The earliest thymic T cell progenitors sustain B cell and myeloid lineage potential.

The stepwise commitment from hematopoietic stem cells in the bone marrow to T lymphocyte-restricted progenitors in the thymus represents a paradigm for understanding the requirement for distinct extrinsic cues during different stages of lineage restriction from multipotent to lineage-restricted progenitors. However, the commitment stage at which progenitors migrate from the bone marrow to the thymus remains unclear. Here we provide functional and molecular evidence at the single-cell level that the earliest progenitors in the neonatal thymus had combined granulocyte-monocyte, T lymphocyte and B lymphocyte lineage potential but not megakaryocyte-erythroid lineage potential. These potentials were identical to those of candidate thymus-seeding progenitors in the bone marrow, which were closely related at the molecular level. Our findings establish the distinct lineage-restriction stage at which the T cell lineage-commitment process transits from the bone marrow to the remote thymus.

A Prospective US National Trauma Center Study of Firearm Injury Survivors Weapon Carriage and Posttraumatic Stress Disorder Symptoms.

OBJECTIVE: To describe the demographic, injury-related, and mental health characteristics of firearm injury patients and trace firearm weapon carriage and PTSD symptoms over the year after injury. SUMMARY AND BACKGROUND DATA: Based on the increasing incidence of firearm injury and need for novel injury prevention strategies, hospital-based violence intervention programs are being implemented in US trauma centers. There is limited data on the long-term outcomes and risk behaviors of firearm injury survivors to guide this work. METHODS: We conducted a secondary analysis of a pragmatic 25-trauma center randomized trial (N = 635). Baseline characteristics of firearm-injured patients (N = 128) were compared with other trauma patients. Mixed model regression was used to identify risk factors for postinjury firearm weapon carriage and PTSD symptoms. RESULTS: Firearm injury patients were younger and more likely to be black, male and of lower socioeconomic status, and more likely to carry a firearm in the year before injury. Relative to preinjury, there was a significant drop in firearm weapon carriage at 3- and 6-months postinjury, followed by a return to preinjury levels at 12-months. Firearm injury was significantly and independently associated with an increased risk of postinjury firearm weapon carriage [relative risk = 2.08, 95% confidence interval (1.34, 3.22), P < 0.01] and higher PTSD symptom levels [Beta = 3.82, 95% confidence interval (1.29, 6.35), P < 0.01]. CONCLUSIONS: Firearm injury survivors are at risk for firearm carriage and high PTSD symptom levels postinjury. The significant decrease in the high-risk behavior of firearm weapon carriage at 3-6 months postinjury suggests that there is an important postinjury "teachable moment" that should be targeted with preventive interventions. TRIAL REGISTRATION: ClinicalTrials.gov NCT02655354.

Catalyzing the Translation of Patient-Centered Research Into United States Trauma Care Systems: A Case Example.

BACKGROUND: The expedient translation of research findings into sustainable intervention procedures is a longstanding health care system priority. The Patient-Centered Outcomes Research Institute (PCORI) has facilitated the development of "research done differently," with a central tenet that key stakeholders can be productively engaged throughout the research process. Literature review revealed few examples of whether, as originally posited, PCORI's innovative stakeholder-driven approach could catalyze the expedient translation of research results into practice. OBJECTIVES: This narrative review traces the historical development of an American College of Surgeons Committee on Trauma (ACS/COT) policy guidance, facilitated by evidence supplied by the PCORI-funded studies evaluating the delivery of patient-centered care transitions. Key elements catalyzing the guidance are reviewed, including the sustained engagement of ACS/COT policy stakeholders who have the capacity to invoke system-level implementation strategies, such as regulatory mandates linked to verification site visits. Other key elements, including the encouragement of patient stakeholder voice in policy decisions and the incorporation of end-of-study policy summits in pragmatic comparative effectiveness trial design, are discussed. CONCLUSIONS: Informed by comparative effectiveness trials, ACS/COT policy has expedited introduction of the patient-centered care construct into US trauma care systems. A comparative health care systems conceptual framework for transitional care which incorporates Research Lifecycle, pragmatic clinical trial and implementation science models is articulated. When combined with Rapid Assessment Procedure Informed Clinical Ethnography (RAPICE), employed as a targeted implementation strategy, this approach may accelerate the sustainable delivery of high-quality patient-centered care transitions for US trauma care systems.

Tick trails: the role of online recreational trail reviews in identifying risk factors and behavioral recommendations associated with tick encounters in Indiana.

BACKGROUND: Recreational trails abound across the United States and represent high risk areas for tick exposure. Although online reviews represent a rich source of user information, they have rarely been used in determining the risk of tick exposure during recreational trail use. Based on online user reviews and comments, the purpose of this study was to determine risk factors and behavioral recommendations associated with tick encounters (Tick Presence) on recreational trails in the state of Indiana, U.S. METHODS: We reviewed 26,016 user comments left on AllTrails.com for 697 Indiana trails. Reviews were evaluated to determine Tick Presence/Absence, the total number of Tick Presence Reviews per trail, and multiple trail and user behavioral characteristics. We used hot spot (Getis-Ord Gi*) analysis to test the hypothesis of whether there are clusters in the number of Tick Presence Reviews. Pearson chi-square tests of independence evaluated whether tick presence was associated with several trail characteristics. Finally, negative binomial regression evaluated the strength of the association between the number of Tick Presence Reviews and several trail characteristics. RESULTS: Tick Presence was recorded at 10% (n = 65) of trails and occurred most frequently in May. Hot spot analysis revealed statistically significant clusters of Tick Presence Reviews on trails in the Southern Indiana State Region. Results of χ2 tests indicated significant associations between Tick Presence Reviews and (a) State Region and (b) Land Management Type; Mann-Whitney U tests detected significant differences in Tick Presence Reviews based on Trail Length and Elevation Gain. Subsequent results of a negative binomial regression model indicated that Southern Indiana State Region, Federal and Private Land Management Type, and Elevation Gain were factors significantly associated with Tick Presence Reviews. Content of user reviews indicated several behaviors employed to prevent tick encounters, particularly Repellent Application and Recreational Deterrence; 25% included a behavior Recommendation to others. CONCLUSIONS: Online, user-generated trail reviews have the potential to serve as rich data sources for identifying recreational trails, where 1) the risk of tick exposure is great, 2) more robust active tick and tick-borne pathogen surveillance may be warranted, and 3) tailored prevention interventions are needed.

Relationship Between Tick Activity, Tick-Borne Diseases, Cognitive and Affective Risk Assessment in Peri-domestic Areas.

Peri-domestic areas constitute an important source of tick exposure and tick-borne diseases (TBD). Nonetheless, the association between distal TBD risk factors (i.e. cognitive-/affective-risk perceptions, knowledge of the effectiveness of personal protective behaviors) and proximal TBD risk (i.e. tick activity and TBD diagnosis), among adult residents of private residential properties (PRP) is unknown. Data was collected from 299 PRP in south and central Indiana. We used Mann-Whitney U and Kruskal-Wallis non-parametric tests to identify differences in proximal and distal outcome measures. We found evidence of 'tick activity' at thirty-nine percent of PRP (n = 116). Thirteen-percent of respondents (n = 40) self-reported a TBD diagnosis within their household. We found no significant association between 'self-reported TBD diagnosis within a household' and 'tick activity in the peri-domestic area.' Mean scores on 'affective tick & TBD risk assessment' were significantly higher among respondents when 'tick activity' was present in the peri-domestic area (median = 2, M = 2.54, p < 0.001). Similarly, respondents who 'self-reported TBD diagnosis within their household' had significantly higher mean scores on 'affective tick & TBD risk assessment' (median = 3, M = 3.30) than those who did not (median = 1, M = 1.93), (U = 2750, p < 0.001). The proportion of peri-domestic areas with 'tick activity' was significantly higher if the primary respondent was male or an older adult respectively, compared to females and younger adults. Occupational/recreation-based settings may be more important pathways of tick exposure than peri-domestic settings in Indiana. Beyond education, it is important to consider the feelings and emotions that are elicited when at-risk populations consider their peri-domestic tick exposure and TBD risk, and where necessary design interventions to address those affective assessments.

Improved outcome in patients following autologous stem cell transplantation for multiple myeloma in south eastern Norway 2001-2010: a retrospective, population based analysis.

BACKGROUND: With the advent of novel drugs improved overall survival in patients with multiple myeloma, including patients who received up-front autologous stem cell transplantation (ASCT), has been reported from several centers. Here we report on overall survival in a population-based cohort of patients receiving ASCT as first line treatment and in whom novel agents were an option for second and later lines of treatment. METHODS: Patients with multiple myeloma ≤ 65 years of age who were considered for ASCT from 01.01.2001-31.06.2005 (period 1) and from 01.07.2005 until 31.12.2009 (period 2) at Oslo University Hospital (OUH) were identified. Relevant data were collected from the patients' medical records. RESULTS: Altogether, 293/355 patients received ASCT. In all, median OS was 82.9 months in patients ≤ 60 years of age and 59.0 months in patients 61-65 years. For patients ≤ 60 years of age median OS increased from 70.6 months to 87.7 months (p = 0. 22) and median survival after start of second line therapy increased from 34.5 months to 46.5 months (p = 0.015) between the two periods. For patients 61-65 years of age median OS increased from 57.3 months to 61.2 months (p = 0. 87) and median survival after start of second line therapy was practically unchanged (32.6 months vs. 33.1 months (p = 0.97) between the periods. In patients ≤ 60 years of age salvage ASCT was used in 34% of the patients while in patients 61-65 years of age salvage ASCT was used in 7.3% of the patients. The use of salvage ASCT and novel drugs, as well as the number of treatment lines, were higher in patients ≤ 60 years of age and increased during the study period. CONCLUSION: In patients ≤ 60 years of age an increased median OS of 17 months between the two periods were noted, but the difference failed to reach statistical significance. However, a statistically significant difference in median survival of 12 months after start of second line therapy was found in this age group, which may be explained by a more active second line treatment. In patients 61-65 years only a slight increase of survival, not statistically significant, was noted between the periods.

Genetic variegation of clonal architecture and propagating cells in leukaemia.

Little is known of the genetic architecture of cancer at the subclonal and single-cell level or in the cells responsible for cancer clone maintenance and propagation. Here we have examined this issue in childhood acute lymphoblastic leukaemia in which the ETV6-RUNX1 gene fusion is an early or initiating genetic lesion followed by a modest number of recurrent or 'driver' copy number alterations. By multiplexing fluorescence in situ hybridization probes for these mutations, up to eight genetic abnormalities can be detected in single cells, a genetic signature of subclones identified and a composite picture of subclonal architecture and putative ancestral trees assembled. Subclones in acute lymphoblastic leukaemia have variegated genetics and complex, nonlinear or branching evolutionary histories. Copy number alterations are independently and reiteratively acquired in subclones of individual patients, and in no preferential order. Clonal architecture is dynamic and is subject to change in the lead-up to a diagnosis and in relapse. Leukaemia propagating cells, assayed by serial transplantation in NOD/SCID IL2Rγ(null) mice, are also genetically variegated, mirroring subclonal patterns, and vary in competitive regenerative capacity in vivo. These data have implications for cancer genomics and for the targeted therapy of cancer.

FLT3 mutations confer enhanced proliferation and survival properties to multipotent progenitors in a murine model of chronic myelomonocytic leukemia.

Despite their known transforming properties, the effects of leukemogenic FLT3-ITD mutations on hematopoietic stem and multipotent progenitor cells and on hematopoietic differentiation are not well understood. We report a mouse model harboring an ITD in the murine Flt3 locus that develops myeloproliferative disease resembling CMML and further identified FLT3-ITD mutations in a subset of human CMML. These findings correlated with an increase in number, cell cycling, and survival of multipotent stem and progenitor cells in an ITD dose-dependent manner in animals that exhibited alterations within their myeloid progenitor compartments and a block in normal B cell development. This model provides insights into the consequences of constitutive signaling by an oncogenic tyrosine kinase on hematopoietic progenitor quiescence, function, and cell fate.

Spatio-temporal patterns of tick-borne disease diagnoses in Indiana, USA (2009-2018).

AIMS: Although tick-borne disease (TBD) incidence has increased in the United States (U.S.) in the past decade, new evidence suggests that notifiable diseases surveillance records may not accurately reflect the true magnitude of TBD diagnoses. Furthermore, while regional electronic health records (EHR) are readily accessible their potential use as a more stable and consistent source of TBD diagnoses data has remained largely unexplored. METHODS AND RESULTS: In this study, we used EHR from a database of more than 100 hospitals, healthcare networks, and insurance providers in Indiana, U.S., to better understand incidence, spatio-temporal and demographic distribution of TBD Diagnoses from 2009-2018. Our results revealed that in Indiana, from 2009 to 2018, there were 5173 unique TBD Diagnoses across three diagnoses categories: Lyme disease (72.5%, n = 3751), Rickettsioses (12.0%, n = 623) and Other TBD Diagnoses (15.4%, n = 799). Using EHR, the average yearly Lyme disease diagnoses was more than double the cases obtained using notifiable disease surveillance data for the same period. Patients with a TBD Diagnoses were generally older (ages 45-59) and less racially diverse (96.3% white). Rickettsiosis diagnoses were reported more among male patients (55.2%), while Lyme disease diagnoses were higher among female patients (57.1%). Temporal data illustrated higher frequencies of diagnoses from May to July. Hot spot analysis identified a Lyme disease hot spot in northwest Indiana, while hotspots of Rickettsiosis and Other TBD Diagnoses category were identified in southwest Indiana. Extrapolated to the Indiana population, chi-squared (χ2) tests of independence revealed that the observed distribution of TBD diagnoses in our data was significantly different from the expected distribution in the Indiana population-based race, gender and age groups. CONCLUSIONS: Our study findings demonstrate that in Indiana, EHR provide a stable data source for elucidating TBD disease burden and for monitoring spatio-temporal trends in TBD diagnoses.

Tumor Grade and Mitotic Count Are Prognostic for Dogs with Cutaneous Mast Cell Tumors Treated with Surgery and Adjuvant or Neoadjuvant Vinblastine Chemotherapy.

OBJECTIVE: Canine cutaneous mast cell tumors (cMCTs) have variable rates of recurrence and metastasis. We evaluated how various prognostic factors affect survival, recurrence, and metastasis in dogs with cMCT who underwent surgery and vinblastine chemotherapy. ANIMALS: 90 dogs with cMCT treated with surgery and vinblastine at a veterinary referral institution were included. METHODS: Medical records were retrospectively reviewed. Prognostic factors were evaluated. RESULTS: Most dogs (94%) had grade 2 or 3 cMCTs. Neoadjuvant vinblastine was used in 18 dogs, and none progressed locally before surgery. The use of neoadjuvant vinblastine was associated with a higher chance of local recurrence (p = 0.03) but not survival. Shorter survival times were found for tumors that were high-grade (p < 0.001), grade 3 (p < 0.001), or a MC of >5 (p < 0.001). Dogs with grade 2 tumors that were low-grade lived longer than those with high-grade tumors (p < 0.001). Histologic tumor-free margins and the ability to achieve local tumor control were not associated with outcome. CLINICAL RELEVANCE: Both grading systems and MC were prognostic for survival in this population of dogs, supporting the need for the standard reporting of histopathologic findings. Neoadjuvant chemotherapy can be effective in downsizing cMCTs but does not influence survival. These findings are consistent with previous publications, showing the benefits of a more modern population of patients, surgical treatments, and histopathologic assessments.

Persistent malignant stem cells in del(5q) myelodysplasia in remission.

BACKGROUND: The in vivo clinical significance of malignant stem cells remains unclear. METHODS: Patients who have the 5q deletion (del[5q]) myelodysplastic syndrome (interstitial deletions involving the long arm of chromosome 5) have complete clinical and cytogenetic remissions in response to lenalidomide treatment, but they often have relapse. To determine whether the persistence of rare but distinct malignant stem cells accounts for such relapses, we examined bone marrow specimens obtained from seven patients with the del(5q) myelodysplastic syndrome who became transfusion-independent while receiving lenalidomide treatment and entered cytogenetic remission. RESULTS: Virtually all CD34+, CD38+ progenitor cells and stem cells that were positive for CD34 and CD90, with undetectable or low CD38 (CD38−/low), had the 5q deletion before treatment. Although lenalidomide efficiently reduced these progenitors in patients in complete remission, a larger fraction of the minor, quiescent, CD34+,CD38-/low, CD90+ del(5q) stem cells as well as functionally defined del(5q) stem cells remained distinctly resistant to lenalidomide. Over time, lenalidomide resistance developed in most of the patients in partial and complete remission, with recurrence or expansion of the del(5q) clone and clinical and cytogenetic progression. CONCLUSIONS: In these patients with the del(5q) myelodysplastic syndrome, we identified rare and phenotypically distinct del(5q) myelodysplastic syndrome stem cells that were also selectively resistant to therapeutic targeting at the time of complete clinical and cytogenetic remission. (Funded by the EuroCancerStemCell Consortium and others.)

Clonal origins of relapse in ETV6-RUNX1 acute lymphoblastic leukemia.

B-cell precursor childhood acute lymphoblastic leukemia with ETV6-RUNX1 (TEL-AML1) fusion has an overall good prognosis, but relapses occur, usually after cessation of treatment and occasionally many years later. We have investigated the clonal origins of relapse by comparing the profiles of genomewide copy number alterations at presentation in 21 patients with those in matched relapse (12-119 months). We identified, in total, 159 copy number alterations at presentation and 231 at relapse (excluding Ig/TCR). Deletions of CDKN2A/B or CCNC (6q16.2-3) or both increased from 38% at presentation to 76% in relapse, suggesting that cell-cycle deregulation contributed to emergence of relapse. A novel observation was recurrent gain of chromosome 16 (2 patients at presentation, 4 at relapse) and deletion of plasmocytoma variant translocation 1 in 3 patients. The data indicate that, irrespective of time to relapse, the relapse clone was derived from either a major or minor clone at presentation. Backtracking analysis by FISH identified a minor subclone at diagnosis whose genotype matched that observed in relapse ∼ 10 years later. These data indicate subclonal diversity at diagnosis, providing a variable basis for intraclonal origins of relapse and extended periods (years) of dormancy, possibly by quiescence, for stem cells in ETV6-RUNX1(+) acute lymphoblastic leukemia.

Distinct patterns of hematopoietic stem cell involvement in acute lymphoblastic leukemia.

The cellular targets of primary mutations and malignant transformation remain elusive in most cancers. Here, we show that clinically and genetically different subtypes of acute lymphoblastic leukemia (ALL) originate and transform at distinct stages of hematopoietic development. Primary ETV6-RUNX1 (also known as TEL-AML1) fusions and subsequent leukemic transformations were targeted to committed B-cell progenitors. Major breakpoint BCR-ABL1 fusions (encoding P210 BCR-ABL1) originated in hematopoietic stem cells (HSCs), whereas minor BCR-ABL1 fusions (encoding P190 BCR-ABL1) had a B-cell progenitor origin, suggesting that P190 and P210 BCR-ABL1 ALLs represent largely distinct tumor biological and clinical entities. The transformed leukemia-initiating stem cells in both P190 and P210 BCR-ABL1 ALLs had, as in ETV6-RUNX1 ALLs, a committed B progenitor phenotype. In all patients, normal and leukemic repopulating stem cells could successfully be separated prospectively, and notably, the size of the normal HSC compartment in ETV6-RUNX1 and P190 BCR-ABL1 ALLs was found to be unaffected by the expansive leukemic stem cell population.

Loss of C/EBP alpha cell cycle control increases myeloid progenitor proliferation and transforms the neutrophil granulocyte lineage.

CCAAT/enhancer binding protein (C/EBP)alpha is a myeloid-specific transcription factor that couples lineage commitment to terminal differentiation and cell cycle arrest, and is found mutated in 9% of patients who have acute myeloid leukemia (AML). We previously showed that mutations which dissociate the ability of C/EBP alpha to block cell cycle progression through E2F inhibition from its function as a transcriptional activator impair the in vivo development of the neutrophil granulocyte and adipose lineages. We now show that such mutations increase the capacity of bone marrow (BM) myeloid progenitors to proliferate, and predispose mice to a granulocytic myeloproliferative disorder and transformation of the myeloid compartment of the BM. Both of these phenotypes were transplantable into lethally irradiated recipients. BM transformation was characterized by a block in granulocyte differentiation, accumulation of myeloblasts and promyelocytes, and expansion of myeloid progenitor populations--all characteristics of AML. Circulating myeloblasts and hepatic leukocyte infiltration were observed, but thrombocytopenia, anemia, and elevated leukocyte count--normally associated with AML-were absent. These results show that disrupting the cell cycle regulatory function of C/EBP alpha is sufficient to initiate AML-like transformation of the granulocytic lineage, but only partially the peripheral pathology of AML.

Specific JAK2 mutation (JAK2R683) and multiple gene deletions in Down syndrome acute lymphoblastic leukemia.

Children with Down syndrome (DS) have a greatly increased risk of acute megakaryoblastic leukemia (AMKL) and acute lymphoblastic leukemia (ALL). Both DS-AMKL and the related transient myeloproliferative disorder (TMD) have GATA1 mutations as obligatory, early events. To identify mutations contributing to leukemogenesis in DS-ALL, we undertook sequencing of candidate genes, including FLT3, RAS, PTPN11, BRAF, and JAK2. Sequencing of the JAK2 pseudokinase domain identified a specific, acquired mutation, JAK2R683, in 12 (28%) of 42 DS-ALL cases. Functional studies of the common JAK2R683G mutation in murine Ba/F3 cells showed growth factor independence and constitutive activation of the JAK/STAT signaling pathway. High-resolution SNP array analysis of 9 DS-ALL cases identified additional submicroscopic deletions in key genes, including ETV6, CDKN2A, and PAX5. These results infer a complex molecular pathogenesis for DS-ALL leukemogenesis, with trisomy 21 as an initiating or first hit and with chromosome aneuploidy, gene deletions, and activating JAK2 mutations as complementary genetic events.

Using i-tree canopy vegetation cover subtype classification to predict peri-domestic tick presence.

While extant literature has generally indicated significant associations between vegetation cover and tick activity, no study has demonstrated the relative association between peri-domestic area vegetation cover subtypes and tick presence. In this study, we seek to determine whether neighborhood wood index and residential tick control practices confound or modify the effect of peri-domestic vegetation cover subtypes on tick presence. We conducted an ecological inventory of vegetation cover distribution using i-Tree Canopy on 210 private residential/peri-domestic properties in Indiana, USA. Results were paired with field obtained tick presence/absence data for each property together with online survey data provided by primary occupant of the property. Amblyomma americanum was the predominant tick species in peri-domestic areas. Higher proportion of vegetation cover in the peri-domestic area was significantly associated with tick presence. Of the four vegetation cover subtypes, (grass, shrubs, understory, and canopy), canopy was the most prevalent vegetation in peri-domestic areas of Indiana, USA. It was also the most significant predictor of tick presence. Among residential tick control processes, frequent leaf litter removal was significantly associated with reduced likelihood of peri-domestic tick presence. Neighborhood Wood Index (NWI) confounded the relationship between canopy and peri-domestic tick presence, while leaf-litter removal confounded the effect of understory vegetation subtype on peri-domestic tick presence. Compared to peri-domestic areas in neighborhoods with sparse NWI, those in neighborhoods with heavy/dense NWI had a 3.5x odd of peri-domestic tick presence (AOR = 3.46; 95 % CI: 1.23-9.65). Compared to peri-domestic areas in the central region, those in the southern region of Indiana were 8.7x more likely to have peri-domestic tick presence. Canopy as a vegetation cover subtype and frequent leaf litter removal represent particularly key peri-domestic variables that have significant implications for peri-domestic tick presence. Beyond parcel-scale landscape features, neighborhood wood index also plays an important role in peri-domestic tick presence. Additionally, i-Tree Canopy represents a promising methodological tool for identifying landscape features that predict tick presence.

The Role of Permission, Supervision, and Precipitating Events in Childhood Pool/Spa Submersion Incidents, United States, 2000-2017.

Drowning is a leading cause of fatality among children in the United States, and pool/spa aquatic structures represent common locations of submersion incidents. This study employed narrative case review to understand characteristics related to permission, supervision, and precipitating events in childhood submersion incidents. Retroactive analysis of 1537 fatal and non-fatal submersion incidents among children age 13 years old and younger was conducted using the U.S. Consumer Products Safety Commission In-Depth Investigations dataset from 2000-2017. Narrative descriptions were coded according to the themes of permission, supervision, and precipitating events. In most (86%) incidents, the child did not have permitted water access, and 80% of narratives indicated the child was alone at time of incident. These attributes were significantly associated with a fatal outcome (No permission: OR 11.98, 95% CI 7.97-18.06; Alone: OR 34.93, 95% CI 19.69-61.96). The average length of inactive supervision time was 15.6 min; this duration significantly differed by non-fatal (3.2 min) and fatal (16.1 min) outcomes (p < 0.001). More than half of cases occurred under the supervision type of a parent (56%), followed by grandparents (14%) and childcare provider (10%). Submersion incidents with a non-parent supervisor were two times more likely to result in a fatal outcome (OR 1.87, 95% CI 1.07-3.64). The most frequently occurring precipitating events included outdoor play (46%), a social gathering (36%), and previous water play (15%). Narrative excerpts further illustrate how tragic submersion events can unfold quickly and unpredictably. Education campaigns should target all adults that supervise children and reiterate key findings in that many submersion incidents occur (1) without permitted pool use, (2) without active supervision, and (3) when a caregiver is distracted. Multiple strategies should be utilized to add layers of projection against submersion injury.

Preventing tick-bites among children in Indiana, USA: An analysis of factors associated with parental protective behaviors.

Despite evidence to the effect that there is low parental adoption of tick-bite personal protective behavior (PPB) for their children - a population at high risk for tick exposure, very limited information is available on factors associated with parental adoption of PPB. The objective of this study was to identify the most significant factors associated with parental adoption of tick-bite PPB on behalf of a child or children at risk of tick encounters. A cross-section of parents in Indiana, USA whose child had spent time outdoors in tick habitat during the summer were recruited from representative online panels maintained by Qualtrics. Binary logistic regression was used to model determinants of five tick-bite PPBs. Our results revealed that the application of tick repellent (89 %, n = 718) followed by conducting a tick check of the child's body soon after returning from the outdoors (84 %, n = 676) were the PPBs most frequently adopted by parents. Conversely, tucking one's shirt into pants and pants into socks was the least frequently adopted PPB (48 %, n = 386). Compared to other factors evaluated in logistic regression models, parents who reported implementing one or more residential tick control practices were significantly more likely to adopt nearly all five tick-bite PPBs for their children. Additionally, parents who were more worried about their health due to ticks and reported being more likely to avoid the outdoors because of ticks were more likely to adopt at least three PPBs on behalf of their children. To ensure children can most safely engage in outdoor activity, identifying the factors associated with parental adoption of tick-bite preventive behaviors represents an important mechanism in the prevention of tick-borne diseases.

B-lineage commitment prior to surface expression of B220 and CD19 on hematopoietic progenitor cells.

Commitment of hematopoietic progenitor cells to B-lymphoid cell fate has been suggested to coincide with the development of PAX5-expressing B220(+)CD19(+) pro-B cells. We have used a transgenic reporter mouse, expressing human CD25 under the control of the B-lineage-restricted Igll1 (lambda5) promoter to investigate the lineage potential of early progenitor cells in the bone marrow. This strategy allowed us to identify a reporter expressing LIN(-)B220(-)CD19(-)CD127(+)FLT3(+)SCA1(low)KIT(low) population that displays a lack of myeloid and a 90% reduction in in vitro T-cell potential compared with its reporter-negative counterpart. Gene expression analysis demonstrated that these lineage-restricted cells express B-lineage-associated genes to levels comparable with that observed in pro-B cells. These data suggest that B-lineage commitment can occur before the expression of B220 and CD19.