-drug interactions. Furthermore, the stability and PK profile of RZF allow for once-weekly dosing. RZF is also in development for treatment of candidemia and invasive candidiasis using a dosing regimen of RZF 400 mg followed by 200 mg once-weekly, which achieved >90% target attainment against Candida. While lower doses might be useful to prevent Candida and Pneumocystis, invasive aspergillosis is a different challenge. We evaluated RZF dosing for prophylaxis against Aspergillus fumigatus in bone marrow transplant (BMT) patients using PK/PD simulations of the treatment dosing regimen. Methods A previous population PK model was refined using data from Phase 1 and Phase 2 trials of IV RZF (NONMEM Vers 7.2). Stepwise forward selection (α = 0.01) and backward elimination (α = 0.001) were used to assess for relationships between interindividual PK variability and covariates, such as age, sex, BSA), albumin, liver and renal function markers, and infection status. The final model was validated by comparing model-based predictions to observed data. The model and demographic data from BMT recipients at Stanford Medical Center (Table 1) were used for Monte Carlo simulation (n=2,000) of expected RZF concentration-time profiles in BMT patients receiving IV RZF 400 mg on Week 1 followed by 200 mg weekly x 11. Free-drug concentration-time profiles were evaluated (97.4% human protein-binding) relative to the A. fumigatus minimal effective concentration required to inhibit 100% of isolates tested (MEC100; JMI 2014-2017 SENTRY international surveillance data). Results The population PK model was a linear, 4-compartment model with zero order IV input. Albumin was a statistically significant predictor of interindividual variability. Non-significant relationships were found with sex, BSA, presence of cirrhosis, and infection status. The model provided precise, unbiased fits to the observed data (r2=0.993 observed vs individual-predicted). RZF plasma free-drug concentrations at weeks 1, 2, and 12 were above the A. fumigatus MEC100 (0.03 mg/L) for the entire dosing interval in 98.4%, 93.3%, and 91.9% of simulated patients, respectively, and in ≥99.9% for all 12 weeks based on the MEC90 (0.015 mg/L). Conclusions These data modeled from BMT patients support the RZF dosing regimen of 400 mg IV followed by 200 mg once-weekly for prophylaxis against A. fumigatus. Current antifungal prophylaxis may be limited by toxicity, DDIs, or patient factors such as mucositis. The PK of RZF and its spectrum, safety, tolerability, and lack of DDIs may address challenges in IFI prophylaxis for BMT and other immunocompromised patients.

Objectives. We characterized trends in mental health services utilization and stigma over the course of the Afghanistan and Iraq wars among active-component US soldiers. Methods. We evaluated trends in mental health services utilization and stigma using US Army data from the Health-Related Behavior (HRB) surveys from 2002, 2005, and 2008 (n = 12 835) and the Land Combat Study (LCS) surveys administered to soldiers annually from 2003 to 2009 and again in 2011 (n = 22 627). Results. HRB and LCS data suggested increased mental health services utilization and decreased stigma in US soldiers between 2002 and 2011. These trends were evident in soldiers with and without posttraumatic stress disorder (PTSD), major depressive disorder (MDD), or PTSD and MDD. Despite the improving trends, more than half of soldiers with mental health problems did not report seeking care. Conclusions. Mental health services utilization increased and stigma decreased over the course of the wars in Iraq and Afghanistan. Although promising, these findings indicate that a significant proportion of US soldiers meeting criteria for PTSD or MDD do not utilize mental health services, and stigma remains a pervasive problem requiring further attention.

BackgroundCytomegalovirus (CMV) infection is a leading cause of illness and death in patients who have undergone allogeneic hematopoietic-cell transplantation. Available treatments are restricted by clinically significant toxic effects and drug resistance. MethodsIn this phase 2 study, we evaluated the effect of letermovir (also known as AIC246), a new anti-CMV drug with a novel mechanism of action, on the incidence and time to onset of prophylaxis failure in CMV-seropositive recipients of allogeneic hematopoietic-cell transplants from matched related or unrelated donors. From March 2010 through October 2011, we randomly assigned 131 transplant recipients in a 3:1 ratio to three sequential study cohorts according to a double-blind design. Patients received oral letermovir (at a dose of 60, 120, or 240 mg per day, or matching placebo) for 12 weeks after engraftment. The primary end point was all-cause prophylaxis failure, defined as discontinuation of the study drug because of CMV antigen or DNA detection,...

Successful hematopoietic cell transplantation (HCT) requires vacating recipient hematopoietic stem cell (HSC) niches to permit donor HSC engraftment to provide life-long hematopoietic and immune function. Currently HCT relies on DNA damaging radiation or chemotherapy to achieve HSC niche clearance. We have pursued a non-toxic approach to target and deplete HSC using humanized monoclonal antibody, AMG 191, that binds human CD117 (c-Kit). We opened a Phase 1 dose escalation trial using AMG 191 as the sole conditioning agent to achieve donor HSC engraftment in patients undergoing HCT for severe combined immunodeficiency (SCID). The primary endpoint is to assess the safety of administering AMG 191. Secondary endpoints include AMG 191 pharmacokinetics (PK), host HSC depletion, and determination of the dose of AMG 191 that achieves adequate donor HSC engraftment, defined as >5% donor granulocyte chimerism at 24 weeks. We have completed the first dose cohort of patients receiving 0.1 mg/kg AMG 191 and treated the first two patients in the second cohort (0.3 mg/kg). All five patients tolerated the AMG 191 infusion and the subsequent infusion of their CD34-selectd donor cells without clinical problems. Here we report efficacy in the first two patients, who have reached the 24-week timepoint. Both patients had T-B-NK+ SCID with mutations in the DCLRE1C (Artemis) gene. Both previously received unconditioned HCT as infants, failed to develop donor B cells and remained dependent on exogenous immunoglobulin. CD34-selected mobilized peripheral blood cells from the original donors were infused when the AMG 191 serum level was Conclusion: These data are proof of concept that a humanized monoclonal antibody targeting CD117 can safely clear human HSC niches and facilitate donor HSC engraftment. This study is ongoing and open for enrollment.

Summary Background There is lack of consensus regarding whether both upper and lower endoscopic examinations are required for diagnosis of gastrointestinal acute graft versus host disease (GI-AGVHD). Aim To evaluate the impact of endoscopic procedures on the diagnosis of GI-AGVHD. Methods We performed a retrospective case–control study of recipients of allogeneic haematopoetic cell transplant (HCT) from 2000 to 2011, who presented with GI symptoms between 20 and 125 days post-HCT. GI-AGVHD status was based on the National Institutes of Health (NIH) clinical grading system. Results One hundred and twenty-nine clinical GI-AGVHD cases and 184 controls underwent endoscopic examinations. Diarrhoea was present in 73% of cases and 38% of controls (P

Purpose The cost-effectiveness of voriconazole versus fluconazole prophylaxis against fungal infections in hematopoietic cell transplant (HCT) recipients is investigated. Methods A decision-analytic model was developed to estimate the drug costs associated with planned or supplemental prophylaxis and empirical therapy and the costs of treating suspected or documented invasive fungal infections (IFIs) in HCT recipients. Published clinical trial data on 599 patients who received 100–180 days of prophylactic therapy with voriconazole or fluconazole were used to model specified IFI-prevention and mortality outcomes; 6-month, 12-month, and lifetime incremental cost-effectiveness ratios (ICERs) were estimated, with a bootstrap analysis performed to reffect the uncertainty of the clinical trial data. Results Estimated mean total prophylaxis and IFI-related costs associated with voriconazole versus fluconazole prophylaxis over 12 months were higher in the entire study population and among patients receiving HCT for diagnoses other than acute myeloid leukemia (AML) but were not significantly different for patients with AML. The cost per IFI avoided ($66,919) and the cost per life-year gained ($5,453) were lower among patients with AML who received voriconazole relative to the full study population. ICERs were more favorable for voriconazole over a 6-month time frame and when modeling was conducted using generic price data. Assuming a threshold value of $50,000 for one year of life gained, the calculated probability of voriconazole being cost-effective was 33% for the full study population and 85% for the AML subgroup. Conclusion The decision model indicated that voriconazole prophylaxis was cost-effective for patients undergoing allogeneic HCT for AML.

Recent reports describe increasing incidence of non-Aspergillus mold infections in hematopoietic cell transplant (HCT) and solid organ transplant (SOT) recipients. To investigate the epidemiology of infections with Mucorales, Fusarium spp., and Scedosporium spp. molds, we analyzed data from the Transplant-Associated Infection Surveillance Network, 23 transplant centers that conducted prospective surveillance for invasive fungal infections during 2001–2006. We identified 169 infections (105 Mucorales, 37 Fusarium spp., and 27 Scedosporium spp.) in 169 patients; 124 (73.4%) were in HCT recipients, and 45 (26.6%) were in SOT recipients. The crude 90-day mortality rate was 56.6%. The 12-month mucormycosis cumulative incidence was 0.29% for HCT and 0.07% for SOT. Mucormycosis incidence among HCT recipients varied widely, from 0.08% to 0.69%, with higher incidence in cohorts receiving transplants during 2003 and 2004. Non-Aspergillus mold infections continue to be associated with high mortality rates. The incidence of mucormycosis in HCT recipients increased substantially during the surveillance period.

Aims An examination of alcohol use patterns in the active duty military to determine the relations of drinking levels and self-reported negative outcomes. Design A population-based cross-sectional study design using two-stage complex sampling methodology. Setting Paper and pencil surveys were administered anonymously in groups at 64 U.S. military installations worldwide. Participants Randomly selected active duty members (28,546) at major military installations representing the total active force, with the exception of recruits, cadets, and incarcerated personnel. Measures Personnel were classified into five drinking levels ranging from abstainer to heavy drinker based on quantity and frequency of alcohol intake. Negative outcomes were measured as self-reported serious consequences of alcohol use and alcohol-related productivity loss. Risk for other alcohol related problems was assessed by the Alcohol Use Disorders Identification Test (AUDIT). Findings Alcohol negative outcomes showed a curvilinear dose–response relationship with drinking levels. Higher levels of drinking were associated with higher rates of alcohol problems, but problem rates were notably higher for heavy drinkers. Heavy alcohol users showed nearly three times the rate of self-reported serious consequences and over twice the rate of self-reported productivity loss than moderate/heavy drinkers. Heavy drinkers also had the highest risk for alcohol problems on the AUDIT. One fifth of military personnel were heavy drinkers and were most likely aged 18 to 35. Conclusions Prevention and clinical interventions should include a major focus on heavy drinkers. Commanders and peers should be trained in recognizing signs of heavy alcohol use and in approaching heavy alcohol users in a way that will foster positive attitudes as opposed to defensiveness and stigma.

We investigated sirolimus and mycophenolate mofetil (MMF) as GVHD prophylaxis in patients with advanced hematological malignancies receiving myeloablative hematopoietic cell transplantation (HCT) from HLA-identical sibling donors. On the basis of pre-study stopping rules, the trial was closed to accrual after enrollment of 11 adult patients. In all, 7 of the 11 patients received BU-containing preparative regimens. Sirolimus was discontinued in three patients because of the toxicity-related events of severe sinusoidal obstructive syndrome, portal vein thrombosis, altered mental status and in one patient because of the risk of poor wound healing. In all, 6 of the 11 patients developed grade II-IV acute GVHD (AGVHD) a median of 15.5 days post HCT. Two of three patients with grade IV AGVHD had sirolimus discontinued by 9 days post HCT. All patients responded to AGVHD therapy without GVHD-related deaths. There were two non-relapse- and two relapse-related deaths. At a median follow-up of 38 months (2-47 months), 7 of 11 patients were alive without disease. MMF and sirolimus GVHD prophylaxis did not reduce the risk of AGVHD, however, there were no GVHD-related deaths. The severe toxicities in the patients receiving the BU-containing preparative regimens limited the continued use of sirolimus and MMF for the prevention of AGVHD.

This study assessed the impact of a motiv ational interv iewing (MI) brief alcohol interv ention and prior v ictimization on alcohol-inv olv ed sexual v ictimization experiences. First-year female college students ( N = 229) were randomly assigned to an interv ention condition: MI, MI with feedback (MIFB), feedback (FB), and assessment only (AO). Findings indicate reduced alcohol use for all conditions and v iolence for MIFB, with interactions for prior v ictimization. The mechanism of change for reduced v ictimization was not reductions in alcohol use and mechanisms for this effectiv eness remain somewhat conv oluted. Tailoring of brief interv entions addressing alcohol use and sexual v iolence, particularly for women with prior v ictimization, is critical.

Stigma associated with substance abuse is less understood than stigma of mental health. Moreover, neither issue has been studied in depth within the military. We conducted focus groups with soldier...

Despite the popularity of motivational interviewing (MI) to address heavy drinking, limited evidence exists on the costs of using MI to address heavy drinking. This study examines the costs of using MI to address heavy drinking at four U.S. Air Force (USAF) bases. Clients were referred to and assessed at a base program to address their drinking as a result of an incident; those who were not alcohol dependent were invited to participate in the study. Participants consented and were randomly assigned to one of three intervention arms: individual MI (IMI), group MI (GMI), and Substance Abuse Awareness Seminar (SAAS). Three cost perspectives were taken: USAF, client, and the two combined. Data were collected from bases and public sources. The start-up cost per base ranged from $1,340 to $2,400 per provider staff member. Average implementation costs across bases were highest for the SAAS intervention ($148 per client).

Patients with high-risk or advanced myeloid malignancies have limited effective treatment options. These include high-dose therapy followed by allogeneic hematopoietic cell transplantation (HCT). We report a single-institution, long-term follow-up of 96 patients, median age 50 (range, 20–60) years, who received HLA-matched related HCT between 1992 and 2007. All patients were treated with a uniform preparatory regimen intended to enhance the widely used regimen of BU and CY that included: BU 16.0 mg/kg (days −8 to −5), etoposide 60 mg/kg (day −4), CY 60 mg/kg (day −2) with GVHD prophylaxis of CsA or FK506 and prednisone. Disease status at transplantation was high-risk AML (n = 41), CML in second chronic phase or blast crisis (n = 8), myelofibrosis and myeloproliferative disorders (n = 8), and myelodysplasia (n = 39). Thirty-six percent (n = 35) of patients received BM whereas 64% (n = 61) received G-CSF-mobilized PBPC. With a median follow-up of 5.6 years (range, 1.6–14.6 years) actuarial 5-year OS was 32% (95% CI 22–42) and 5-year EFS was 31% (95% CI 21–41). Relapse rate was 24% (95% CI 15–33) at 2 and 5 years. Nonrelapse mortality was 29% (95% CI 20–38) at day 100 and 38% (95% CI 29–47) at 1 year. Cumulative incidence of acute (grade II–IV) and extensive chronic GVHD was 27% (95% CI 18–36) and 29% (95% CI 18–40), respectively. There was no statistically significant difference in OS (31 vs 32%, P = 0.89) or relapse rates (17 vs 28%, P = 0.22) for recipients of BM vs PBPC, respectively. These results confirm that patients with high-risk or advanced myeloid malignancies can achieve long-term survival following myeloablative allogeneic HCT with aggressive conditioning.

Every fall and winter, patients with cancer and their families ask oncologists whether they should be vaccinated for influenza. This season, with escalating concerns regarding the novel H1N1 influenza virus and its recently approved vaccine, this question has become more frequent and increasingly urgent. The purpose of this article is to review evidence related to the ability of patients with cancer to mount protective immunological responses to influenza vaccination. The literature on immunogenicity in pediatric and adult patients, those with solid tumors and hematologic malignancies, untreated and actively treated patients, and patients receiving biologic agents is summarized and reviewed. In addition, we report on potential strategies to improve the efficacy of influenza vaccination in patients with cancer, such as the timing of vaccination, use of more than a one-shot series, increasing the antigen dose, and the use of adjuvant therapies. We conclude that there is evidence that patients with cancer receiving chemotherapy are able to respond to influenza vaccination, and because this intervention is safe, inexpensive, and widely available, vaccination for seasonal influenza and the novel H1N1 strain is indicated.

Background The incidence and epidemiology of invasive fungal infections (IFIs), a leading cause of death among hematopoeitic stem cell transplant (HSCT) recipients, are derived mainly from single-institution retrospective studies. Methods The Transplant Associated Infections Surveillance Network, a network of 23 US transplant centers, prospectively enrolled HSCT recipients with proven and probable IFIs occurring between March 2001 and March 2006. We collected denominator data on all HSCTs preformed at each site and clinical, diagnostic, and outcome information for each IFI case. To estimate trends in IFI, we calculated the 12-month cumulative incidence among 9 sequential subcohorts. Results We identified 983 IFIs among 875 HSCT recipients. The median age of the patients was 49 years; 60% were male. Invasive aspergillosis (43%), invasive candidiasis (28%), and zygomycosis (8%) were the most common IFIs. Fifty-nine percent and 61% of IFIs were recognized within 60 days of neutropenia and graft-versus-host disease, respectively. Median onset of candidiasis and aspergillosis after HSCT was 61 days and 99 days, respectively. Within a cohort of 16,200 HSCT recipients who received their first transplants between March 2001 and September 2005 and were followed up through March 2006, we identified 718 IFIs in 639 persons. Twelve-month cumulative incidences, based on the first IFI, were 7.7 cases per 100 transplants for matched unrelated allogeneic, 8.1 cases per 100 transplants for mismatched-related allogeneic, 5.8 cases per 100 transplants for matched-related allogeneic, and 1.2 cases per 100 transplants for autologous HSCT. Conclusions In this national prospective surveillance study of IFIs in HSCT recipients, the cumulative incidence was highest for aspergillosis, followed by candidiasis. Understanding the epidemiologic trends and burden of IFIs may lead to improved management strategies and study design.

Using data from the 2002 Department of Defense Survey of Health Related Behaviors, we examined levels of drinking and alcohol-related problems (dependence symptoms, driving after drinking, productivity loss, serious consequences) for enlisted men and women and male and female officers. Findings showed that men were more likely than women to be heavy or binge drinkers and to experience alcohol-related problems. Similarly, enlisted men and women were more likely than male and female officers to be heavy or binge drinkers. Driving after drinking was more common among men than women and more common among officers than enlisted personnel. Officers had lower rates of dependence symptoms and other serious consequences than enlisted personnel. Despite men's heavier drinking, women showed equal or higher rates of dependence symptoms and productivity loss and appeared to be at risk for alcohol problems at lower levels of consumption.

The present study examined drinking rates of U.S. Navy and Air Force trainees during the month before attending basic training and after the ban on drinking alcohol was lifted during advanced training.Surveys were obtained at five training bases (one U.S. Navy, four U.S. Air Force) from 6,298 persons for a response rate of 65%. Analyses were based on 4,962 young adults ages 18-25 (82% male) who gave valid responses about pre-basic drinking.Findings showed a rate of 43.1% heavy episodic drinking during the month before basic training, 15.8% by infrequent heavy episodic drinkers (five or more drinks per occasion at least once, four or more for women), and 27.3% by frequent heavy episodic drinkers (five or more drinks per occasion, four or more for women, at least once a week). Pre-basic frequent heavy episodic drinkers averaged 7.9 drinks per occasion and nearly 15 heavy episodic drinking days during the month. In contrast, heavy episodic drinking following basic training was substantially lower: 12.0% for infrequent heavy episodic drinkers and 9.0% for frequent heavy episodic drinkers. Comparisons with the U.S. Department of Defense Health Related Behaviors Survey suggest that post-basic frequent heavy episodic drinking rates are likely to increase over time but not to pre-basic levels. Pre-basic infrequent and frequent heavy episodic drinkers were more likely than nondrinkers or non-heavy episodic drinkers to initiate or re-initiate frequent heavy episodic drinking. Frequent heavy episodic drinking after basic tended to occur 1-6 weeks after the ban on alcohol use was lifted.Selection and socialization help explain heavy episodic drinking of U.S Navy and U.S. Air Force trainees.

By use of an automated polymerase chain reaction test of plasma and a qualitative polymerase chain reaction assay on polymorphonuclear leukocytes, we identified a subgroup of hematopoietic cell transplant recipients who were able to control cytomegalovirus infection early after hematopoietic cell transplantation without antiviral therapy. Thirty-one percent of patients had cytomegalovirus DNA detected by qualitative polymerase chain reaction assay but had no cytomegalovirus DNA detected by the automated test; this group maintained a lower peak cytomegalovirus load, compared with the group of patients who had cytomegalovirus DNA detected by both tests (P = .03), suggesting a greater degree of functional immune reconstitution.

Murine cytomegalovirus encodes a secreted, pro-inflammatory chemokine-like protein, MCK-2, that recruits leukocytes and facilitates viral dissemination. We have shown that MCK-2-enhanced recruitment of myelomonocytic leukocytes with an immature phenotype occurs early during infection and is associated with efficient viral dissemination. Expression of MCK-2 drives the mobilization of a population of leukocytes from bone marrow that express myeloid marker Mac-1 (CD11b), intermediate levels of Gr-1 (Ly6 G/C), platelet-endothelial-cell adhesion molecule-1 (PECAM-1, CD31), together with heterogeneous levels of stem-cell antigen-1 (Sca-1, Ly-6 A /E). Recombinant MCK-2 mediates recruitment of this population even in the absence of viral infection. Recruitment of this cell population and viral dissemination via the bloodstream to salivary glands proceeds normally in mice that lack CCR2 and MCP-1 (CCL2), suggesting that recruitment of macrophages is not a requisite component of pathogenesis. Thus, a systemic impact of MCK-2 enhances the normal host response and causes a marked increase in myelomonocytic recruitment with an immature phenotype to initial sites of infection. Mobilization influences levels of virus dissemination via the bloodstream to salivary glands and is dependent on a myelomonocytic cell type other than mature macrophages.

We identified committed T cell progenitors (CTPs) in the mouse bone marrow that have not rearranged the TCRβ gene; express a variety of genes associated with commitment to the T cell lineage, including GATA-3, T cell-specific factor-1, Cβ, and Id2; and show a surface marker pattern (CD44+CD25−CD24+CD5−) that is similar to the earliest T cell progenitors in the thymus. More mature committed intermediate progenitors in the marrow have rearranged the TCR gene loci, express Vα and Vβ genes as well as CD3ε, but do not express surface TCR or CD3 receptors. CTPs, but not progenitors from the thymus, reconstituted the αβ T cells in the lymphoid tissues of athymic nu/nu mice. These reconstituted T cells vigorously secreted IFN-γ after stimulation in vitro, and protected the mice against lethal infection with murine CMV. In conclusion, CTPs in wild-type bone marrow can generate functional T cells via an extrathymic pathway in athymic nu/nu mice.

In contrast to the recipient of a solid organ transplantation, the immunological competence of recipients of hematopoietic cell transplantation does not correlate well with the administration of non-corticosteroid immunosuppressive agents. This apparent paradox reflects the unique and dynamic conglomeration of factors that affect immune reconstitution after hematopoietic cell transplantation. The following is the second part of a review of the recent primary literature regarding exogenous immunomodulatory influences as they pertain to infections in the setting of hematopoietic cell transplantation.The main themes of published primary research from 2004 to the present include the influence of exogenously administered immunomodulatory agents on infectious complications after hematopoietic cell transplantation.The use of immunomodulatory agents such as monoclonal antibodies directed against lymphocyte antigens in the treatment of hematopoietic malignancy has greatly expanded during the past decade. Separate trials of the potential utility of these agents, particularly in the reduction of graft-versus-host disease, in the setting of hematopoietic cell transplantation have yielded encouraging results. Given the infancy of these new approaches, it is not possible to make definitive statements regarding the relative risk of serious infection with each therapy. It is clear that a reduction in regimen-related non-infectious complications or mortality does not necessarily ensure a reduction in clinically significant infections. Improvements in early diagnostic and therapeutic options for these infections now bring us to an era of understanding pathogens such as cytomegalovirus as probes of the functional reconstitution of immunity.

Invasive fungal infections have become the leading infectious cause of death in recipients of hematopoietic cell transplantation. Several factors have led to a renaissance in the study of invasive fungal infections. The growing incidence of both commonly encountered as well as emerging pathogens and the lethality of these infections coupled with the unprecedented number of available broad-spectrum antifungal drugs has lent a renewed vigor and enthusiasm to attempts to understand the pathogenesis of these diseases and, by doing so, improve prevention, diagnosis, and treatment. The following is a review of the primary research published from 2003 to the present that is pertinent to invasive fungal infection in the setting of hematopoietic cell transplantation.The main themes of published primary research during 2003 to the present include the efficacy and tolerability of antifungal prophylaxis, epidemiologic analyses of risk factors following nonmyeloablative preparative regimens, and more-detailed analyses of nonmyeloid immune responses.Although few definitive recommendations emerged from the studies during the review period, these investigations do contribute to a greater understanding of the immunobiology of invasive fungal infection and of the utility and limitations of newer antifungal agents in the prophylaxis or treatment of invasive fungal infection.

Previous research indicates that brief motivational interventions for college student drinkers may be less effective in group settings than individual settings. Social psychological theories about counterproductive group dynamics may partially explain this finding. The present study examined potential problems with group motivational interventions by comparing outcomes from a standard group motivational intervention (SGMI; n = 25), an enhanced group motivational intervention (EGMI; n = 27) designed to suppress counterproductive processes, and a no intervention control ( n = 23). SGMI and EGMI participants reported disruptive group dynamics as evidenced by low elaboration likelihood, production blocking, and social loafing, though the level of disturbance was significantly lower for EGMI individuals ( p = .001). Despite counteracting group dynamics in the EGMI condition, participants in the two interventions were statistically similar in post-intervention problem recognition and future drinking intentions. The results raise concerns over implementing individually-based interventions in group settings without making necessary adjustments.

Urban regeneration strategies in the UK have placed considerable emphasis on the development of homeownership and particularly low-cost homeownership. The paper assesses the long-term viability of ...

Background Recipients of auto-HSCT have an increased risk of herpes zoster (HZ) infection; however, live attenuated varicella-zoster virus (VZV) vaccine is contraindicated in these patients. In this pivotal Phase III study (V212-001; NCT01229267) inactivated VZV vaccine (ZVIN) reduced the rate of HZ infection compared with placebo (estimated vaccine efficacy, 63.8%) and was well tolerated. Immunogenicity of ZVINin recipients of auto-HSCT was assessed in the Phase III study as an exploratory objective. Methods Adults undergoing auto-HSCT were randomized to receive either ZVIN(n = 560) or placebo (n = 564), administered in a 4-dose regimen. Doses 1 through 4 were administered ~30 days before and ~30, ~60, and ~90 days following auto-HSCT. VZV-specific immune responses were measured at Day 1, ~28 days post-vaccinations 3 and 4, and annually until the end of the study. VZV-specific antibody responses were measured by glycoprotein enzyme-linked immunosorbent assay (gpELISA) in all patients; cell-mediated immune responses were measured by VZV interferon-gamma enzyme-linked immunospot (IFN-γ ELISPOT) assay in a randomized subset of patients (n = 403). Results Geometric mean titers (GMT) were significantly higher and the ratios of the gpELISA and IFN-γ ELISPOT were significantly greater in the ZVINgroup compared with the placebo group (Tables 1 and 2). Conclusion ZVIN elicited higher VZV-specific humoral and cell-mediated responses in adult auto-HSCT recipients when compared with placebo ~28 days and ~1 year post-dose 4. These results indicate that ZVIN is immunogenic in these patients who are ineligible for live attenuated HZ vaccine, which is consistent with previously observed clinical efficacy. Disclosures M. Boeckh, Merck: Investigator, Research Contractor and Scientific Advisor, Consulting fee and Research support; GlaxoSmithKline: Research Contractor, Research support; A. Arvin, Merck: Scientific Advisor, Consulting fee; K. Mullane, Merck: Scientific Advisor, Grant recipient; D. J. Winston, Merck: Grant Investigator and Scientific Advisor, Consulting fee and Grant recipient; J. Brown, Merck: Clinical adjudication and site investigator and Investigator, Consulting fee; Cellerant Therapeutics: Consultant, Cellerant developing and executing clinical trials of myeloid progenitor cells in neutropenia for which I hold the patent; S. Pergam, Merck: Consultant and Investigator, Consulting fee; K. Hurtado, Merck: Employee and Shareholder, Salary; L. Pang, Merck: Employee and Shareholder, Salary; I. Lee, Merck: Employee, Salary; Z. Popmihajlov, Merck & Co., Inc.: Employee and Shareholder, Salary

The objective of the study is to evaluate the effectiveness of two Web-based brief interventions (BIs) for reducing stress and substance use among post-deployment active duty and National Guard military personnel. The interventions are designed to (1) educate personnel about the use of substances as a poor coping mechanism for combat and operational stress reactions (COSRs) and (2) boost resilience to COSRs, thereby reducing the tendency to self-medicate through substance use. These data are vital to understanding additional steps the military might take in addressing issues of behavioral health, such as developing new, more broadly focused treatment interventions, and starting additional prevention approaches and programs. Volunteers will complete a brief Web assessment for alcohol use and current stress reactions. Participants are randomly assigned to one of three intervention conditions: Wait-list control, Stress BI, or Stress plus Substance Use BI. A Web-based intervention provides a private and convenient approach and should facilitate access to care by reducing the stigma and common barriers associated with seeking treatment.

A growing body of data supports the benefit of first-line rituximab therapy for EBV- associated post-transplant lymphoproliferative disorder (PTLD) the potential for adoptive cellular therapy, and the benefit of early diagnosis. Quantitative PCR has proven to be an important, albeit not infallible, diagnostic test; however, data regarding the utility We reviewed the records of 731 adult patients who underwent allogeneic hematopoietic cell transplantation (HCT) at Stanford University Medical Center from January 2010 through Feb 2016. (Table 1. Demographics) With respect to EBV screening, all patients received 400 mg po acyclovir tid for one year, preemptive strategies based on plasma PCR for CMV were used with either IV ganciclovir (MA) or valganciclovir (NMA) administered. Quantitative EBV PCR was performed on whole blood (Jan 2010 through mid-2011) or plasma (mid-2011 to present) every other week in asymptomatic patients or at any time a patient developed symptoms that may be attributed to EBV. Observations/Conclusions: · Both the initial measureable and the rate of increase in viral load were significantly greater in patients with PTLD than those with isolated viremia. · Promptly administered rituximab was effective in improving resolution of PTLD when compared to historically reported data. · Conversely, patients with low grade viremia without increase in viral load may be watched expectantly. · Although not standard practice, importance of EBV serology of donor has been demonstrated in SOT and pediatric HCT and would be anticipated to be of equal importance in adults, especially · Early biopsy or flow cytometric analysis of EBV+ lymphocyte to determine polymorphic versus monomorphic disease can further refine our understanding the pathophysiology of disease · The crucial limitation of our study is that determination of EBV serology was not routine; however, by limiting our analysis to patients with EBV reactivation and the use of a standardized protocol to respond to viremia has permitted the current observations to be made. Table 2 Table 2. Disclosures No relevant conflicts of interest to declare.

Parainfluenza viruses (PIV) ARE associated with severe respiratory tract infections among immunocompromised patients. However, the most perplexing feature of PIV following hematopoietic cell transplantation (HCT) is the dichotomous nature of risk for life-threatening infection. Specifically, the vast majority of patients will not require treatment of any kind whereas a small subset appears to be at such high risk of death that it has been questioned if successful treatment is even possible. In 2007, we implemented a standardized approach to patients diagnosed with Parainfluenza virus (PIV) following HCT at Stanford University Medical Center (Fig 1) based on the need for supplemental oxygen and/or specific risk factors. We performed both a prospective analysis of cases of lower respiratory tract infection and a retrospective review of all 2495 patients transplanted during this period. The epidemiology, risk factors, clinical status, and outcome of the 115 PIV patients using this protocol from September 2007 through May 2015 shows that prudent, risk-stratified application of antiviral therapies in can result higher survival rates among patients with PIV post-HCT. Moreover, high risk patients who received aerosolized ribavirin had a lower mortality rate than those who were either not treated or received oral ribavirin. Disclosures No relevant conflicts of interest to declare.