Natural airway as an alternative to intubation for pediatric endoscopic esophageal foreign body removal: A retrospective cohort study of 326 patients.

BACKGROUND: Anesthesia is required for endoscopic removal of esophageal foreign bodies (EFBs) in children. Historically, endotracheal intubation has been the de facto gold standard for airway management in these cases. However, as more elective endoscopic procedures are now performed under propofol sedation with natural airway, there has been a move toward using similar Monitored Anesthesia Care (MAC) for select patients who require endoscopic removal of an EFB. METHODS: In this single-center retrospective cohort study, we compared endoscopic EFB removal with either MAC or endotracheal intubation. Descriptive statistics summarized factors stratified by initial choice of airway technique, including intra- and postanesthesia complications and the frequency of mid-procedure conversion to endotracheal intubation in those initially managed with MAC. To demonstrate the magnitude of associations between these factors and the anesthesiologist's choice of airway technique, univariable Firth logistic and quantile regressions were used to estimate odds ratios (95% CI) and beta coefficients (95% CI). RESULTS: From the initial search, 326 patients were identified. Among them, 23% (n = 75) were planned for intubation and 77% (n = 251) were planned for MAC. Three patients (0.9%) who were initially planned for MAC required conversion to endotracheal intubation after induction. Two (0.6%) of these children were admitted to the hospital after the procedure and treated for ongoing airway reactivity. No patient experienced reflux of gastric contents to the mouth or dislodgement of the foreign body to the airway, and no patient required administration of vasoactive medications or cardiopulmonary resuscitation. Patients had higher odds that the anesthesiologist chose to utilize MAC if the foreign body was a coin (OR, 3.3; CI, 1.9-5.7, p < .001) or if their fasting time was >6 h. Median total operating time was 15 min greater in intubated patients (11 vs. 26 min, p < .001). CONCLUSIONS: This study demonstrates that MAC may be considered for select pediatric patients undergoing endoscopic removal of EFB, especially those who have ingested coins, who do not have reactive airways, who have fasted for >6 h, and in whom the endoscopic procedure is expected to be short and uncomplicated. Prospective multi-site studies are needed to confirm these findings.

Tumor lysis syndrome in premature infant prompting early resection of a large sacrococcygeal teratoma: a case report.

BACKGROUND: Sacrococcygeal teratomas (SCTs) are the most common congenital neoplasm and often require resection soon after birth. There are rare reports of cardiac arrest during surgery due to manipulation of the tumor triggering secondary necrosis and hyperkalemia. CASE PRESENTATION: This case describes a very preterm infant with a SCT who develops spontaneous preoperative tumor lysis syndrome (TLS). The medical team utilized rasburicase and the patient underwent total gross resection at 40 h of life. CONCLUSIONS: We emphasize the importance of the early recognition and management of tumor lysis syndrome in SCT with rasburicase, aggressive management of hyperkalemia and consideration of early resection of SCTs even in the case of a very premature infant.

Activated stromal cells transfer mitochondria to rescue acute lymphoblastic leukemia cells from oxidative stress.

We investigated and modeled the mesenchymal stromal cell (MSC) niche in adult acute lymphoblastic leukemia (ALL). We used gene expression profiling, cytokine/chemokine quantification, flow cytometry, and a variety of imaging techniques to show that MSCs, directly isolated from the primary bone marrow specimens of patients with ALL, frequently adopted an activated, cancer-associated fibroblast phenotype. Normal, primary human MSCs and the MSC cell line HS27a both were activated de novo, when exposed to the reactive oxygen species (ROS)-inducing chemotherapy agents cytarabine (AraC) and daunorubicin (DNR), a phenomenon blocked by the antioxidant N-acetyl cysteine. Chemotherapy-activated HS27a cells were functionally evaluated in a coculture model with ALL targets. Activated MSCs prevented therapy-induced apoptosis and death in ALL targets, via mitochondrial transfer through tunneling nanotubes (TNTs). Reduction of mitochondrial transfer by selective mitochondrial depletion or interference with TNT formation by microtubule inhibitors, such as vincristine (VCR), prevented the "rescue" function of activated MSCs. Corticosteroids, also a mainstay of ALL therapy, prevented the activation of MSCs. We also demonstrated that AraC (but not VCR) induced activation of MSCs, mitochondrial transfer, and mitochondrial mass increase in a murine NSG model of disseminated SEM cell-derived ALL, wherein CD19+ cells closely associated with nestin+ MSCs after AraC, but not in the other conditions. Our data propose a readily clinically exploitable mechanism for improving treatment of ALL, in which traditional ROS-inducing chemotherapies are often ineffective at eradicating residual disease, despite efficiently killing the bulk population.

Type 1 Interferon Responses Underlie Tumor-Selective Replication of Oncolytic Measles Virus.

The mechanism of tumor-selective replication of oncolytic measles virus (MV) is poorly understood. Using a stepwise model of cellular transformation, in which oncogenic hits were additively expressed in human bone marrow-derived mesenchymal stromal cells, we show that MV-induced oncolysis increased progressively with transformation. The type 1 interferon (IFN) response to MV infection was significantly reduced and delayed, in accordance with the level of transformation. Consistently, we observed delayed and reduced signal transducer and activator of transcription (STAT1) phosphorylation in the fully transformed cells. Pre-treatment with IFNß restored resistance to MV-mediated oncolysis. Gene expression profiling to identify the genetic correlates of susceptibility to MV oncolysis revealed a dampened basal level of immune-related genes in the fully transformed cells compared to their normal counterparts. IFN-induced transmembrane protein 1 (IFITM1) was the foremost basally downregulated immune gene. Stable IFITM1 overexpression in MV-susceptible cells resulted in a 50% increase in cell viability and a significant reduction in viral replication at 24 h after MV infection. Overall, our data indicate that the basal reduction in functions of the type 1 IFN pathway is a major contributor to the oncolytic selectivity of MV. In particular, we have identified IFITM1 as a restriction factor for oncolytic MV, acting at early stages of infection.

Long-term Impact of Pneumococcal Conjugate Vaccines on Invasive Disease and Pneumonia Hospitalizations in Indigenous and Non-Indigenous Australians.

BACKGROUND: Universal pneumococcal conjugate vaccine (PCV) programs began in Indigenous Australian children in 2001 and all children in 2005, changing to 13-valent PCV (PCV13) in 2011. We used laboratory data for invasive pneumococcal disease (IPD) and coded hospitalizations for noninvasive pneumococcal community-acquired pneumonia (PnCAP) to evaluate long-term impact. METHODS: Annual incidence (per 100 000 population) was calculated for age-specific total IPD, PCV13 non-7-valent PCV (PCV7) serotypes, and PnCAP by Indigenous status. Incidence in the pre-universal PCV7 (2002-2004), early PCV7 (2005-2007), pre-PCV13 (2008 to mid-2011), and post-PCV13 (mid-2011 to 2016) periods was used to calculate incidence rate ratios (IRRs). RESULTS: In the total population, all-age incidence of IPD declined from 11.8 pre-PCV7 to 7.1 post-PCV13 (IRR, 0.61 [95% confidence interval {CI}, .59-.63]) but for PnCAP declined among ages <1 year (IRR, 0.34 [95% CI, .25-.45]) and 1-4 years (IRR, 0.50 [95% CI, .43-.57]) but increased significantly among age ≥5 years (IRRs, 1.08-1.14). In Indigenous people, baseline PCV13 non-PCV7 IPD incidence was 3-fold higher, amplified by a serotype 1 epidemic in 2011. By 2015-2016, although incidence of IPD and PnCAP in children aged <5 years decreased by 38%, neither decreased in people aged ≥5 years. CONCLUSIONS: Fifteen years post-PCV and 5 years post-PCV13, direct and indirect impact on IPD and PnCAP differed by age and between Indigenous and non-Indigenous people, with potential implications for long-term PCV impact in comparable settings.Fifteen years after pneumococcal conjugate vaccine (PCV) introduction and 5 years post-PCV13, direct and indirect impact on invasive pneumococcal disease and pneumococcal community-acquired pneumonia differed by age and between Indigenous and non-Indigenous people, with potential implications for long-term PCV impact in comparable settings.

Immunostimulatory effect of chitosan conjugated green copper oxide nanoparticles in tumor immunotherapy.

Current study demonstrates the immunogenic role of biopolymer coated green synthesized copper oxide nanoparticles by the induction of cellular immunity through the activation immune cells. Alongside humoral immunity response was triggered by the surface coated NPs through IgG response which indicate the adjuvanic role of the nano conjugate. Th1 (Type 1 and Type 2 helper T cells) and Th2 cells were activated after the treatment with nano conjugate and act as an immunostimulant which would inhibit the proliferation of breast cancer (MCF-7) and cervical cancer (HeLa) cells in in vitro. Solid tumor induced by 4 T1 cells were also inhibited in in vivo Balb/C mice model. Secretion of pro-inflammatory cytokines and the increase in CD + 4 populations indicate the activation of immune cells in the current study. Immunotherapy by the help of metal nano conjugate can be an effective tool to eradicate the cancer cells from the system.

Limited Role of Bots in Spreading Vaccine-Critical Information Among Active Twitter Users in the United States: 2017-2019.

Objectives. To examine the role that bots play in spreading vaccine information on Twitter by measuring exposure and engagement among active users from the United States.Methods. We sampled 53 188 US Twitter users and examined who they follow and retweet across 21 million vaccine-related tweets (January 12, 2017-December 3, 2019). Our analyses compared bots to human-operated accounts and vaccine-critical tweets to other vaccine-related tweets.Results. The median number of potential exposures to vaccine-related tweets per user was 757 (interquartile range [IQR] = 168-4435), of which 27 (IQR = 6-169) were vaccine critical, and 0 (IQR = 0-12) originated from bots. We found that 36.7% of users retweeted vaccine-related content, 4.5% retweeted vaccine-critical content, and 2.1% retweeted vaccine content from bots. Compared with other users, the 5.8% for whom vaccine-critical tweets made up most exposures more often retweeted vaccine content (62.9%; odds ratio [OR] = 2.9; 95% confidence interval [CI] = 2.7, 3.1), vaccine-critical content (35.0%; OR = 19.0; 95% CI = 17.3, 20.9), and bots (8.8%; OR = 5.4; 95% CI = 4.7, 6.3).Conclusions. A small proportion of vaccine-critical information that reaches active US Twitter users comes from bots.

"No jab, no pay": catch-up vaccination activity during its first two years.

OBJECTIVES: To assess catch-up vaccination of older children and adolescents during the first two years of the "No jab, no pay" policy linking eligibility for federal family assistance payments with childhood vaccination status. DESIGN, SETTING, PARTICIPANTS: Cross-sectional analysis of Australian Immunisation Register data on catch-up vaccination of children aged 5 to less than 7 years before (January 2013 - December 2014; baseline) and during the first two years of "No jab, no pay" (December 2015 - December 2017), and of children aged 7 to less than 10 years and young people aged 10 to less than 20 years ("No jab, no pay" period only). MAIN OUTCOMES: Catch-up vaccination rates for measles-mumps-rubella vaccine second dose (MMR2), by age group, Indigenous status, and socio-economic status; catch-up vaccination of children aged 5 to less than 7 years (third dose of diphtheria-tetanus-pertussis vaccine [DTPa3], MMR1), before and after introduction of "No jab, no pay". RESULTS: The proportion of incompletely vaccinated children aged 5 to less than 7 years who received catch-up DTPa3 was higher under "No jab, no pay" than during the baseline period (15.5% v 9.4%). Of 407 332 incompletely vaccinated people aged 10 to less than 20 years, 71 502 (17.6%) received catch-up MMR2 during the first two years of "No jab, no pay", increasing overall coverage for this age group from 86.6% to 89.0%. MMR2 catch-up activity in this age group was greater in the lowest socio-economic status areas than in the highest status areas (29.1% v 7.6%), and also for Indigenous than for non-Indigenous Australians (35.8% v 17.1%). MMR2 catch-up activity in 2016 and 2017 peaked mid-year. CONCLUSIONS: Linking family assistance payments with childhood vaccination status and associated program improvements were followed by substantial catch-up vaccination activity, particularly in young people from families of lower socio-economic status.

Comparison of Tolerance and Complication Rates Between Early and Delayed Feeding After Percutaneous Endoscopic Gastrostomy Placement in Children.

BACKGROUND: Enteral nutrition is commonly initiated 24 hours after percutaneous endoscopic gastrostomy (PEG) in children. Adult studies report safe refeeding within 1 to 6 hours of PEG, and these findings have been cautiously applied to children. Comparative studies assessing early versus next-day refeeding in children are currently lacking. This study evaluates feeding tolerance and complications following early versus next-day refeeding in children. METHODS: This is a single-center, pre-post study. In June 2015 our clinical practice changed to begin refeeding within 6 hours of PEG. Children receiving early refeeding from December 2015 to August 2017 were included. A retrospective cohort from February 2013 to April 2015 was used for comparison. RESULTS: Forty-six children received early refeeding after PEG and 37 received next-day refeeding. Gender distribution was similar in the 2 groups. Early refeeding patients were slightly older (3.5 vs 2.2 years) and heavier (15.5 vs 11.5 kg) at PEG placement compared to next-day refeeding patients. Early refeeding patients experienced greater postprocedural nausea and/or vomiting (19% vs 8%, P < 0.001) and leakage, irritation, and infection around the stoma (19% vs 0.0%, P < 0.001). Compared to early refeeders, next-day refeeding patients experienced higher occurrence of fever (35% vs 13%, P = 0.021), longer nutritional disruption (24.6 vs 3.7 hours, P < 0.001), and longer length of stay (51 vs 27 hours; P < 0.001). One next-day refeeding patient experienced peritonitis. One early refeeding patient experienced cellulitis requiring hospitalization and a second experienced gastrostomy tube migration into the peritoneal cavity requiring removal. CONCLUSION: Early refeeders experienced higher rates of postprocedural nausea or vomiting and irritation, leakage, or infection around the stoma; but experienced lower rates of postoperative fever. Early refeeding resulted in reduced nutritional interruption and hospital length of stay.

A systematic review of studies that measure parental vaccine attitudes and beliefs in childhood vaccination.

BACKGROUND: Acceptance of vaccines is an important predictor of vaccine uptake. This has public health implications as those who are not vaccinated are at a higher risk of infection from vaccine preventable diseases. We aimed to examine how parental attitudes and beliefs towards childhood vaccination were measured in questionnaires through a systematic review of the literature. METHODS: We systematically reviewed the literature to identify primary research studies using tools to measure vaccine attitudes and beliefs, published between January 2012 and May 2018. Studies were included if they involved a quantitative survey of the attitudes and beliefs of parents about vaccinations recommended for children. We undertook a synthesis of the results with a focus on evaluating the tools used to measure hesitancy. RESULTS: A total of 116 studies met the inclusion criteria, 99 used a cross sectional study design, 5 used a case control study design, 4 used a pre-post study design and 8 used mixed methods study designs. Sample sizes of included studies ranged from 49 to 12,259. The most commonly used tool was the Parent Attitudes about Childhood Vaccines (PACV) Survey (n = 7). The most common theoretical framework used was the Health Belief Model (n = 25). Questions eliciting vaccination attitudes and beliefs varied widely. CONCLUSIONS: There was heterogeneity in the types of questionnaires used in studies investigating attitudes and beliefs about vaccination in parents. Methods to measure parental attitudes and beliefs about vaccination could be improved with validated and standardised yet flexible instruments. The use of a standard set of questions should be encouraged in this area of study.

Respiratory syncytial virus-associated hospitalisations in Australia, 2006-2015.

OBJECTIVE: To estimate rates of respiratory syncytial virus (RSV)-associated hospitalisation across the age spectrum, and to identify groups at particular risk of serious RSV-associated disease. DESIGN, SETTING AND PARTICIPANTS: Retrospective review of National Hospital Morbidity Database data for all RSV-associated hospitalisations in Australia, 2006-2015. MAIN OUTCOMES AND MEASURES: RSV-coded hospitalisation rates by age, sex, Indigenous status, jurisdiction, and seasonality (month and year); hospital length of stay; in-hospital deaths. RESULTS: During 2006-2015, there were 63 814 hospitalisations with an RSV-specific principal diagnostic code; 60 551 (94.9%) were of children under 5 years of age. The hospitalisation rate for children under 5 years was 418 per 100 000 population; for children under 6 months of age it was 2224 per 100 000 population; the highest rate was for infants aged 0-2 months (2778 per 100 000 population). RSV-coded hospitalisation rates were higher for adults aged 65 or more than for people aged 5-64 years (incidence rate ratio [IRR], 6.6; 95% CI, 6.2-7.1), and were also higher for Indigenous Australians than other Australians (IRR, 3.3; 95% CI, 3.2-3.5). A total of 138 in-hospital deaths were recorded, including 82 of adults aged 65 years or more (59%). CONCLUSIONS: Prevention strategies targeting infants, such as maternal or early infant vaccination, would probably have the greatest impact in reducing RSV disease rates. Further characterisation of RSV disease epidemiology, particularly in older adults and Indigenous Australians, is needed to inform health care strategies.

Closing the vaccination coverage gap in New South Wales: the Aboriginal Immunisation Healthcare Worker Program.

OBJECTIVES: To assess vaccination coverage and timeliness among Indigenous and non-Indigenous children in New South Wales and the rest of Australia, with a particular focus on changes in the vaccination coverage gaps after the introduction of the Aboriginal Immunisation Healthcare Worker (AIHCW) Program in NSW in 2012. DESIGN: Cross-sectional analysis of Australian Immunisation Register data (2008-2016). MAIN OUTCOME MEASURES: Annual estimates of full vaccination coverage at 9, 15 and 51 months of age for Indigenous and non-Indigenous children in NSW and the rest of Australia; differences in coverage between Indigenous and non-Indigenous children at each milestone. RESULTS: The proportion of Indigenous and non-Indigenous children classified as fully vaccinated at 9, 15, and 51 months increased significantly in both NSW and the rest of Australia after the introduction of the AIHCW Program. The mean annual difference in full vaccination coverage between Indigenous and non-Indigenous children in NSW aged 9 months declined from 6.6 (95% CI, 5.2-8.0) during 2008-2011 to 3.7 percentage points (95% CI, 2.5-4.8) during 2012-2016; for those aged 15 months it declined from 4.6 (95% CI, 3.1-6.0) to 2.2 percentage points (95% CI, 1.0-3.4), and for those aged 51 months it declined from 8.5 (95% CI, 7.2-9.8) to 0.6 percentage points (95% CI, -0.6 to 1.8). Reductions in the differences in coverage were not as marked in the rest of Australia. In 2016, there was no statistically significant difference in coverage at any of the three milestones in NSW: at 9 months the difference was 1.6 percentage points (95% CI, -1.0 to 4.1); at 15 months, 0.4 percentage points (95% CI, -2.2 to 2.9); and at 51 months, -1.8 percentage points (95% CI, -4.4 to 0.8). CONCLUSION: Our findings suggest that a dedicated program can help overcome barriers to timely vaccination and significantly improve timely vaccination rates in Indigenous Australian children.

Surface modification minimizes the toxicity of silver nanoparticles: an in vitro and in vivo study.

Currently toxicological research in Silver nanoparticle is a leading issue in medical science. The surface chemistry and physical dimensions of silver nanoparticles (Ag-NPs) play an important role in toxicity. The aim of this present study was to evaluate the in vitro and in vivo toxicity of Ag-NPs as well as the alteration of toxicity profile due to surface functionalization (PEG and BSA) and the intracellular signaling pathways involved in nanoparticles mediated oxidative stress and apoptosis in vitro and in vivo system. Ag-NPs released excess Ag+ ions leads to activation of NADPH oxidase and helps in generating the reactive oxygen species (ROS). Silver nanoparticles elicit the production of excess amount of ROS results activation of TNF-α. Ag-NPs activates caspase-3 and 9 which are the signature of mitochondrial pathway. Ag-NPs are responsible to decrease the antioxidant enzymes and imbalance the oxidative status into the cells but functionalization with BSA and PEG helps to protect the adverse effect of Ag-NPs on the cells. This study suggested that Ag-NPs are toxic to normal cells which directly lead with human health. Surface functionalization may open the gateway for further use of Ag-NPs in different area such as antimicrobial and anticancer therapy, industrial use or in biomedical sciences.

The Role of Neutrophils in Measles Virus-mediated Oncolysis Differs Between B-cell Malignancies and Is Not Always Enhanced by GCSF.

The mechanism by which oncolytic measles virus (MV) kills cancer cells remains obscure. We previously showed that neutrophils are involved in MV-mediated tumor regressions and become activated, upon MV infection. In the present study, we attempted to enhance the neutrophil response toward MV-infected tumor targets by generating an oncolytic MV-expressing human granulocyte colony-stimulating factor (MVhGCSF). Evaluating the effects in two different models of B-cell malignancy, we showed that depletion of neutrophils abrogated the MV therapeutic effect in an in vivo Raji-but not Nalm-6 tumor model. Next, we compared MVhGCSF with the unmodified backbone virus MVNSe. MVhGCSF enhanced the oncolytic capacity of MV in the Raji model in vivo, whereas in the Nalm-6 model, the opposite was unexpectedly the case. This finding was recapitulated by exogenously administered hGCSF. MVhGCSF replicated within an MV-infectable CD46 transgenic mouse model with detectable serum levels of hGCSF but no toxicity. Our data suggest that a "one-size-fits-all" model of immune response to viral oncolysis is not appropriate, and each tumor target will need full characterization for the potential of both direct and indirect, innate immune responses to generate benefit.

Surveillance of adverse events following immunisation in Australia, 2015.

This report summarises Australian passive surveillance data for adverse events following immunisation (AEFI) for 2015 reported to the Therapeutic Goods Administration and compares them to long-term trends. There were 2,924 AEFI records for vaccines administered in 2015; an annual AEFI reporting rate of 12.3 per 100,000 population. There was a decline of 7% in the overall AEFI reporting rate in 2015 compared with 2014. This decline in reported adverse events in 2015 compared to the previous year was mainly attributable to fewer reports following the HPV vaccine and replacement of monovalent vaccines (Hib, MenCCV and varicella) with combination vaccines such as Hib-MenC, and MMRV. AEFI reporting rates for most individual vaccines were lower in 2015 compared with 2014. The most commonly reported reactions were injection site reaction (26%), pyrexia (17%), rash (16%), vomiting (8%) and headache (7%). The majority of AEFI reports (85%) were described as non-serious events. There were two deaths reported, but no clear causal relationship with vaccination was found.

Evaluation of bacille Calmette-Guérin immunisation programs in Australia.

BACKGROUND: bacille Calmette-Guérin (BCG) immunisation programs in Australia are funded and operated by the individual states and territories. In recent years BCG vaccine shortages have required use of unregistered products. We aimed to evaluate BCG immunisation programs in Australia, with particular reference to program implementation and national consistency.
 Methods: Between September and November 2015, 12 key stakeholders, representing Australian states and territories, completed surveys. We analysed BCG vaccination coverage data from the Australian Childhood Immunisation Register (ACIR), and data on adverse events following immunisation (AEFI) with BCG vaccine from the Therapeutic Goods Administration's Adverse Drug Reactions System, for 2001 to 2014.
 Results: Access to BCG vaccination varies between jurisdictions, with some states providing this only in major city locations. Analysis of ACIR data suggests significant differences in vaccine delivery between jurisdictions, but varying levels of under-reporting to the ACIR were also acknowledged. The rate of BCG AEFI appeared to increase between 2011 and 2014; however, these data need to be interpreted with caution due to small numbers, likely under-reporting of both numerator (AEFI) and denominator (vaccine doses administered), and the general increase in reporting of AEFI related to other vaccines in children over this period.
 Conclusions: BCG immunisation programs aim to prevent severe forms of tuberculosis in young children who live in or travel to high burden settings. A range of factors, particularly inconsistent vaccine supply are leading to low, variable and inequitable vaccine delivery across Australian jurisdictions. Improved BCG vaccination uptake and AEFI data quality are required for accurate monitoring of program delivery and vaccine safety - this is particularly important given the current need to use unregistered vaccines. Improved and consistent access to BCG vaccine is suggested to optimise equity for at-risk children Australia-wide.

Immunisation coverage annual report, 2014.

This 8th annual immunisation coverage report shows data for 2014 derived from the Australian Childhood Immunisation Register and the National Human Papillomavirus Vaccination Program Register. This report includes coverage data for 'fully immunised' and by individual vaccines at standard age milestones and timeliness of receipt at earlier ages according to Indigenous status. Overall, 'fully immunised' coverage has been mostly stable at the 12- and 24-month age milestones since late 2003, but at 60 months of age, it has increased by more than 10 percentage points since 2009. As in previous years, coverage for 'fully immunised' at 12 months of age among Indigenous children was 3.7% lower than for non-Indigenous children overall, varying from 6.9 percentage points in Western Australia to 0.3 of a percentage point in the Australian Capital Territory. In 2014, 73.4% of Australian females aged 15 years had 3 documented doses of human papillomavirus vaccine (jurisdictional range 67.7% to 77.4%), and 82.7% had at least 1 dose, compared with 71.4% and 81.5%, respectively, in 2013. The disparity in on-time vaccination between Indigenous and non-Indigenous children in 2014 diminished progressively from 20.2% for vaccines due by 12 months to 11.5% for those due by 24 months and 3.0% at 60 months of age.

Human mesenchymal stromal cells deliver systemic oncolytic measles virus to treat acute lymphoblastic leukemia in the presence of humoral immunity.

Clinical trials of oncolytic attenuated measles virus (MV) are ongoing, but successful systemic delivery in immune individuals remains a major challenge. We demonstrated high-titer anti-MV antibody in 16 adults with acute lymphoblastic leukemia (ALL) following treatments including numerous immunosuppressive drugs. To resolve this challenge, human bone marrow-derived mesenchymal stromal cells (BM-MSCs) were used to efficiently deliver MV in a systemic xenograft model of precursor B-lineage-ALL. BM-MSCs were successfully loaded with MV ex vivo, and MV was amplified intracellularly, without toxicity. Live cell confocal imaging demonstrated a viral hand-off between BM-MSCs and ALL targets in the presence of antibody. In a murine model of disseminated ALL, successful MV treatment (judged by bioluminescence quantification and survival) was completely abrogated by passive immunization with high-titer human anti-MV antibody. Importantly, no such abrogation was seen in immunized mice receiving MV delivered by BM-MSCs. These data support the use of BM-MSCs as cellular carriers for MV in patients with ALL.

Mouse xenograft modeling of human adult acute lymphoblastic leukemia provides mechanistic insights into adult LIC biology.

The distinct nature of acute lymphoblastic leukemia (ALL) in adults, evidenced by inferior treatment outcome and different genetic landscape, mandates specific studies of disease-initiating mechanisms. In this study, we used NOD/LtSz-scid IL2Rγ null(c) (NSG) mouse xenotransplantation approaches to elucidate leukemia-initiating cell (LIC) biology in primary adult precursor B (pre-B) ALL to optimize disease modeling. In contrast with xenografting studies of pediatric ALL, we found that modification of the NSG host environment using preconditioning total body irradiation (TBI) was indispensable for efficient engraftment of adult non-t(4;11) pre-B ALL, whereas t(4;11) pre-B ALL was successfully reconstituted without this adaptation. Furthermore, TBI-based xenotransplantation of non-t(4;11) pre-B ALL enabled detection of a high frequency of LICs (<1:6900) and permitted frank leukemic engraftment from a remission sample containing drug-resistant minimal residual disease. Investigation of TBI-sensitive stromal-derived factor-1/chemokine receptor type 4 signaling revealed greater functional dependence of non-t(4;11) pre-B ALL on this niche-based interaction, providing a possible basis for the differential engraftment behavior. Thus, our studies establish the optimal conditions for experimental modeling of human adult pre-B ALL and demonstrate the critical protumorogenic role of microenvironment-derived SDF-1 in regulating adult pre-B LIC activity that may present a therapeutic opportunity.

Dietary obesity reversibly induces synaptic stripping by microglia and impairs hippocampal plasticity.

Obesity increases risk of age-related cognitive decline and is accompanied by peripheral inflammation. Studies in rodent models of obesity have demonstrated that impaired hippocampal function correlates with microglial activation, but the possibility that neuron/microglia interactions might be perturbed in obesity has never been directly examined. The goal of this study was to determine whether high fat diet-induced obesity promotes synaptic stripping by microglia, and whether any potential changes might be reversible by a return to low-fat diet (LFD). Time course experiments revealed that hippocampal inflammatory cytokine induction and loss of synaptic protein expression were detectable after three months of HFD, therefore subsequent groups of mice were maintained on HFD for three months before being switched to LFD for an additional two months on LFD (HFD/LFD). Additional HFD mice continued to receive HFD during this period (HFD/HFD), while another group of mice were maintained on LFD throughout the experiment (LFD/LFD). Dietary obesity impaired hippocampus-dependent memory, reduced long-term potentiation (LTP), and induced expression of the activation marker major histocompatibility complex II (MHCII) in hippocampal microglia. Diet reversal only partially attenuated increases in adiposity in HFD/LFD mice, but plasticity deficits and MHCII induction were normalized to within the range of LFD/LFD mice. Microglial activation and deficits in hippocampal function were accompanied by perturbation of spatial relationships between microglial processes and synaptic puncta. Analysis of primary microglia isolated from HFD/HFD mice revealed selective increases in internalization of synaptosomes labeled with a pH-sensitive fluorophore. Taken together, these findings indicate that dietary obesity reversibly impairs hippocampal function, and that deficits may be attributable to synaptic stripping by microglia.