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Long-lived antibody memory is mediated by the combined effects of long-lived plasma cells (PCs) and memory B cells generated in response to T cell-dependent antigens (Ags). IL-10 and IL-21 can activate multiple signaling pathways, including STAT1, STAT3, and STAT5; ERK; PI3K/Akt, and potently promote human B cell differentiation. We previously showed that loss-of-function mutations in STAT3, but not STAT1, abrogate IL-10- and IL-21-mediated differentiation of human naive B cells into plasmablasts. We report here that, in contrast to naive B cells, STAT3-deficient memory B cells responded to these STAT3-activating cytokines, differentiating into plasmablasts and secreting high levels of IgM, IgG, and IgA, as well as Ag-specific IgG. This was associated with the induction of the molecular machinery necessary for PC formation. Mutations in IL21R, however, abolished IL-21-induced responses of both naive and memory human B cells and compromised memory B cell formation in vivo. These findings reveal a key role for IL-21R/STAT3 signaling in regulating human B cell function. Furthermore, our results indicate that the threshold of STAT3 activation required for differentiation is lower in memory compared with naive B cells, thereby identifying an intrinsic difference in the mechanism underlying differentiation of naive versus memory B cells.

Background: The 2009/A/H1N1 influenza vaccination campaign was managed mainly by general practitioners (GPs); however, little is known about the challenges GPs encountered during the vaccination campaign., Aim: To analyse the challenges GPs encountered during the 2009/A/H1N1 vaccination campaign., Methods: In-depth, semi-structured qualitative interviews were conducted with GPs in Australia, Israel and England, and subjected to thematic analysis., Results: GPs experienced different levels of autonomy when organising vaccinations in clinics. Their significant role was the provision of advice about the vaccine to the patients. This role was challenged by the necessity to provide the advice as a response to the anti-vaccination messages in the media and because GPs harboured doubts about mass vaccination policies., Discussion: It is important that GPs accept the rationale behind vaccination campaigns and should be given accurate information about the vaccine before the campaign commences. Trustful, two-way channels for communication between GPs and public health authorities should also be established.

Purpose: Colistin is increasingly used as the last-resort treatment option against infections caused by multidrug-resistant (MDR) Gram-negative pathogens, but its nephrotoxicity is of concern, especially in severely ill patients. The aim of this study was to analyze the toxicity of colistin therapy in adults and children with hematological malignancies (HM) and hematopoietic stem cell transplantation (HSCT) recipients., Methods: Data on HSCT recipients and HM patients, treated with intravenous colistin (2.5-5 mg/kg/day in children and 3-6 million international units (IU) in adults, adjusted to renal function) during the period 2008-2011 in our center, were retrospectively collected and analyzed. Nephrotoxicity was defined according to the RIFLE criteria (Risk, Injury, Failure, Loss, and End-stage kidney disease)., Results: Twenty-nine children and adults received 38 courses of intravenous colistin (2.5-5 mg/kg/day in children and 3-6 × 10(6) IU in adults, adjusted to renal function) [allogeneic HSCT (22 courses) and HM (16 courses)] for 3-28 days (median 10 days) for empirical therapy for nosocomial clinical sepsis (28) or local infection (6), and bacteremia with MDR Gram-negative rods (4). Nephrotoxicity was observed at the end of 4 (10.5%) courses. In 32 (84%) courses, nephrotoxic medications were concomitantly administered. Two patients had convulsions, probably unrelated to colistin. Seven patients (18%) died while on colistin therapy. No death was attributed to an adverse effect of colistin., Conclusions: Treatment with intravenous colistin, with dosage adjusted to renal function, was relatively safe for HM/HSCT patients, even with concomitantly administered nephrotoxic medications. Concern about nephrotoxicity should not justify a delay in initiating empirical colistin treatment in situations where infection with MDR Gram-negative rods is likely.

Objective: Previous research has identified gaps in pandemic response planning for primary care. Identifying the challenges that general practitioners (GPs) face during public health crises of infectious diseases will help to improve prepandemic planning. In this integrative systematic review, we identified research-based evidence to (1) challenges that GPs have when participating in pandemics or epidemics and (2) whether GPs from different countries encountered different challenges., Methods: A systematic search was conducted in MEDLINE, PubMed, Scopus, EMBASE, PsycINFO, Cochrane Library, and ProQuest Dissertations and Theses databases during October to November 2012 to identify studies relevant to experience by GPs during epidemics or pandemics., Results: Six quantitative, 2 mixed method, and 2 qualitative studies met the inclusion criteria. The challenges identified were not exclusive to specific countries and encompassed different responses to outbreaks. These challenges included difficulties with information access; supply and use of personal protective equipment; performing public health responsibilities; obtaining support from the authorities; appropriate training; and the emotional effects of participating in the response to an infectious disease with unknown characteristics and lethality., Conclusion: GPs' response to public health crises in different countries presents potential for improving pandemic preparedness.

Background: The capacity of CD8(+) T cells to control infections and mediate antitumor immunity requires the development and survival of effector and memory cells. IL-21 has emerged as a potent inducer of CD8(+) T-cell effector function and memory development in mouse models of infectious disease. However, the role of IL-21 and associated signaling pathways in protective CD8(+) T-cell immunity in human subjects is unknown., Objective: We sought to determine which signaling pathways mediate the effects of IL-21 on human CD8(+) T cells and whether defects in these pathways contribute to disease pathogenesis in patients with primary immunodeficiencies caused by mutations in components of the IL-21 signaling cascade., Methods: Human primary immunodeficiencies resulting from monogenic mutations provide a unique opportunity to assess the requirement for particular molecules in regulating human lymphocyte function. Lymphocytes from patients with loss-of-function mutations in signal transducer and activator of transcription 1 (STAT1), STAT3, or IL-21 receptor (IL21R) were used to assess the respective roles of these genes in human CD8(+) T-cell differentiation in vivo and in vitro., Results: Mutations in STAT3 and IL21R, but not STAT1, led to a decrease in multiple memory CD8(+) T-cell subsets in vivo, indicating that STAT3 signaling, possibly downstream of IL-21R, regulates the memory cell pool. Furthermore, STAT3 was important for inducing the lytic machinery in IL-21-stimulated naive CD8(+) T cells. However, this defect was overcome by T-cell receptor engagement., Conclusion: The IL-21R/STAT3 pathway is required for many aspects of human CD8(+) T-cell behavior but in some cases can be compensated by other signals. This helps explain the relatively mild susceptibility to viral disease observed in STAT3- and IL-21R-deficient subjects., (Published by Mosby, Inc.)

Influenza may cause severe disease and mortality in leukemia patients and in hematopoietic stem cell transplantation recipients. The 4th European Conference of Infections in Leukemia (ECIL-4) has developed evidence-based guidelines for prevention and management of influenza infections in these patients. Real-time reverse-transcription polymerase chain reaction is the diagnostic test of choice, as it is the most sensitive and specific test for influenza. The risks for severe influenza and fatal outcome include lymphopenia, older age, influenza soon after transplantation or chemotherapy, steroid treatment, and lack of early antiviral therapy. Neuraminidase inhibitors (oral oseltamivir or inhalation of zanamivir) are currently the most effective therapeutic agents for influenza. Main preventive measures include annual vaccination of patients, household contacts, and hospital staff. This review summarizes ECIL-4's main recommendations., (© 2013 John Wiley & Sons A/S.)

Background: During the influenza pandemic 2009/A/H1N1, the main burden of managing patients fell on primary care physicians (PCP). This provided an excellent opportunity to investigate the implications of pandemic policies for the PCP role., Aim: To examine policies affecting the role of PCP in the pandemic response in Australia (in the state of Victoria), Israel and England., Methods: Content analysis of the documents published by the health authorities in Australia, Israel and England during the pandemic 2009/A/H1N1., Results: The involvement of PCP in the pandemic response differed among the countries in timing and allocated responsibilities. The Israeli approach during the containment phase was to maximise the protection of PCP at the expense of putting pressure on hospitals where the suspected cases were tested and treated. In Australia and England, PCP managed the suspected patients from the beginning of the pandemic. The work of PCP in England was supported by the introduction of the National Pandemic Flu Service during the mitigation phase, whereas Australian PCP had no additional support structures and their role was constant and intensive throughout the pandemic period., Conclusion: Health authorities need to engage with representatives of PCP to evaluate policies for pandemic planning and management. Adequate support and protection for PCP during different stages of pandemic management should be provided. What is known about the topic? During the influenza pandemic 2009/A/H1N1, the main burden of diagnosing and managing the patients fell on PCP. The prominent role of PCP in the 2009/A/H1N1 pandemic presents an excellent opportunity to investigate implications of pandemic policies for primary care and to tackle the possible problems that these policies may impose on the ability of PCP to effectively participate in the public health response. What does this paper add? This paper examines policies that affected the roles of PCP in managing the influenza pandemic 2009/A/H1N1 in three countries: Australia, Israel and England. Although general evaluations of the pandemic response in different countries have previously been reported, this is the first study that focuses on policies for pandemic management at the primary care level. What are the implications for practitioners? Practitioners (PCP and primary care workers in general) would benefit if pandemic preparedness plans were constructed to provide an adequate system of support and protection to primary care workers during different stages of pandemic management. For policy makers, this analysis may help to overhaul the strategies for primary care engagement in the pandemic response.

Human adenovirus (HAdV) infections are increasingly recognized as important pathogens in immunocompromised hosts, especially in patients with severely suppressed T-cell function. The 4th European Conference of Infections in Leukemia (ECIL-4) has developed evidence-based guidelines for diagnosis and management of HAdV infections. The risk for HAdV-associated disease is increased in children, and risk factors for HAdV disease are T-cell depletion, unrelated and cord blood hematopoietic stem cell transplantation, graft-versus-host disease grades III-IV, and lymphopenia. The recommended technique for monitoring of high-risk patients is quantitative polymerase chain reaction. Cidofovir is the most used antiviral therapy, although no controlled study has been performed. HAdV-specific T-cell therapy is in development., (© 2012 John Wiley & Sons A/S.)

T follicular helper (Tfh) cells are critical for providing the necessary signals to induce differentiation of B cells into memory and Ab-secreting cells. Accordingly, it is important to identify the molecular requirements for Tfh cell development and function. We previously found that IL-12 mediates the differentiation of human CD4(+) T cells to the Tfh lineage, because IL-12 induces naive human CD4(+) T cells to acquire expression of IL-21, BCL6, ICOS, and CXCR5, which typify Tfh cells. We have now examined CD4(+) T cells from patients deficient in IL-12Rβ1, TYK2, STAT1, and STAT3 to further explore the pathways involved in human Tfh cell differentiation. Although STAT1 was dispensable, mutations in IL12RB1, TYK2, or STAT3 compromised IL-12-induced expression of IL-21 by human CD4(+) T cells. Defective expression of IL-21 by STAT3-deficient CD4(+) T cells resulted in diminished B-cell helper activity in vitro. Importantly, mutations in STAT3, but not IL12RB1 or TYK2, also reduced Tfh cell generation in vivo, evidenced by decreased circulating CD4(+)CXCR5(+) T cells. These results highlight the nonredundant role of STAT3 in human Tfh cell differentiation and suggest that defective Tfh cell development and/or function contributes to the humoral defects observed in STAT3-deficient patients.

Background: Adenoviruses cause a variety of clinical symptoms, involving the respiratory, gastrointestinal, urogenital, and neurologic systems. Only a few of the 55 known serotypes of adenovirus that affect humans can cause outbreaks of respiratory tract infection., Aim: To describe the characteristics and clinical manifestations of severe respiratory disease contracted by 8 physically and cognitively disabled children during a very short outbreak of adenovirus serotype 7 infection in a residential facility., Methods: The clinical, imaging, and laboratory findings of the patients who were hospitalized with severe respiratory symptoms were retrospectively reviewed. Molecular typing of the adenovirus was performed., Results: During 10 days in February 2010, 8 severely disabled children, 9 months to 5 years of age (median 22.5 months), from the same residential facility, were hospitalized due to severe acute respiratory disease with hypoxemia. Four of them (50%) needed mechanical ventilation for 2 to 8 days and one developed multisystem failure, including acute renal failure. Adenovirus serotype 7 was detected in the respiratory specimens of all 8 children. Two patients were treated with intravenous cidofovir. All 8 patients survived and were discharged after hospitalization of 6 to 15 (median: 11.5) days. The epidemiologic investigation revealed that all the 8 affected children shared a playroom and a caregiver worked with them while suffering fever, sore throat, and conjunctivitis before the onset of the outbreak., Conclusions: Adenovirus type 7 may cause short outbreaks of infection in institutions, causing children to develop life-threatening disease. Early detection of pathogens causing respiratory infections in institutions, isolation, and other preventive precautions are advocated. Moreover, vaccination of health care providers in institutions with the currently available live, oral adenovirus vaccine for types 4 and 7 should be considered.

We report a successful umbilical cord blood transplantation (UCBT) in an 8-month male with Wiskott-Aldrich syndrome (WAS) and congenital cytomegalovirus (CMV) infection. The child presented at 3 months of age with symptomatic thrombocytopenia and CMV infection. Despite appropriate antiviral treatment no rise in the platelet count was observed. Genetic analysis confirmed the diagnosis of WAS. The clinical course was complicated by severe CMV retinitis with bilateral retinal hemorrhages and renal vasculitis. He underwent unrelated UCBT resulting in a rapid resolution of autoimmunity and thrombocytopenia., (Copyright © 2011 Wiley-Liss, Inc.)

Background: An outbreak of respiratory illness caused by a novel swine-origin influenza virus (influenza A/H1N1 2009) that began in Mexico was declared a global pandemic by the World Health Organization in June 2009. The pandemic affected many countries, including Israel., Objectives: To compare the course of chest radiographic and computed tomography findings in patients who survived and those who died following admission to the intensive care unit (ICU) or intubation due to severe laboratory-confirmed swine-origin influenza A/H1N1 2009., Methods: We retrospectively reviewed the patient records (267 radiographs, 8 CTs) of 22 patients (10 males, 12 females) aged 3.5-66 years (median 34) with confirmed influenza A/ H1N1 2009, admitted to the ICU and/or intubated in five major Israeli medical centers during the period July-November 2009. We recorded demographic, clinical, and imaging findings--including pattern of opacification, extent, laterality, distribution, zone of findings, and presence/absence of nodular opacities--at initial radiography and during the course of disease, and compared the findings of survivors and non-survivors. Statistical significance was calculated using the Wilcoxon (continuous variables) and Fisher exact tests., Results: The most common findings on the initial chest radiography were airspace opacities, which were multifocal in 17 patients (77%) and bilateral in 16 (73%), and located in the lower or lower and middle lung zones in 19 patients (86%). Large airspace nodules with indistinct margins were seen in 8 patients (36%). Twelve patients survived, 10 died. Patients who died had multiple background illnesses and were significantly older than survivors (P = 0.006). Radiologic findings for the two groups were not significantly different., Conclusion: Airspace opacities, often with nodular appearance, were the most common findings among patients with severe influenza A/H1N1 2009. The course of radiologic findings was similar in patients with severe influenza A/ H1N1 2009 who survived and those who died.

Chronic mucocutaneous candidiasis disease (CMCD) may be caused by autosomal dominant (AD) IL-17F deficiency or autosomal recessive (AR) IL-17RA deficiency. Here, using whole-exome sequencing, we identified heterozygous germline mutations in STAT1 in 47 patients from 20 kindreds with AD CMCD. Previously described heterozygous STAT1 mutant alleles are loss-of-function and cause AD predisposition to mycobacterial disease caused by impaired STAT1-dependent cellular responses to IFN-γ. Other loss-of-function STAT1 alleles cause AR predisposition to intracellular bacterial and viral diseases, caused by impaired STAT1-dependent responses to IFN-α/β, IFN-γ, IFN-λ, and IL-27. In contrast, the 12 AD CMCD-inducing STAT1 mutant alleles described here are gain-of-function and increase STAT1-dependent cellular responses to these cytokines, and to cytokines that predominantly activate STAT3, such as IL-6 and IL-21. All of these mutations affect the coiled-coil domain and impair the nuclear dephosphorylation of activated STAT1, accounting for their gain-of-function and dominance. Stronger cellular responses to the STAT1-dependent IL-17 inhibitors IFN-α/β, IFN-γ, and IL-27, and stronger STAT1 activation in response to the STAT3-dependent IL-17 inducers IL-6 and IL-21, hinder the development of T cells producing IL-17A, IL-17F, and IL-22. Gain-of-function STAT1 alleles therefore cause AD CMCD by impairing IL-17 immunity.

During 2009, a new strain of A/H1N1 influenza appeared and became pandemic. A prospective study was performed to collect data regarding risk factors and outcome of A/H1N1 in hematopoietic stem cell transplant recipients. Only verified pandemic A/H1N1 influenza strains were included: 286 patients were reported, 222 allogeneic and 64 autologous recipients. The median age was 38.3 years and the median time from transplant was 19.4 months. Oseltamivir was administered to 267 patients and 15 patients received zanamivir. One hundred and twenty-five patients (43.7%) were hospitalized. Ninety-three patients (32.5%) developed lower respiratory tract disease. In multivariate analysis, risk factors were age (OR 1.025; 1.01-1.04; P=0.002) and lymphopenia (OR 2.49; 1.33-4.67; P<0.001). Thirty-three patients (11.5%) required mechanical ventilation. Eighteen patients (6.3%) died from A/H1N1 infection or its complications. Neutropenia (P=0.03) and patient age (P=0.04) were significant risk factors for death. The 2009 A/H1N1 influenza pandemic caused severe complications in stem cell transplant recipients.

Macrolide resistance in Mycoplasma pneumoniae is often found in Asia but is rare elsewhere. We report the emergence of macrolide-resistant M. pneumoniae in Israel and the in vivo evolution of such resistance during the treatment of a 6-year-old boy with pneumonia.

STAT-1 (Signal Transducer and Activator of Transcription-1) is a key signaling component of interferon gamma responses. We present long-term manifestations in siblings with a mutation in the STAT1 gene, which include invasive salmonellosis, recurrent severe respiratory syncytial virus pneumonitis, and hepatosplenic mycobacterial disease, and we summarize all other reported cases with STAT-1 deficiency.

Purpose: Environmental conditions often serve as critical enabling factors for health promotion. This article describes the effect of a preschool hygiene intervention program on classroom environmental conditions., Design: Cluster randomized trial, with randomization at the level of the preschool., Setting: State-run preschools in Jerusalem., Subjects: Forty secular and religious Jerusalem preschools (including 1029 children)., Intervention: A multidisciplinary hygiene intervention that included changes to the preschool environment., Measures: Presence of soap, soap dispenser, paper towel, paper towel dispenser, cloth towels, communal cup, or personal cups., Analysis: Generalized estimating equations and Fisher's exact test were used to estimate the effect of the intervention program on environmental conditions., Results: Information was obtained from most (97.9%) visits. Baseline environmental hygienic conditions were poor. Relative to the control group, the following environmental conditions were better in the intervention group after program implementation: soap (odds ratio [OR] = 14.7; p < .01), paper towels (OR = 13.5; p < .01), communal cups (OR = .05; p < .01), soap dispensers (secular preschools only, p < .01), individual cups (secular, p < .01; religious, OR = 18.7; p < .02)., Conclusions: Environmental hygiene in the Israeli preschools studied was deficient at baseline but amenable to change. Improvement in environmental conditions was a necessary enabling factor for the changes in hand-washing behavior that were observed among the children. Sustained environmental change is possible in the preschool environment.

Objective: The chemokine receptor CXCR4 and its ligand CXCL12 are involved in the progression and dissemination of a diverse number of solid and hematological malignancies. Binding CXCL12 to CXCR4 activates a variety of intracellular signal transduction pathways that regulate cell chemotaxis, adhesion, survival, proliferation, and apoptosis., Materials and Methods: Here, we demonstrate that the CXCR4 antagonist, 4F-benzoyl-TN14003 (BKT140), but not AMD3100, exhibits a CXCR4-dependent preferential cytotoxicity toward malignant cells of hematopoietic origin. BKT140 significantly and preferentially stimulated multiple myeloma apoptotic cell death. BKT140 treatment induced morphological changes, phosphatidylserine externalization, decreased mitochondrial membrane potential, caspase-3 activation, sub-G1 arrest, and DNA double-stranded breaks., Results: In vivo, subcutaneous injections of BKT140 significantly reduced, in a dose-dependent manner, the growth of human acute myeloid leukemia and multiple myeloma xenografts. Tumors from animals treated with BKT140 were smaller in size and weights, had larger necrotic areas and high apoptotic scores., Conclusions: Taken together, these results suggest a potential therapeutic use for BKT140 in multiple myeloma and leukemia patients., (Copyright © 2011 ISEH - Society for Hematology and Stem Cells. Published by Elsevier Inc. All rights reserved.)

We evaluated the formation of hemagglutination-inhibition (HI) antibodies in response to vaccination of 55 allogeneic and 23 autologous hematopoietic stem cell transplantation (HSCT) recipients with 3.75 μg inactivated influenza A/California/7/2009 (H1N1)v-like virus adjuvanted with AS03, given towards the end of the 2009 influenza pandemic. The 78 HSCT recipients, aged 11-72 (median 50) years, were vaccinated 1-290 (median 27) months post-HSCT. Of the 55 allogeneic HSCT recipients, 50.9% received reduced intensity conditioning, 74.5% had a sibling donor, 67.2% had active graft-versus-host disease and 43.6% were on steroid therapy. At baseline, 14/78 (17.9%) had HI titers ≥ 1:40. Blood samples of 77 patients were available post-1st vaccination; of these, 34 (44.2%) patients had HI titers ≥ 1:40. Blood samples of 43 patients were available post-2nd vaccination; of these, 21 (48.8%) had HI titers ≥ 1:40. There was a significant increase in HI titers ≥ 1:40 from baseline to both post-1st and 2nd vaccinations (p<0.001 each), and also from 1st to 2nd vaccination (p=0.008). In seronegative (HI titers <1:10) patients, whose sera were available before, after one dose, and after 2 doses of vaccine, seroconversion (to ≥ 1:40) occurred in 4/24 (16.7%) after 1-dose and in a total of 10/24 (41.7%) after 2-dose vaccination (p=0.031). Logistic regression analysis revealed that ≥ 1:40 HI titers were significantly associated with higher lymphocyte counts and higher HI baseline titers and, in allogeneic HSCT, with having a sibling donor and higher baseline titers. In conclusion, 2-dose vaccination with AS03-adjuvanted vaccine containing 3.75 μg antigen resulted in a statistically significant, yet limited, serological response. Therefore, additional precautions should be taken during influenza outbreaks., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Schools are a natural place from which to disseminate health messages to the community. Sending an entertaining handwashing video home with preschoolers as a component of a school-based program yielded impressive degrees of penetration and reach among families; consequently, this strategy offers a promising alternative to traditional media campaigns.

Engagement of cytokine receptors by specific ligands activate Janus kinase-signal transducer and activator of transcription (STAT) signaling pathways. The exact roles of STATs in human lymphocyte behavior remain incompletely defined. Interleukin (IL)-21 activates STAT1 and STAT3 and has emerged as a potent regulator of B cell differentiation. We have studied patients with inactivating mutations in STAT1 or STAT3 to dissect their contribution to B cell function in vivo and in response to IL-21 in vitro. STAT3 mutations dramatically reduced the number of functional, antigen (Ag)-specific memory B cells and abolished the ability of IL-21 to induce naive B cells to differentiate into plasma cells (PCs). This resulted from impaired activation of the molecular machinery required for PC generation. In contrast, STAT1 deficiency had no effect on memory B cell formation in vivo or IL-21-induced immunoglobulin secretion in vitro. Thus, STAT3 plays a critical role in generating effector B cells from naive precursors in humans. STAT3-activating cytokines such as IL-21 thus underpin Ag-specific humoral immune responses and provide a mechanism for the functional antibody deficit in STAT3-deficient patients.

The current pandemic (H1N1) 2009 influenza is spreading worldwide with a significant increase in morbidity and mortality noted in Israel, as well as in many other countries of the Northern Hemisphere. In an attempt to minimize severe morbidity and mortality, immunization projects have been initiated. This review describes the scientific data regarding safety and immunogenicity of the pandemic (H1N1) influenza vaccines which were approved for use in Israel. The approval was based on: (1) broad experience with seasonal flu vaccines; (2) data from the research and development processes of pandemic vaccines; (3) experience with adjuvants used in other vaccines and (4) post-marketing data. The immunogenicity of the approved vaccines is excellent: at least 92% develop protective antibody titers following a single vaccine dose. The vaccines are considered safe and severe side effects are very rare. Mild and transient adverse effects are similar to those following seasonal flu vaccines: local side effects in up to 12-18% and systemic adverse effects in up to 8%. The safety of the adjuvants and thiomersal is described in this review. The vaccines currently used in Israel were approved by the European Medicines Agency (EMEA) after the agency was satisfied with available safety data. Finally, the current pandemic 2009 (H1N1) influenza immunization program in Israel is described.

This paper describes the effect of a preschool hygiene intervention program on psychosocial measures of educators regarding handwashing and communicable pediatric disease. A cluster-randomized trial, with randomization at the level of the preschool, was run in 40 Jerusalem preschool classrooms. Eighty preschool educators participated. The program used a multipronged approach which included elements aimed at staff, children, parents, school nurses and the classroom environment. Frontal lectures by medical, epidemiological and educational experts, along with printed materials and experiential learning, were provided to staff. Responses from a validated survey instrument were used to build four scales for each respondent regarding beliefs, attitudes, self-efficacy and knowledge. The scales were built on a Likert-type 1-7 scale (1 = minimum, 7 = maximum). The effect of the intervention was tested using mixed model analysis of variance. Response was received from 92.5% of educators. Educators believed that handwashing could affect health (mean = 5.5, SD = 1.1), had high levels of self-efficacy (mean = 6.1, SD = 0.9) and had positive attitudes toward handwashing (mean = 5.7, SD = 1.2). Knowledge was affected by the intervention (intervention: mean = 6.2, SD = 0.7; control: mean = 5.8, SD = 0.8). The combination of positive attitudes toward handwashing among educators and the program's effectiveness in imparting knowledge helped to create a sustained social norm of handwashing among many children in disparate locations.

Objective: To propose a scheme for comprehensive development and evaluation of lifestyle interventions., Methods: We adapted the four-phase system used in drug development, the engine of progress in medicine for decades, to construct a system for developing lifestyle intervention programs., Results: Phase I: The intervention is constructed and tested with a small number of individuals. Acceptability and feasibility are assessed. Evaluation is primarily qualitative. Phase II: Effectiveness on intermediate endpoints (e.g. behavior) is tested in a real field setting, with a limited number of individuals, using a before-and-after design. An iterative process of testing and refinement may be necessary. Phase III: The effectiveness of the intervention on health-related outcomes is tested, using, where possible, a randomized design. Phase IV: Large-scale implementation and penetration are assessed in other populations. Process variables and local and national health indicators are studied. The development and evaluation of our hygiene intervention, which took place in Jerusalem from 1999 to 2001, is presented as a case study., Conclusions: Adaptation of the phased system of drug development to lifestyle interventions is a conceptually simple approach to building effective, sustainable programs for community-based public health.

Complete STAT1 deficiency is an autosomal recessive primary immunodeficiency caused by null mutations that abolish STAT1-dependent cellular responses to both IFN-alpha/beta and IFN-gamma. Affected children suffer from lethal intracellular bacterial and viral diseases. Here we report a recessive form of partial STAT1 deficiency, characterized by impaired but not abolished IFN-alpha/beta and IFN-gamma signaling. Two affected siblings suffered from severe but curable intracellular bacterial and viral diseases. Both were homozygous for a missense STAT1 mutation: g.C2086T (P696S). This STAT1 allele impaired the splicing of STAT1 mRNA, probably by disrupting an exonic splice enhancer. The misspliced forms were not translated into a mature protein. The allele was hypofunctional, because residual full-length mRNA production resulted in low but detectable levels of normally functional STAT1 proteins. The P696S amino acid substitution was not detrimental. The patients' cells, therefore, displayed impaired but not abolished responses to both IFN-alpha and IFN-gamma. We also show that recessive STAT1 deficiencies impaired the IL-27 and IFN-lambda1 signaling pathways, possibly contributing to the predisposition to bacterial and viral infections, respectively. Partial recessive STAT1 deficiency is what we believe to be a novel primary immunodeficiency, resulting in impairment of the response to at least 4 cytokines (IFN-alpha/beta, IFN-gamma, IFN-lambda1, and IL-27). It should be considered in patients with unexplained, severe, but curable intracellular bacterial and viral infections.

These guidelines on the management of HSV, VZV and EBV infection in patients with hematological malignancies and after SCT were prepared by the European Conference on Infections in Leukemia following a predefined methodology. A PubMed search was conducted using the appropriate key words to identify studies pertinent to management of HSV, VZV and EBV infections. References of relevant articles and abstracts from recent hematology and SCT scientific meetings were also reviewed. Prospective and retrospective studies identified from the data sources were evaluated, and all data deemed relevant were included in this analysis. The clinical and scientific background was described and discussed, and the quality of evidence and level of recommendation were graded according to the Centers for Disease Control criteria.

Background: The Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial (PLCO) is a US National Cancer Institute (NCI)-funded randomized controlled trial designed to evaluate whether certain screening tests reduce mortality from prostate, lung, colorectal, and ovarian cancer. To obtain adequate statistical power, it was necessary to enroll over 150,000 healthy volunteers. Recruitment began in 1993 and ended in 2001., Purpose: Our goal is to evaluate the success of recruitment methods employed by the 10 PLCO screening centers. We also provide estimates of recruitment yield and cost for our most successful strategy, direct mail., Methods: Each screening center selected its own methods of recruitment. Methods changed throughout the recruitment period as needed. For this manuscript, representatives from each screening center provided information on methods utilized and their success., Results: In the United States between 1993 and 2001, ten screening centers enrolled 154,934 study participants. Based on participant self-report, an estimated 95% of individuals were recruited by direct mail. Overall, enrollment yield for direct mail was 1.0%. Individual center enrollment yield ranged from 0.7% to 3.8%. Cost per enrolled participant was $9.64-35.38 for direct mail, excluding personnel costs., Limitations: Numeric data on recruitment processes were not kept consistently at individual screening centers. Numeric data in this manuscript are based on the experiences of 5 of the 10 centers., Conclusions: Direct mail, using rosters of names and addresses from profit and not-for-profit (including government) organizations, was the most successful and most often used recruitment method. Other recruitment strategies, such as community outreach and use of mass media, can be an important adjunct to direct mail in recruiting minority populations.

Background: In recent years, mother to child transmission of human immunodeficiency virus in the west has decreased markedly due to the advent of antiretroviral drugs given during pregnancy, cessation of lactation, and careful monitoring of viral load in the perinatal period., Objective: To assess mother to child transmission of HIV among Ethiopian immigrants and non-Ethiopians in the Jerusalem area., Methods: We conducted a prospective analysis of all deliveries of HIV-positive women in the Jerusalem district over a 10 year period., Results: Between 1996 and 2006, 35 HIV+ women gave birth to 45 infants. Thirty-one (88%) of these women were of Ethiopian origin and gave birth to 39 infants. Of the 35 HIV+ women, 30 were aware of being HIV positive. They gave birth to 40 infants. Another 5 women (14%) were not aware of being HIV+ during delivery. They gave birth to five infants. Of the group of known HIV+ women, 26 (87%) were Ethiopian immigrants who delivered 34 infants and 4 were non-Ethiopians who delivered 6 infants. In the group of five women not aware of being HIV+, all were Ethiopians. Breast-feeding data were available for 32 of the 35 women. Only 2 women (6.2%) breast-fed their babies. Neither was aware of being HIV+. In the Ethiopian immigrant group (both known and unknown HIV status), 11 deliveries (28%) were vaginal, 18 (46%) were elective cesarean section and 10 (26%) were delivered by emergency cesarean section. Of the 26 known HIV+ Ethiopian women, 3 (12%) refused antiretroviral treatment despite repeated counseling. In the non-Ethiopian group, all deliveries were elective cesarean sections. Mother to child transmission of HIV occurred in 4 of the total 45 deliveries (8.8%). Of the 4 transmission cases, 2 occurred among 40 deliveries of known HIV+ women (5%), and 2 occurred among the 5 deliveries of women not aware of being HIV+ (40%, P=0.05). In the group of Ethiopian women only, HIV transmission occurred in 4 of 39 deliveries (10%), of which 2 occurred among 34 deliveries (5.8%) of women know to be HIV+ and 2 among 5 deliveries (40%) of women not aware of being HIV+ (P=0.08)., Conclusions: Pregnant Ethiopian immigrants whose HIV status was known during pregnancy were at relatively high risk of HIV transmission despite the availability of antiretroviral drugs and counseling. This is likely due to inadequate adherence to ART preventive regimens, not dissimilar to the poor adherence observed among other immigrant groups in western countries. The substantial proportion of women, all Ethiopians, unaware being HIV+ at delivery, together with the significantly higher HIV transmission in that group compared to women who knew their HIV status, call for a revision of the current Ministry of Health opt-in policy for prenatal HIV screening.

These recommendations were prepared by the European Conference on Infections in Leukaemia following a predefined methodology. Literature searches were made to identify studies pertinent to management of CMV, HHV-6, -7 and -8 infections. For CMV, 76 studies were reviewed: 72 published and 4 presented as abstracts. Twenty-nine of these studies were prospective randomized trials. For the other herpesviruses, HHV-6, -7 and -8, no randomized controlled trial has been performed, although data from some studies with other primary endpoints have been used to assess the management of HHV-6 infection. Works presented only as abstracts were used to a very limited extent. The quality of evidence and level of recommendation were graded according to the Center for Disease Control (CDC) criteria.

Summary: The approach to treating febrile non-neutropenic hematooncologic patients with central venous catheters varies. We recently introduced once-daily administration of cefonicid and gentamicin for such children who were in good clinical condition and without focal signs of infection. Our 2-year experience of 125 episodes in 54 children is hereby reported. Absolute neutrophil counts were 550 to 16,700/mm. Bacteremia occurred in 6.4% episodes: only in patients with Hickman/Broviac catheters and not in those with port-a-caths [8/37 (21.6%) vs. 0/17 patients, P=0.046; 8/86 (9.3%) vs. 0/39 episodes, P=0.056]. The pathogens were coagulase-negative staphylococci (3), Streptococcus pneumoniae (2), Pseudomonas aeruginosa and Klebsiella pneumoniae (1), methicillin-sensitive Staphylococcus aureus (1), and Streptococcus milleri (1). All patients remained in stable clinical condition and all, except for 2 who became neutropenic and 1 with S. aureus bacteremia who developed cellulitis, defervesced while on the empiric therapy. Three episodes could not be managed as outpatients. No adverse effects were observed. We conclude that our approach is efficacious and safe and, furthermore, that empiric antibiotic therapy may not be indicated for selected patients with port-a-caths. Future study of children with Hickman/Broviac catheters will evaluate the use of cefonicid alone.

Background: Rotavirus is a major cause of infantile gastroenteritis worldwide and remains a common cause of hospitalizations in developed countries. The study aimed to assess the hospitalizations due to rotavirus gastroenteritis in Israel and their characteristics., Methods: A retrospective review of the records of children < 18 years hospitalized in six medical centers in Israel between April 2004 and March 2006 with acute gastroenteritis (AGE) and stool positive for rotavirus. Children with nosocomial infections, immune deficiency or under immunosuppressive therapy were excluded., Results: During the study period, 1912 children were hospitalized with AGE due to rotavirus, of whom 1719 were included in this study. The peak rate of admission due to rotavirus was in November and December, when 34% of the admissions for AGE were caused by rotavirus, and the lowest rate was in August (7%, p < 0.0001). Annually, rotavirus caused 18.4% and 2.8% of the hospitalization for AGE and of all pediatric hospitalizations, respectively. The mean age on admission was 14 months (median 12 months) and the mean hospitalization--3.9 days. According to the annual pediatric statistics in Israel for 2004, the estimated annual rotavirus-associated hospitalization in Israel is 3816, with 14,692 hospitalization days., Conclusions: Rotavirus gastroenteritis is an important cause for hospitalizations and complications in children < 5 years in Israel, stressing the need for safe and efficacious vaccines to reduce the burden of the infection.

A 16-month-old girl presented with herpes simplex virus type 1 encephalitis with involvement of bilateral parietofrontal lobes, left thalamus and cerebellum. She was treated with intravenous acyclovir. As her condition deteriorated, high-dose methylprednisolone was administered, resulting in remarkable improvement. This case suggests considering a short course of high-dose steroid therapy in severe herpes simplex encephalitis when there is clinical and radiologic deterioration in spite of appropriate antiviral therapy and decreasing viral load in the cerebrospinal fluid.

Background: We retrospectively studied the effect of the lamivudine-induced reverse transcription mutation M184V on selection of thymidine analog mutations (TAMs) in HIV subtype C-infected children and on clinical outcome., Methods: We genotyped 135 blood samples from 55 children. TAMs accumulation, viral load and clinical outcome were compared in children maintained on zidovudine/stavudine + lamivudine + protease inhibitor/nonnucleoside reverse transcriptase inhibitor (PI/NNRTI) despite loss of viral suppression and in children treated with, or switched to, other nucleoside reverse transcriptase inhibitors (NRTIs). Drug susceptibility and replication capacity of selected samples were measured., Results: M184V developed in 18 of 22 of children who had received only zidovudine/stavudine + lamivudine + PI/NNRTI during a mean of 23.2 +/- 3.2 months versus in 3 of 14 children treated with other drugs and/or having multiple regimen changes (P = 0.001). TAMs appeared, respectively, in 2 of 22 versus 12 of 14 (P < 0.0001). The 2 groups did not differ significantly in baseline HIV-RNA or CD4 count, sampling time, and follow-up period. In M184V-containing samples, we found large reductions in susceptibility to lamivudine and emtricitabine but not to other NRTIs. When T215Y was present without M184V, susceptibility to zidovudine was reduced 8-fold. When both M184V + T215Y occurred, susceptibility to zidovudine was substantially increased. Average inhibition concentration 50 values were similar to those documented in the Stanford database for subtype B HIV with these mutation patterns., Conclusions: Maintaining a thymidine analog + lamivudine-based regimen reduced accumulation of TAMs and increased zidovudine susceptibility. This is likely the result of an increased susceptibility to thymidine analog (zidovudine) in the context of M184V documented here for the first time in subtype C-infected children. This retrospective study supports the strategy of maintaining lamivudine-containing therapy in subtype C-infected children. This strategy may be beneficially applied in the treatment of children in Africa, where thymidine analog + lamivudine-based regimen became available recently but further options are limited.

The incidence of complicated pneumonia caused by S. pneumoniae is reported to be increasing. This increase may be related to host susceptibility and/or pathogen virulence. The objective of this study was to evaluate clinical and laboratory characteristics associated with complicated pneumococcal pneumonia, and to identify risk factors associated with prolonged fever and hospitalization. The study involved reviewing the records of all children who were hospitalized in four major hospitals in Jerusalem with a confirmed diagnosis of pneumococcal pneumonia during a 12-year period (1986-1997). Demographic, clinical, laboratory, and outcome variables were compared between those with uncomplicated and complicated pneumonia. One hundred and eleven children (median age, 2.2 years) were hospitalized with pneumococcal pneumonia during the study period. Forty-four (39%) of them had complicated pneumonia, characterized by pleural effusion, empyema, pneumothorax, pneumatocele, and/or atelectasis. There was no correlation between the isolation of penicillin-resistant S. pneumonia (16% of cases) and complicated pneumonia. Factors that were significantly associated with complicated pneumonia included weight

The overwhelming evidence about the role lifestyle plays in mortality, morbidity, and quality of life has pushed the young field of modern health promotion to center stage. The field is beset with intense debate about appropriate evaluation methodologies. Increasingly, randomized designs are considered inappropriate for health promotion research. We have reviewed criticisms against randomized trials that raise philosophical and practical issues, and we will show how most of these criticisms can be overcome with minor design modifications. By providing rebuttal to arguments against randomized trials, our work contributes to building a sound methodological base for health promotion research.

Background: Preschools are often focal points for the spread of illness among young children. The objective of this preschool intervention trial was to determine whether a hygiene program can promote handwashing and thereby reduce illness absenteeism., Methods: This cluster randomized trial included 40 Jerusalem preschools with 1029 children for 6 baseline days and 66 study days, yielding 73,779 child days. The main outcomes were rates of handwashing and illness absenteeism. The intervention included an educational program and environmental changes. A simultaneous subtrial was run to test a home component., Results: This multi-site intervention program produced sustained behavioral and environmental changes over a 6-month period. An approximately threefold increase in handwashing with soap was observed among preschool children exposed to the intervention. Neither the preschool nor the home intervention program reduced illness absenteeism or overall absenteeism., Conclusions: This trial illuminates the potential of the preschool as a promising venue for health promotion activities leading to sustained behavioral change, yet suggests the need for enhanced approaches for reducing illness absenteeism.

Background: Rates of communicable disease among young children are considerably higher in Israel than in other western countries. Strategies for reducing the disease rates are needed., Purpose: The goal of the Jerusalem Handwashing Study (JHS) was to evaluate a preschool-based hygiene programme aimed at reducing illness absenteeism., Methods: The trial employed cluster randomization of preschools to intervention or control. The intervention programme was multifaceted, including various educational activities and environmental changes. The control group received the programme at the end of the study. A supplementary home component was tested using the innovative design strategy of an embedded individually-randomized trial. All-cause absenteeism and illness-related absenteeism was assessed by daily phone calls to the teachers, supplemented with phone calls to the parents to identify the cause of the absence. The primary endpoint was illness-related absenteeism. In an attempt to avoid bias, survey staff were blinded to the study design and the main outcome as well as intervention status. Validity checks were incorporated to assess the accuracy of educator absenteeism reports and were analysed for differences between the study arms. Observation of handwashing behaviour allowed assessment of behavioural change in the intervention group and spontaneous handwashing changes in the control group., Results: Cluster randomization with delayed implementation in the control group was a feasible and efficient strategy. The individually-randomized embedded sub-trial proved to be an efficient way to test a supplemental intervention component, and is particularly well-suited to programmes run in educational or other group settings, including workplaces, clinics, and community centres., Limitations: The trial design did not permit analysis of the intervention effect on illness., Conclusions: The techniques used in this trial made it possible for a rigorous study of a complex community-based health intervention to be carried out successfully. They should prove helpful to future researchers.

We report of twins who underwent hematopoietic stem cell transplantation (HSCT) for neonatal acute leukemia. Hospitalized in the same room from the time the first one demonstrated respiratory symptoms, they both developed Pneumocystis jiroveci (formerly carinii) pneumonia (PCP) 2 wk apart. This observation suggests that PCP may be a contagious disease in HSCT recipients. This may be especially true for infants and young children who are at risk of primary P. jiroveci infection, and should be avoided.

Over the last 25 years, the numbers of hematopoietic stem cell transplant (SCT) patients have increased rapidly. Infections have been major obstacles for successful transplantation. Thus, infection prevention is very important in transplant recipients. As the results of transplantation have improved, the number of long-term survivors has increased. Vaccination is a potentially important strategy for reducing the risk for vaccine-preventable infections after SCT. The EBMT produced recommendations for vaccination of SCT recipients published in Bone Marrow Transplantation in 1995. This paper updates the previous recommendations based on current knowledge.

The Lung Screening Study (LSS) was a pilot study designed to assess the feasibility of conducting a large scale randomized controlled trial (RCT) of low radiation dose spiral computed tomography (LDCT) versus chest X-ray (CXR) for lung cancer screening. Baseline results of LSS have been previously reported. Here, we report on the findings at the year one screen and on the final results of the LSS study. A total of 1660 subjects were randomized to the LDCT arm and 1658 to the CXR arm. Compliance with screening declined from 96% at baseline to 86% at year one in the LDCT arm and declined from 93% at baseline to 80% at year one in the CXR arm. Positivity rates for the year one screen were 25.8% for LDCT and 8.7% for CXR. Cancer yield was significantly less at year one for LDCT, 0.57%, than at baseline, 1.9%; cancer yield for CXR increased from 0.45% at baseline to 0.68% at year one. Forty lung cancers in the LDCT arm and 20 in the CXR arm were diagnosed over the study period. Stage I cancers comprised 48% of cases in the LDCT arm and 40% in the CXR arm. A total of 16 stage III-IV cancers were observed in the LDCT arm versus nine in the CXR arm. The LSS has established the feasibility of a RCT comparing annual spiral CT to chest X-ray for lung cancer screening.

We assessed the activity and safety of liposomal nystatin, a broad-spectrum antifungal agent, for invasive aspergillosis in patients refractory to or intolerant of amphotericin B. Thirty-three patients were enrolled, received at least one dose of the study drug, and were evaluable for safety. Twenty-six patients had confirmed probable or definite aspergillosis and were fully eligible. Most patients had a hematological malignancy (53.8%) or hematopoietic stem cell transplantation (23.0%), were neutropenic (61.5%), and were refractory to previous amphotericin B (92.3%). The median duration of previous amphotericin B treatment was 16.5 days (range, 5 to 64 days). Aspergillosis was definite in 3 cases and probable in 23 cases. Liposomal nystatin was initiated at a dose of 4 mg/kg of body weight/day. Twenty-five patients were evaluable for response: a complete response was achieved for one patient, and a partial response was achieved for six. Thus, the overall response rate is 7 of 25 (28%; 95% confidence interval, 12 to 49%). Seventeen (68.0%) of the 25 evaluable patients died during therapy or within 1 month after the end of therapy. The primary cause of death was invasive aspergillosis for nine patients and underlying malignancy for eight patients. The most frequent side effects included chills, shivering, and fever, leading to discontinuation of therapy for two patients. Grade 1 decline in renal function was seen for 10 (30.3%) patients, and hypokalemia was seen for 13 (39.4%). We conclude that liposomal nystatin can be effective for salvage therapy of invasive aspergillosis. Infusion-related adverse events have been observed frequently.

Influenza morbidity affects the entire population and has an enormous impact upon the economic burden and the health care systems. Available vaccines are often unsatisfactory and many individuals are reluctant to receive injections. Intranasal immunization is painless, side effect free and may encourage a large number of individuals to participate in the vaccination programs. Ninety-two students were immunized intranasally once or twice, 21 days apart, with a trivalent inactivated whole influenza vaccine during three separate seasons (1996/1997, 1997/1998 and 1998/1999) with the recommended seasonal strains. The vaccine was well tolerated, without adverse effect and morbidity in the vaccinees during the winter season was low. Serum antibody response was determined by the hemagglutination inhibition (HI) test and nasal response by the enzyme-linked immunoadsorbant assay (ELISA). Following the second dose, mucosal antibody response was detected in 48.1-73.3% of immunized subjects. Serum and mucosal antibody levels (GMT) increased significantly to all the strains, with the exception of A/H3N2 in the mucosal response in 1997/1998. At the end of the trial, the percentage of immune subjects was over 93% to A/H1N1 strains, 60-71% to A/H3N2 and 64-66% to B/Harbin in 1996/1997 and 1997/1998, and 75-91% following one dose in 1998/1999. When serum and mucosal responses were combined, a higher percentage of responders was found (60-86%). Repeated vaccination does not seem to interfere with serum or mucosal response. The double barrier of mucosal and serum antibody may inhibit infection and decrease morbidity when infection occurs, thus limiting the spread of influenza in the community.