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

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

The Irish potato famine pathogen Phytophthora infestans originated in central Mexico rather than the Andes

Phytophthora infestans is a destructive plant pathogen best known for causing the disease that triggered the Irish potato famine and remains the most costly potato pathogen to manage worldwide. Identification of P. infestan’s elusive center of origin is critical to understanding the mechanisms of repeated global emergence of this pathogen. There are two competing theories, placing the origin in either South America or in central Mexico, both of which are centers of diversity of Solanum host plants. To test these competing hypotheses, we conducted detailed phylogeographic and approximate Bayesian computation analyses, which are suitable approaches to unraveling complex demographic histories. Our analyses used microsatellite markers and sequences of four nuclear genes sampled from populations in the Andes, Mexico, and elsewhere. To infer the ancestral state, we included the closest known relatives Phytophthora phaseoli, Phytophthora mirabilis, and Phytophthora ipomoeae, as well as the interspecific hybrid Phytophthora andina. We did not find support for an Andean origin of P. infestans; rather, the sequence data suggest a Mexican origin. Our findings support the hypothesis that populations found in the Andes are descendants of the Mexican populations and reconcile previous findings of ancestral variation in the Andes. Although centers of origin are well documented as centers of evolution and diversity for numerous crop plants, the number of plant pathogens with a known geographic origin are limited. This work has important implications for our understanding of the coevolution of hosts and pathogens, as well as the harnessing of plant disease resistance to manage late blight.The potato pathogen Phytophthora infestans, the causal agent of potato late blight, is the plant pathogen that has most greatly impacted humanity to date. This pathogen is best known for its causal involvement in the Irish potato famine after introduction of the HERB-1 strain to Ireland from the Americas in the 19th century (1). To this day, potato late blight remains a major threat to food security and carries a global cost conservatively estimated at more than $6 billion per year (2). In the 1980s, a single asexual lineage named US-1, possibly derived from the same metapopulation as HERB-1 (1), dominated global populations, whereas a genetically diverse and sexual population of P. infestans in central Mexico led to formulation of the hypothesis identifying Mexico as this pathogen’s center of origin (3, 4). A competing hypothesis argues that the center of origin of the potato, the South American Andes, is the center of origin of P. infestans (5). This hypothesis recently gained prominence after an analysis demonstrated ancestral variation in Andean lineages of P. infestans (5). Other evidence supporting this hypothesis includes infection of native Solanum hosts and an Andean distribution for Phytophthora andina, a phylogenetic relative of P. infestans (6).Evidence supporting a Mexican center of origin is substantial, but inconclusive (4). Two close relatives of P. infestans, Phytophthora ipomoeae and Phytophthora mirabilis, are endemic to central Mexico (7, 8). P. ipomoeae and P. mirabilis cause disease on two endemic plant host groups, Ipomoea spp. and Mirabilis jalapa, respectively. Populations of P. infestans in the Toluca Valley, southwest of Mexico City, are genetically diverse, are in Hardy–Weinberg equilibrium, and contain mating types A1 and A2 in the expected 1:1 ratio for sexual populations (9, 10). Before a migration event from Mexico to Europe in the 1970s (11, 12), only A1 mating types of P. infestans were found worldwide outside of central Mexico, limiting other populations to asexual reproduction (13). Tuber-bearing native Solanum species occur throughout the Toluca Valley (14). Of the R genes that have been used to confer resistance to strains of P. infestans in potato, the majority described to date originated from Solanum demissum or Solanum edinense in the Toluca Valley, with some discovered in South America (15).Support for the alternate hypothesis that P. infestans originated in the Andes is based on a coalescent analysis conducted by Gómez-Alpizar et al. (5). This analysis used the nuclear RAS locus and the mitochondrial P3 and P4 regions to infer rooted gene genealogies that showed ancestral lineages rooted in the Andes. Furthermore, the Mexico sample harbored less nucleotide diversity than the Andean population. P. andina was identified as the ancestral lineage for the mitochondrial genealogy; however, P. mirabilis and P. ipomoeae were not included in that study. P. andina has since been shown to be a hybrid species derived from P. infestans and a Phytophthora sp. unknown to science (16). Surprisingly, populations of P. infestans and P. andina are clonal in South America and are not in Hardy–Weinberg equilibrium (6, 17–19). Thus, the question of whether P. infestans originated in the Andes or central Mexico remained unresolved.Powerful approaches for determining the demographic and evolutionary history of organisms are now available (20). Many of these approaches rely on the power of coalescent theory for inferring the genealogical history of a species based on a representative population sample (21–23). Bayesian phylogeography uses geographic information in light of phylogenetic uncertainty to provide model-based inference of geographic locations of ancestral strains (24). The isolation with migration (IM) model and associated software uses likelihood-based inference to infer divergence time between evolutionary lineages (25). Approximate Bayesian computation (ABC) makes use of coalescent simulations and likelihood-free inference to contrast complex demographic scenarios. Each of these methods has proven useful in reconstructing the demography of pests and pathogens (24, 26–29).The objective of the present study was to reconcile the two competing hypotheses on the origin of P. infestans using Bayesian phylogenetics and ABC. We sampled key populations of P. infestans from central Mexico and the Andes and expanded on the analysis of Gómez-Alpizar et al. (5) by sequencing additional nuclear loci to assess support for the center of origin across multiple loci. To determine ancestral state, we added sequences from the sister taxa P. andina, P. mirabilis, P. ipomoeae, and Phytophthora phaseoli, all of which belong to Phytophthora clade 1c (30, 31). Finally, we aimed to reconcile the biology of P. infestans in Mexico with the findings of Gómez-Alpizar et al. (5) of ancestral variation in the Andes.     

An educational framework for triage nursing based on gatekeeping, timekeeping and decision-making processes

INTRODUCTION: The role of the triage nurse has emerged in response to growing community demand for a more accessible and efficient emergency department (ED) service. The focus of triage research has been on measuring outcomes and improving the delivery of emergency care. This has meant that the context of care, and triage processes and practices have remained concealed. Thus, little evidence about the role and ways to prepare nurses for this role is available. The aim of this study was to provide insight and understanding needed to educate and support the triage nursing role in Australian EDs. METHODS: A 12-month ethnographic study of triage nursing practice was conducted in Sydney metropolitan EDs. Data were then collected from participant observation in four EDs and interviews with 10 triage nurses. Analysis used standard content and thematic analysis techniques. FINDINGS: Findings reveal that notions of timeliness, efficiency and equity are embedded in a culture of ED care. This sustains a particular cadence of care to which triage nurses are culturally oriented. Triage nurses maintain, negotiate and restore this cadence of emergency care by using gatekeeping, timekeeping and decision-making processes. CONCLUSION: The comprehensive study of triage nursing has led to the development of an educational framework based on the processes of gatekeeping, timekeeping and decision-making.     

Retroviral transfer of donor MHC class I or MHC class II genes into recipient bone marrow cells can induce operational tolerance to alloantigens in vivo

Infusion of allogeneic, donor bone marrow (BM) can induce specific immunological unresponsiveness in vivo resulting in long-term acceptance of subsequent fully allogeneic, donor-type solid organ grafts, but this may be associated with graft-versus-host disease. We hypothesize that transfer of donor MHC gene(s) to recipient-type BM or hematopoietic stem cells would enable delivery of donor alloantigens to the recipient without the risk of graft-versus-host disease. This strategy could also potentially take advantage of linked suppression to induce specific unresponsiveness to additional alloantigens expressed by the solid organ graft. We found that infusion of 5 x 10(6) CBA (H-2(k)) recipient mouse BM cells transduced with a recombinant replication-defective retrovirus encoding either a single donor MHC class I or class II gene (H-2K(b) or H-2IA(b)) in combination with anti-CD4 monoclonal antibody resulted in long-term survival of C57BL/10 (H-2(b)) but not third-party NZW (H-2(z)) heart grafts. BM cells (3 x 10(3)) enriched for hematopoietic stem cells by sorting for c-Kit(+), lineage-negative cells, were able to induce long-term allograft survival in 50% of recipients after transduction with the vector encoding a single donor MHC class I gene. These results have important implications for future strategies to enhance clinical allograft survival by delivery of donor alloantigens.     

Postgastrostomy tube deformity on upper GI series

Three cases are presented in which a focal concave deformity occurred along the greater curvature of the stomach on upper gastrointestinal (GI) series. These patients all had recent removal of a surgically placed gastrostomy tube from a similar location. This deformity appears to be related, at least in part, to invaginated gastric mucosa intentionally produced during surgical gastrostomy tube placement. This association and appearance should be noted as it may mimic other lesions.     

Administration of rhIL-7 in humans increases in vivo TCR repertoire diversity by preferential expansion of naive T cell subsets

Interleukin-7 (IL-7) is a homeostatic cytokine for resting T cells with increasing serum and tissue levels during T cell depletion. In preclinical studies, IL-7 therapy exerts marked stimulating effects on T cell immune reconstitution in mice and primates. First-in-human clinical studies of recombinant human IL-7 (rhIL-7) provided the opportunity to investigate the effects of IL-7 therapy on lymphocytes in vivo. rhIL-7 induced in vivo T cell cycling, bcl-2 up-regulation, and a sustained increase in peripheral blood CD4(+) and CD8(+) T cells. This T cell expansion caused a significant broadening of circulating T cell receptor (TCR) repertoire diversity independent of the subjects' age as naive T cells, including recent thymic emigrants (RTEs), expanded preferentially, whereas the proportions of regulatory T (T reg) cells and senescent CD8(+) effectors diminished. The resulting composition of the circulating T cell pool more closely resembled that seen earlier in life. This profile, distinctive among cytokines under clinical development, suggests that rhIL-7 therapy could enhance and broaden immune responses, particularly in individuals with limited naive T cells and diminished TCR repertoire diversity, as occurs after physiological (age), pathological (human immunodeficiency virus), or iatrogenic (chemotherapy) lymphocyte depletion.