Search

Dendritic cells (DC) play a major role during the priming phase of anti-tumor immunization, as they are required for an efficient tumor-associated antigens presentation. At least one dendritic cell-based therapy has already been successfully approved by regulators for clinical application in prostate cancer patients. Moreover, DC development is dependent on the granulocyte macrophage colony stimulating factor (GM-CSF), a cytokine that has been successfully used as a potent inducer of anti-tumoral immunity. To better understand the relation between DC and GM-CSF in anti-tumor immunity, we studied the DC function in mice lacking the cytokine receptor common subunit beta (βc-/-) for GM-CSF, IL-3 and IL-5 and immunized with irradiated tumor cells. Such immunization induces a protective, specific tumor immunization in wild-type mice, while βc-/- mice failed to mount an immune response. Upon in vitro stimulation, DC from βc-/- mice (DCβc-/-) are unable to undergo a full maturation level. In vivo experiments show that they lack the ability to prevent tumor growth, in contrast to DCWT. Moreover, matured DCWT rescued immunization in βc-/- mice. DC maturation is dependent on a functional pathway involving GM-CSF signaling through a biologically functional receptor. These findings may contribute to new strategies for efficient anti-tumor immunotherapies.

There has been little exploration of acute myocarditis trends in children despite notable advancements in care over the past decade. We explored trends in pediatric hospitalizations for acute myocarditis from 2007 to 2016 in the United States (US). This was a retrospective, serial cross-sectional study of the National Inpatient Sample database from 2007 to 2016, identifying patients ≤18 years hospitalized with acute myocarditis. Patient demographics and incidence trends were examined. Other relevant clinical and resource utilization outcomes were also explored. Out of 60,390,000 weighted pediatric hospitalizations, 6371 were related to myocarditis. The incidence of myocarditis increased from 0.7 to 0.9 per 100,000 children (p0.0001) over the study period. The mortality decreased from 7.5% to 6.1% (p = 0.02). A significant inflation-adjusted increase by $4,574 in the median hospitalization cost was noted (p = 0.02) while length of stay remained stable (median 6.1 days). Tachyarrhythmias were identified as the most common type of associated arrhythmia. The occurrence of congestive heart failure remained steady at 27%. In conclusion, in-hospital mortality associated with pediatric acute myocarditis has decreased in the United States over years 2007 to 2016 with a concurrent rise in incidence. Despite steady length of stay, hospitalization costs have increased. Future studies investigating long-term outcomes relating to acute myocarditis are warranted.

OBJECTIVE To determine the trends in tracheostomy placement and resource use in preterm infants less than or equal to 30 weeks gestational age (GA) with bronchopulmonary dysplasia (BPD) in the United States from 2008 to 2017. STUDY DESIGN This was a retrospective, serial cross-sectional study using data from the NIS. Inclusion criteria were: GA less than or equal to 30 weeks, hospitalization at less than or equal to 28 days of age, assignment of International Classification of Diseases, Ninth Revision, Clinical Modification (ICD9-CM) or ICD10-CM codes for BPD and tracheostomy. Trends in tracheostomy and resource utilization were assessed using Jonckheere-Terpstra test. p-value

Decades of research for an ideal sedative agent that could provide both sedation and analgesia with minimal side effects to the patients has failed to find one. Research was then shifted to finding combination of drugs which could suffice the ideal sedative agent. Of these Ketofol showed promising results.Aim of this study is to “Assess the efficacy and safety of propofol and ketamine amalgamation (ketofol) and comparing the superiority over ketamine and midazolam combination for procedural sedation”. In this prospective randomized single blind study, 50 patients between 15 to 60 years of both males and females, ASA Grade I and Grade II were allocated into two groups. Patients in group 1 received ketofol and group 2 patients received ketamine and midazolam. The comparison between the two groups was done using Two-Sample T-Test, With the help of SPSS version 15.0 Statistical calculator, sample size calculated = 5 to 17, and actual power calculated with this sample size was 0.990 to 0.997 which shows significance of the study.: The study showed statistically significant (p Ketofol is safe and efficient sedative combination which can be utilized in emergency department, daycare and OT settings with comfort, ease and without any complications. It is close to ideal sedative agent.

OBJECTIVES: Infantile hypertrophic pyloric stenosis (IHPS) is the most common reason for abdominal surgery in infants; however, national-level data on incidence rate and resource use are lacking. We aimed to examine the national trends in hospitalizations for IHPS and resource use in its management in the United States from 2012 to 2016. METHODS: We performed a retrospective serial cross-sectional study using data from the National Inpatient Sample, the largest health care database in the United States. We included infants aged ≤1 year assigned an International Classification of Diseases, Ninth Revision, or International Classification of Diseases, 10th Revision, code for IHPS who underwent pyloromyotomy or pyloroplasty. We examined the temporal trends in the incidence rate (cases per 1000 live births) according to sex, insurance status, geographic region, and race. We examined resource use using length of stay (LOS) and hospital costs. Linear regression was used for trend analysis. RESULTS: Between 2012 and 2016, there were 32 450 cases of IHPS and 20 808 149 live births (incidence rate of 1.56 per 1000). Characteristics of the study population were 82.7% male, 53% white, and 63.3% on Medicaid, and a majority were born in large (64%), urban teaching hospitals (90%). The incidence of IHPS varied with race, sex, socioeconomic status, and geographic region. In multivariable regression analysis, the incidence rate of IHPS decreased from 1.76 to 1.57 per 1000 (adjusted odds ratio 0.93; 95% confidence interval 0.92–0.93). The median cost of care was $6078.30, whereas the median LOS was 2 days, and these remained stable during the period. CONCLUSIONS: The incidence rate of IHPS decreased significantly between 2012 and 2016, whereas LOS and hospital costs remained stable. The reasons for the decline in the IHPS incidence rate may be multifactorial.

OBJECTIVES:We examined the trends in the rate of Henoch-Schönlein purpura (HSP) hospitalizations and the associated resource use among children in the United States from 2006 through 2014.METHODS:Pediatric hospitalizations with HSP were identified by using International Classification of Diseases, Ninth Revision, code 287.0 from the National Inpatient Sample. HSP hospitalization rate was calculated by using the US population as the denominator. Resource use was determined by length of stay (LOS) and hospital cost. We used linear regression for trend analysis.RESULTS:A total of 16 865 HSP hospitalizations were identified, and the HSP hospitalization rate varied by age, sex, and race. The overall HSP hospitalization rate was 2.4 per 100 000 children, and there was no trend during the study period. LOS remained stable at 2.8 days, but inflation-adjusted hospital cost increased from $2802.20 in 2006 to $3254.70 in 2014 (P < .001).CONCLUSIONS:HSP hospitalization rate in the United States remained stable from 2006 to 2014. Despite no increase in LOS, inflation-adjusted hospital cost increased. Further studies are needed to identify the drivers of increased hospitalization cost and to develop cost-effective management strategies.

microRNAs are short noncoding RNAs that regulate protein expression posttranscriptionally. We previously showed that miR-155 promotes effector CD8+ T-cell responses. However, little is known about the regulation of miR-155 expression. Here, we report that antigen affinity and dose determine miR-155 expression in CD8+ T cells. In B16 tumors expressing a low-affinity antigen ligand, tumor-specific infiltrating CD8+ T cells showed variable miR-155 expression, whereby high miR-155 expression was associated with more cytokine-producing cells and tumor control. Moreover, anti–PD-1 treatment led to both increased miR-155 expression and tumor control by specific CD8+ T cells. In addition, miR-155 overexpression enhanced exhausted CD8+ T-cell persistence in the LCMV cl13 chronic viral infection model. In agreement with these observations in mouse models, miR-155 expression in human effector memory CD8+ T cells positively correlated with their frequencies in tumor-infiltrated lymph nodes of melanoma patients. Low miR-155 target gene signature in tumors was associated with prolonged overall survival in melanoma patients. Altogether, these results raise the possibility that high miR-155 expression in CD8+ tumor-infiltrating T cells may be a surrogate marker of the relative potency of in situ antigen-specific CD8+ T-cell responses.

Background The incidence rate and economic burden of neonatal abstinence syndrome (NAS) are increasing in the United States (US). We explored the link between the length of stay (LOS) and hospitalization cost for neonatal abstinence syndrome in 2018. Methods This was a cross-sectional analysis of the 2018 national inpatient sample database. Newborn hospitalizations with neonatal abstinence syndrome and their accompanying comorbid conditions were identified using the International Classification of Diseases, 10th Edition diagnostic codes. Logistic regression was used to determine the impact of length of stay and the co-morbidities on inflation-adjusted hospital costs. Results The incidence of neonatal abstinence syndrome was 7.1 per 1000 births (95% CI 6.8-7.3) in 2018. The majority had Medicaid (84.1%), with a neonatal abstinence syndrome incidence of 13.2 (95% CI: 12.8-13.6). In adjusted analysis, every one-day increase in length of stay increased the hospital cost by $1,685 (95% CI: 1,639-1,731). Neonatal abstinence syndrome hospitalizations with Medicaid had a longer length of stay by 1.8 days (95% CI: 0.5-3.1). Co-morbidities further increased the length of stay: seizures: 13.8 days; sepsis: 4.1 days; respiratory complications: 4.4 days; and feeding problems: 5.8 days. Those at urban teaching hospitals had a longer length of stay by 7.3 days (95% CI: 5.8-8.8). Co-morbidities increased hospital cost as follows: seizures: $71,380; sepsis: $12,837; respiratory complications: $8,268; feeding problems: $7,737. The cost of hospitalization at large bed-size hospitals and urban teaching was higher by $5,243 and $12,005, respectively. Conclusion The incidence rate of neonatal abstinence syndrome remained high and was resource-intensive in 2018. Co-morbid conditions and hospitalization at urban teaching hospitals were major contributors to increased length of stay and hospital costs.

OBJECTIVES Although a growing body of evidence suggests that early transition to oral antimicrobial therapy is equally efficacious to prolonged intravenous antibiotics for treatment of acute pediatric osteomyelitis, little is known about the pediatric trends in peripherally inserted central catheter (PICC) placements. Using a national database, we examined incidence rates of pediatric hospitalizations for acute osteomyelitis in the United States from 2007 through 2016, as well as the trends in PICC placement, length of stay (LOS), and cost associated with these hospitalizations. METHODS This was a retrospective, serial cross-sectional study of the National Inpatient Sample database from 2007 through 2016. Patients ≤18 years of age with acute osteomyelitis were identified by using appropriate diagnostic codes. Outcomes measured included PICC placement rate, LOS, and inflation-adjusted hospitalization costs. Weighted analysis was reported, and a hierarchical regression model was used to analyze predictors. RESULTS The annual incidence of acute osteomyelitis increased from 1.0 to 1.8 per 100 000 children from 2007 to 08 to 2015 to 16 (P < .0001), whereas PICC placement rates decreased from 58.8% to 5.9% (P < .0001). Overall, changes in LOS and inflation-adjusted hospital costs were not statistically significant. PICC placements and sepsis were important predictors of increased LOS and hospital costs. CONCLUSIONS Although PICC placement rates for acute osteomyelitis significantly decreased in the face of increased incidence of acute osteomyelitis in children, LOS and hospital costs for all hospitalizations remained stable. However, patients receiving PICC placements had longer LOS. Further studies are needed to explore the long-term outcomes of reduced PICC use.

Background: Acute hematogenous osteomyelitis is a frequent cause of hospitalization and current literature suggests that early transition to oral antibiotics may be equally as effective as long-term intravenous antimicrobial administration. Our aim was to explore contemporary trends in acute osteomyelitis hospitalizations, resource utilization, and central/peripherally inserted central catheter (PICC) line placement among hospitalized children with osteomyelitis in the United States. Methods: This was a retrospective, serial cross-sectional study using data from the 2007-2016 editions of the National Inpatient Sample, the largest healthcare database in the United …

CD1d-restricted invariant natural killer T cells (iNKT cells) mediate strong antitumor immunity when stimulated by glycolipid agonists. However, attempts to develop effective iNKT cell agonists for clinical applications have been thwarted by potential problems with dose-limiting toxicity and by activation-induced iNKT cell anergy, which limits the efficacy of repeated administration. To overcome these issues, we developed a unique bispecific T-cell engager (BiTE) based on covalent conjugates of soluble CD1d with photoreactive analogues of the glycolipid α-galactosylceramide. Here we characterize the in vivo activities of iNKT cell–specific BiTEs and assess their efficacy for cancer immunotherapy in mouse models using transplantable colorectal cancer or melanoma tumor lines engineered to express human Her2 as a tumor-associated antigen. Systemic administration of conjugated BiTEs stimulated multiple iNKT cell effector functions including cytokine release, secondary activation of NK cells, and induction of dendritic cell maturation and also initiated epitope spreading for tumor-specific CD8+ cytolytic T-cell responses. The antitumor effects of iNKT-cell activation with conjugated BiTEs were further enhanced by simultaneous checkpoint blockade with antibodies to CTLA-4, providing a potential approach for combination immunotherapy. Multiple injections of covalently stabilized iNKT cell–specific BiTEs activated iNKT cells without causing iNKT cell anergy or exhaustion, thus enabling repeated administration for effective and nontoxic cancer immunotherapy regimens. Significance: Covalently stabilized conjugates that engage the antigen receptors of iNKT cells and target a tumor antigen activate potent antitumor immunity without induction of anergy or depletion of the responding iNKT cells.

In engineering, plate structures are one type of the main load-bearing structures. However, most of the designed plate-like metamaterials/metasurfaces need to be heavily grooved or drilled on the original plate surface, which will inevitably cause some destruction to the strength and stiffness of the host plate structures. To overcome this weakness, we propose a new conceptual design of pillared elastic metasurface (~0.495λ) to manipulate flexural waves in plates by considering constructive interference. The interference, which manifests itself as the coupling through out-of-plane vibration of the plate for the two adjacent subunits, is analyzed to reveal the physical mechanisms. In addition, we reveal the mechanism of the phase shift of transmitted waves across the sub-wavelength subunits and establish an analytical model for the multi-resonator subunits to accurately predict the phase shift and amplitude of the transmitted wave. We theoretically design and experimentally demonstrate the deflecting and focusing functionalities of the proposed elastic metasurface. Our design can provide a new route to broad applications of the constructive interference in elastic metamaterials/metasurfaces, which can be used to efficiently engineer arbitrary wave profiles.

Invariant natural killer T (iNKT) cells display important properties that could bridge the innate and adaptive immunity, and they have been shown to play key roles in cancer immunotherapy. However, administration of iNKT cell agonist αGalCer fails to induce sustained antitumor immunity due to the rapid anergy induction after an initial strong activation. To this end, we have designed a recombinant CD1d protein that is fused to an anti-TAA scFv, which is able to recruit iNKT cells to the tumor site and induce tumor regression. Importantly, recombinant CD1d fusion proteins loaded with α-GalCer demonstrated sustained activation of iNKT cells upon repeated injections and superior tumor control, as compared to α-GalCer treatment.

PD-1/PD-L1 pathway plays a role in inhibiting immune response. Therapeutic antibodies aimed at blocking the PD-1/PD-L1 interaction have entered clinical development and have been approved for a variety of cancers. However, the clinical benefits are reduced to a group of patients. The research in combined therapies, which allow for a greater response, is strongly encouraging. We previously characterized a polyphenol-rich extract from Caesalpinia spinosa (P2Et) with antitumor activity in both melanoma and breast carcinoma, as well as immunomodulatory activity. We hypothesize that the combined treatment with P2Et and anti-PD-L1 can improve the antitumor response through an additive antitumor effect. We investigated the antitumor and immunomodulatory activity of P2Et and anti-PD-L1 combined therapy in B16-F10 melanoma and 4T1 breast carcinoma. We analyzed tumor growth, hematologic parameters, T cell counts, cytokine expression, and T cell cytotoxicity. In the melanoma model, combined P2Et and anti-PD-L1 therapy has the following effects: decrease in tumor size; increase in the number of activated CD4 + and CD8 + T cells; decrease in the number of suppressor myeloid cells; increase in PD-L1 expression; decrease in the frequency of CD8 + T cell expressing PD-1; improvement in the cytotoxic activity of T cells; and increase in the IFN γ secretion. In the breast cancer model, P2Et and PD-L1 alone or in combination show antitumor effect with no clear additive effect. This study shows that combined therapy of P2Et and anti-PD-L1 can improve antitumor response in a melanoma model by activating the immune response and neutralizing immunosuppressive mechanisms.

Objectives: Cognitive training using technology has potential to be an effective treatment method for people with mild cognitive impairment (MCI). Touchscreen tablet applications might provide a fu...

Background: Intracranial hemorrhage (ICH) is a rare but severe complication in patients with immune thrombocytopenia (ITP). We aimed to examine the incidence and outcomes of ICH among ITP hospitalizations and factors associated with it. Additionally, we studied resource utilization for these hospitalizations. Methods: Using National (Nationwide) Inpatient Sample, International Classification of Diseases, Ninth and Tenth Revision, Clinical Modification (ICD-9-CM/ICD-10-CM) codes, we studied ITP hospitalizations with occurrence of ICH between 2007 and 2016. Result: Out of 348,906 weighted ITP hospitalizations, ICH occurred in 3,408 encounters (incidence 1.1 ± 0.04%). The incidence remained stable over time (2007-2008: 1.01%, 2015-2016: 1.20%; P = 0.3). People with age ≥25 years, especially those aged ≥65 years (odds ratio [OR] 3.69, 95% confidence interval [CI] 2.34-5.84), or those with gastrointestinal bleed (OR 1.60, 95% CI 1.18-2.16) were significantly more likely to develop ICH. Female gender (OR 0.81, 95% CI 0.68-0.97) had lower odds for developing ICH. Overall mortality in ITP hospitalizations with ICH was 26.7%. Length of stay (LOS) was longer (4.8 vs. 2.6 days) and costs of hospitalization (COH) were higher ($20,081 vs. $8,355) in ICH hospitalizations compared to non-ICH ITP hospitalizations. Increasing age and comorbidities such as gastrointestinal bleed, hematuria, and other bleeding were also associated with longer LOS and higher COH. Conclusion: Although rare, ICH in ITP was associated with a high mortality and increased resource utilization. Clinicians should be cognizant of factors associated with risk of ICH in ITP, and future studies should reassess the ICH trends to study the impact of novel therapeutic options such as thrombopoietin receptor agonists.

Background: Air or barium enema reduction is becoming increasingly common and safer for pediatric intussusception. However, little is known about trends of pediatric intussusception requiring surgical intervention in the United States. Methods: National Inpatient Sample database was analyzed from 2005-2014 to identify pediatric (≤18 years) intussusceptions along with procedures such as enema and/or surgical intervention. Trends in the rates of surgical intervention were examined according to encounter-level (age, gender, race, comorbidities) and hospital-level (hospital census region, teaching status) characteristics. Outcomes of pediatric intussusception requiring surgical intervention were analyzed in terms of length of stay and cost of hospitalization. Factors associated with surgical intervention were also analyzed. P value of < 0.05 was considered significant. Results: Out of 21,835 intussusception hospitalizations requiring enema or surgical intervention, 14,415 (66%) had surgical intervention; 90% of which (12,978) had no preceding enema. Surgical intervention rates among intussusception hospitalizations varied by age (highest < 1 year), gender (male > females) and race (Hispanics > Whites and Blacks). During the study period, overall surgical intervention rate remained stable (2.2 to 1.7, P=0.07) although it declined in those under 1 year of age. Children with severe disease, gastrointestinal comorbidities over the age of 4 years had increased odds of surgical intervention, whereas hospitalization in large and urban teaching hospitals had decreased odds of surgical intervention. Length of stay and hospital cost remained stable from 2005-2014. Conclusion: The rates of surgical intervention and resource utilization for pediatric intussusception remained stable from 2005-2014, however they declined significantly in infants. The proportion of intussusception hospitalization requiring surgery remains high and further studies are needed to explore the possible factors.

To examine the temporal trends in the incidence and outcomes of neonatal herpes simplex infections (NHSV) in the United States. We conducted a retrospective study using the National Inpatient Sample (NIS). Neonates ≤28 days old with ICD-9 codes for NHSV (054.xx) from 2003 to 2014 were included. Trends in the incidence, mortality, length of stay (LOS), and hospital cost were analyzed using Jonckheere–Terpstra test. NHSV increased from 7.9 to 10 per 100,000 live births from 2003–05 to 2012–14 (P = 0.04). Hospital costs increased from $21,650 to $27,843; P

BACKGROUND The management practices of Respiratory Distress Syndrome (RDS) in the newborn have changed over time. We examine the trends in the epidemiology, resource utilization, and outcomes (mortality and bronchopulmonary dysplasia [BPD]) of RDS in preterm neonates ≤34 weeks gestational age (GA) in the United States. METHODS In this retrospective serial cross-sectional study, we used ICD-9 codes to classify preterm infants GA ≤34 weeks between 2003 and 2014 from the National Inpatient Sample as having RDS or not. Trends in the prevalence of infants defined as RDS by ICD-9 code (ICD9-RDS), length of stay, BPD, and mortality were analyzed using Cochran-Armitage and Jonckheere-Terpstra tests and multivariable logistic regression. RESULTS Of 1 526 186 preterm live births with GA ≤34 weeks, 554 409 had ICD9-RDS (260 cases per 1000 live births) with the prevalence increasing from 170 to 361 (Ptrend 96 h (60.4 to 56.6%; Ptrend

Gastroschisis is a severe congenital anomaly associated with a significant morbidity and mortality. There are limited temporal trend data on incidence, mortality, length of stay, and hospital cost of gastroschisis. Our aim was to study these temporal trends using the National Inpatient Sample (NIS). We identified all neonatal admissions with a diagnosis of gastroschisis within the NIS from 2010 through 2014. We limited admission age to ≤ 28 days and excluded all those transferred to other hospitals. We estimated gastroschisis incidence, mortality, length of hospital stay, and cost of hospitalization. For continuous variables, trends were analyzed using survey regression. Cochrane–Armitage trend test was used to analyze trends for categorical variables. P

Antitumor T cell responses involve CD8+ T cells with high affinity for mutated self-antigen and low affinity for nonmutated tumor-associated Ag. Because of the highly individual nature of nonsynonymous somatic mutations in tumors, however, immunotherapy relies often on an effective engagement of low-affinity T cells. In this study, we studied the role of T cell affinity during peripheral priming with single-peptide vaccines and during the effector phase in the tumor. To that end, we compared the antitumor responses after OVA257–264 (N4) peptide vaccination of CD8+ T cells carrying TCRs with high (OT-1) and low (OT-3) avidity for the N4 peptide in B16.N4 tumor-bearing C57BL/6 mice. Additionally, we assessed the response of OT-1 cells to either high-affinity (B16.N4) or low-affinity (B16.T4) Ag-expressing tumors after high-affinity (N4) or low-affinity (T4) peptide vaccination. We noticed that although low-affinity tumor-specific T cells expand less than high-affinity T cells, they express lower levels of inhibitory receptors and produce more cytokines. Interestingly, tumor-infiltrating CD8+ T cells show similar in vivo re-expansion capacity to their counterparts in secondary lymphoid organs when transferred to tumor-free hosts, suggesting that T cells in tumors may be rekindled upon relief of tumor immunosuppression. Moreover, our results show that αPD-1 treatment enhances tumor control of high- and low-affinity ligand-expressing tumors, suggesting that combination of high-affinity peripheral priming by altered peptide ligands and checkpoint blockade may enable tumor control upon low-affinity Ag recognition in the tumor.

Background: The American Academy of Pediatrics reissued its guidelines on the management of jaundice in newborns born at ≥35 weeks gestation in 2004. The impact of this on the management of jaundice and the incidence of kernicterus in the United States (US) is unknown Objective: To examine the trends in hospitalization for neonatal jaundice and kernicterus and their associated resource utilization in the United States from 2006 to 2017 Design/Methods: This was a retrospective, serial cross-sectional study using data …

O objetivo neste artigo é apresentar reflexões a partir da análise dos resultados de uma pesquisa realizada com oito docentes da Educação Básica que atuam em contextos socioculturais distintos, como na Educação Escolar Indígena, Educação Escolar do Campo, Educação Especial e Inclusiva, Educação de Jovens e Adultos, entre outras, em diferentes cidades e regiões brasileiras. A intenção é apresentar indícios de como a Educação Escolar está tentando acontecer nestes tempos de isolamento social; quais os desafios e as implicações educacionais enfrentadas pelos educadores e seus educandos; como a Educação Matemática está sendo praticada e; como a Etnomatemática pode ser mobilizada. As informações que respaldam as discussões perpassam as respostas a um questionário encaminhado remotamente e a sua apreciação acontece qualitativamente por meio de aproximações com a análise textual discursiva. Trata-se de uma pesquisa exploratória e os dados indicam que as escolas e os docentes estão atuantes, implementando práticas e aulas remotas usando diferentes tecnologias, apesar das suas limitações e dificuldades, intentando a inclusão de todos com uma Educação Matemática dinâmica e de qualidade, e na medida do possível, mobilizando a Etnomatemática, mesmo diante das adversidades e consequências incertas.

Hyperoxia plays a key role in the development of bronchopulmonary dysplasia (BPD), a chronic lung disease of preterm infants. Infants with BPD often have brain injury that leads to long-term neurodevelopmental impairment, but the underlying mechanisms that control BPD-induced neurodevelopmental impairment remain unclear. Our previous studies have shown that hyperoxia-induced BPD in rodents is associated with lung inflammasome activation. Here, we tested the hypothesis that hyperoxia-induced lung and brain injury is mediated by inflammasome activation, and that inhibition of caspase-1, a key component of the inflammasome, attenuates hyperoxia-induced lung and brain injury in neonatal mice. C57/BL6 mouse pups were randomized to receive daily intraperitoneal injections of Ac-YVAD-CMK, an irreversible caspase-1 inhibitor, or placebo during exposure to room air or hyperoxia (85% O2) for 10 days. We found that hyperoxia activated the NLRP1 inflammasome, increased production of mature IL-1β, and upregulated expression of p30 gasdermin-D (GSDMD), the active form of GSDMD that is responsible for the programmed cell death mechanism of pyroptosis in both lung and brain tissue. Importantly, we show that inhibition of caspase-1 decreased IL-1β activation and p30 GSDMD expression, and improved alveolar and vascular development in hyperoxia-exposed lungs. Moreover, caspase-1 inhibition also promoted cell proliferation in the subgranular zone and subventricular zone of hyperoxia-exposed brains, resulting in lessened atrophy of these zones. Thus, the inflammasome plays a critical role in hyperoxia-induced neonatal lung and brain injury, and targeting this pathway may be beneficial for the prevention of lung and brain injury in preterm infants.

Cross-presenting Xcr1 + CD8α DCs are attractive APCs to target for therapeutic cancer vaccines, as they are able to take up and process antigen from dying tumor cells for their MHCI-restricted presentation to CD8 T cells. To this aim, we developed fusion proteins made of the Xcr1 ligand Xcl1 fused to an OVA synthetic long peptide (SLP) and IgG1 Fc fragment. We demonstrated the specific binding and uptake of the Xcl1 fusion proteins by Xcr1 + DCs. Most importantly, their potent adjuvant effect on the H-2Kb/OVA specific T cell response was associated with a sustained tumor control even against the poorly immunogenic B16-OVA melanoma tumor. The increased tumor protection correlated with higher tumor infiltration of antigen-specific CD8+ T cells, increased IFNγ production and degranulation potential. Altogether, these results demonstrate that therapeutic cancer vaccines may be greatly improved by the combination of SLP antigen and Xcl1 fusion proteins.

Polyphenols have tumoricidal effects via anti-proliferative, anti-angiogenic and cytotoxic mechanisms and have recently been demonstrated to modulate the immune response through their anti- or pro- oxidant activity. Nevertheless, it remains controversial whether antioxidant-rich supplements have real beneficial effects on health, especially in complex diseases such as cancer. We previously identified a polyphenol-rich extract obtained from Caesalpinia spinosa (P2Et) with anti-tumor activity in both breast carcinoma and melanoma. The present work evaluated the ability of P2Et extract to modulate the immune system in either the steady state or following tumor challenge. We found that the prophylactic treatment of healthy mice increased the number of CD4 + and CD8 + activated T, NK, regulatory T, dendritic and myeloid-derived suppressor cells in lymphoid organs together with a significant increase in plasma IL-6. Interestingly, this pre-conditioning of the host immune system with P2Et did not involve a protective effect against the control of tumor growth and metastasis in transplantable models of melanoma (B16) and breast cancer (4T1), but in contrast, a detrimental effect was observed in both models. We further demonstrated that this effect was at least partly due to an increase in regulatory T cells, myeloid-derived suppressor cells, and proinflammatory cytokines, with a concomitant decrease in CD4 + and CD8 + T cells. Taken together, these results suggest that the anti-tumor and immunomodulation properties of the P2Et extract critically depend on the presence of the tumor and might be mediated by the complex interactions between the tumor cells and the other components of the tumor microenvironment.

To assess the trends of inpatient resource use and mortality in pediatric hospitalizations for fever with neutropenia in the US from 2007 to 2014.Using National (Nationwide) Inpatient Sample (NIS) and International Classification of Diseases, Ninth Revision, Clinical Modification codes, we studied pediatric cancer hospitalizations with fever with neutropenia between 2007 and 2014. Using appropriate weights for each NIS discharge, we created national estimates of median cost, length of stay, and in-hospital mortality rates.Between 2007 and 2014, there were 104 315 hospitalizations for pediatric fever with neutropenia. The number of weighted fever with neutropenia hospitalizations increased from 12.9 (2007) to 18.1 (2014) per 100 000 US population. A significant increase in fever with neutropenia hospitalizations trend was seen in the 5- to 14-year age group, male sex, all races, and in Midwest and Western US hospital regions. Overall mortality rate remained low at 0.75%, and the 15- to 19-year age group was at significantly greater risk of mortality (OR 2.23, 95% CI 1.36-3.68, P = .002). Sepsis, pneumonia, meningitis, and mycosis were the comorbidities with greater risk of mortality during fever with neutropenia hospitalizations. Median length of stay (2007: 4 days, 2014: 5 days, P .001) and cost of hospitalization (2007: $8771, 2014: $11 202, P .001) also significantly increased during the study period.Our study provides information regarding inpatient use associated with fever with neutropenia in pediatric hospitalizations. Continued research is needed to develop standardized risk stratification and cost-effective treatment strategies for fever with neutropenia hospitalizations considering increasing costs reported in our study. Future studies also are needed to address the greater observed mortality in adolescents with cancer.

Summary: Upon infection, antigen-specific naive CD8 T cells are activated and differentiate into short-lived effector cells (SLECs) and memory precursor cells (MPECs). The underlying signaling pathways remain largely unresolved. We show that Rictor, the core component of mammalian target of rapamycin complex 2 (mTORC2), regulates SLEC and MPEC commitment. Rictor deficiency favors memory formation and increases IL-2 secretion capacity without dampening effector functions. Moreover, mTORC2-deficient memory T cells mount more potent recall responses. Enhanced memory formation in the absence of mTORC2 was associated with Eomes and Tcf-1 upregulation, repression of T-bet, enhanced mitochondrial spare respiratory capacity, and fatty acid oxidation. This transcriptional and metabolic reprogramming is mainly driven by nuclear stabilization of Foxo1. Silencing of Foxo1 reversed the increased MPEC differentiation and IL-2 production and led to an impaired recall response of Rictor KO memory T cells. Therefore, mTORC2 is a critical regulator of CD8 T cell differentiation and may be an important target for immunotherapy interventions. : Zhang et al. demonstrate that mTORC2 deficiency favors CD8 T cell memory differentiation during the primary antigen-specific T cell response to Listeria infection. The effects result from higher Foxo1 transcriptional activity without dampening effector functions. They also show enhanced recall responses by mTORC2-deficient memory CD8 T cells. Keywords: Rictor, mTORC2, Foxo1, CD8 T cell, infection

A simple, precise and accurate isocratic RP-HPLC method was successfully developed for the simultaneous determination of chlorpheniramine maleate (CPM), phenylephrine hydrochloride (PHE) and ibuprofen (IBU) in bulk and pharmaceutical preparation. The separation of the drugs was achieved using Inertsil ODS C18 column with mobile phase consisting of methanol and 0.1% triethylamine (55:45 V/V) in water, pH 3 (adjusted with orthophosphoric acid). These drugs were resolved successfully with retention time of 3.0 min for CPM, 4.6 min for PHE and 18.9 min for IBU, when the eluate was monitored at 240 nm. Linearity was found in the concentration range of 10 to 50 μg mL-1 for CPM, 25 to 125 μg mL-1 for PHE and 100 to 500 μg mL-1 for IBU, with a correlation coefficient (r2) of 0.9987, 0.9965 and 0.9998 for CPM, PHE and IBU, respectively. Thus, the proposed method can be successfully applied to the pharmaceutical preparation containing the above mentioned drugs without any interference of excipients.

To determine trends in neonatal extracorporeal membrane oxygenation (ECMO) utilization from 2002–2011. Using the Nationwide inpatient sample (NIS), we conducted a population-based retrospective cohort study to identify ECMO utilization among neonates. Incidence of ECMO utilization, length of stay (LOS), cost and mortality were estimated. In all, 33,367,146 neonates were identified of which 7603 (18 per 100,000 live births) underwent ECMO. Neonatal ECMO increased from 12 to 23 runs per 100,000 live births. Mortality was 48.4%, decreasing from 47.5 to 41.9% between 2002 and 2011. On multivariate analysis, mortality was significantly higher for infectious indications (OR 4.1; CI 1.1–16.0), E-CPR (OR 3.8; CI 1.4–10.7) and cardiac indications (OR 2.0; CI 1.5–2.8). On hierarchical regression, LOS increased by 1.6 days each year (p = 0.02) and cost of hospitalization increased by $14,033 each year (p

International audience; Type 1 diabetes is an autoimmune disease initiated by the invasion of pancreatic islets by immune cells that selectively kill the beta cells. We found that rodent and human T lymphocytes release exosomes containing the microRNAs (miRNAs) miR-142-3p, miR-142-5p, and miR-155, which can be transferred in active form to beta cells favoring apoptosis. Inactivation of these miRNAs in recipient beta cells prevents exosome-mediated apoptosis and protects non-obese diabetic (NOD) mice from diabetes development. Islets from protected NOD mice display higher insulin levels, lower insulitis scores, and reduced inflammation. Looking at the mechanisms underlying exosome action, we found that T lymphocyte exosomes trigger apoptosis and the expression of genes involved in chemokine signaling, including Ccl2, Ccl7, and Cxcl10, exclusively in beta cells. The induction of these genes may promote the recruitment of immune cells and exacerbate beta cell death during the autoimmune attack. Our data point to exosomal-miRNA transfer as a communication mode between immune and insulin-secreting cells.

Major progress in cancer immunotherapies have been obtained by the use of tumor targeting strategies, in particular with the development of bi-functional fusion proteins such as ImmTacs or BiTes, which engage effector T cells for targeted elimination of tumor cells. Given the significance of invariant natural killer T (iNKT) cells in bridging innate and adaptive immunity, we have developed a bi-functional protein composed of the extracellular part of CD1d molecule that was genetically fused to an scFv fragment from high affinity antibodies against HER2 or CEA. Systemic treatments with the CD1d-antitumor fusion proteins loaded with the agonist alpha-galactosylceramide (αGalCer) led to specific iNKT cell activation, resulting in a sustained growth inhibition of established tumors expressing HER2 or CEA, while treatment with the free αGalCer was ineffective. Importantly, we discovered that αGalCer/CD1d-antitumor fusion proteins were able to maintain iNKT cells reactive to multiple re-stimulations in contrast to their anergic state induced after a single injection of free αGalCer. We further demonstrated that the antitumor effects by αGalCer/CD1d-antitumor fusion proteins were largely dependent on the iNKT cell-mediated transactivation of NK cells. Moreover, prolonged antitumor effects could be obtained when combining the CD1d-antitumor fusion protein treatment with a therapeutic peptide/CpG cancer vaccine, which favored the capacity of iNKT cells to transactivate cross-presenting DCs for efficient priming of tumor-specific CD8 T cells. We will also summarize these pre-clinical results with a special focus on the cellular mechanisms underlying iNKT cell unresponsiveness to antigen re-challenge. Finally, we will discuss the perspectives regarding iNKT cell-mediated tumor targeting strategy in cancer immunotherapy.

We analyzed the activity of the enhancer, the promoter and the silencer of the human CD4 gene during T cell development using transgenic mice. Immunofluorescence studies on thymic populations of mice carrying transgenes in various combinations of these regulatory DNA elements revealed that thymocytes control the CD4 gene in a different manner than mature peripheral T lymphocytes. The 5'-positive regulatory unit, consisting of the promoter and the 5' enhancer, is already active at the CD4-CD8-double-negative (DN) stage of development. However, its activity becomes lower in the double-positive and a fraction of the CD4+ CD8int/- cell population, indicating that an additional enhancer, located in either the first or the third intron of the CD4 gene, is required for CD4 gene expression in this population. The other studied regulatory element is the minimal CD4 silencer which inhibits CD4 gene expression in peripheral CD8 T lymphocytes. This silencer is inactive in the most immature DN thymocytes, which probably use a distinct silencer mechanism to down-regulate CD4 gene expression. Unexpectedly, the CD4 silencer is also active in CD4+ CD8int/- cells of the thymus, implying that an anti-silencer may be required to resume CD4 expression in this cell population. Altogether, the CD4 gene is regulated by several positive and negative regulatory mechanisms which come into play in a developmentally coordinated manner.

Background: Intracranial hemorrhage (ICH) is a rare but severe complication in patients with immune thrombocytopenia (ITP). It is unclear whether the incidence of ICH has changed over time. We aimed study the incidence of ICH among ITP hospitalizations and factors associated with its occurrence from 2007-2016. Additionally, we examined the outcomes of ITP hospitalizations with ICH and resource utilization (length of stay, cost of hospitalization) during this time period. Methods: We used data from the National Inpatient Sample (NIS) database from 2007-2016. ITP hospitalizations were identified using International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) code '287.31' and ICD-10-CM code 'D69.3'. Pertinent ICD-9-CM and ICD-10-CM codes were used to identify ICH. Baseline characteristics of ITP hospitalizations with and without ICH were compared using chi-square test and Wilcoxon rank-sum test for categorical and continuous variables, respectively. For trend analysis, chi-square test of trend for proportions was used with Cochrane Armitage test. Survey logistic regression was used to analyze factors associated with the occurrence of ICH and mortality in ITP hospitalizations with ICH. To account for the complex design of NIS, hierarchical regression was used to analyze the factors associated with of length of stay (LOS) and cost of hospitalization (COH). Beta coefficient and 95% confidence intervals (CI) were reported. P-value Results: Between 2007 and 2016, 348,906 ITP hospitalizations were identified. The incidence of ICH was 0.98% (n=3,408). Median age of patients with reported ICH was significantly higher than those without ICH [63.4 (range 47.1-76.7) vs. 51.6 (28.6-70.0), P While the overall incidence of ICH remained stable during the study period (P=0.3), it varied by age, gender, and hospital region. Incidence significantly decreased in age ≤24 years (0.7% to 0.4%). On the contrary, it significantly increased among those ≥65 years (1.5% to 1.9%), females (0.9% to 1.1%), and hospitalizations in Northeast region (0.9% to 1.1%). Similarly, trend of mortality in hospitalizations with ICH increased from 28.1% in 2007-08 to 34.6% in 2015-16 (P On multivariate regression analysis, factors associated with higher likelihood of ICH were (Table 1): age 25-64 years [odds ratio (OR) 2.23; 95% CI 1.51-3.31], ≥65 years (OR 3.69; 95% CI 2.34-5.84), gastrointestinal (GI) bleed (OR 1.60; 95% CI 1.18-2.16), other bleed (OR 1.69; 95% CI 1.19-2.42), hospitalization in the West region (OR 1.62; 95% CI 1.26-2.08), in a medium (OR 1.64; 95% CI 1.08-2.47) or large hospital (OR 2.42; 95% CI 1.65-3.55) and in an urban-teaching hospital (OR 2.73; 95% CI 1.80-4.13). Female gender (OR 0.81; 95% CI 0.68-0.97) was associated with lower likelihood of ICH. Similarly, factors were associated with higher likelihood of mortality in ICH hospitalizations were: age 25-64 years (OR 6.73; 95% CI 4.11-11.03), ≥ 65 years (OR 16.94; 95% CI 10.14-28.30), GI bleed (OR 3.13; 95% CI 2.72-3.60), other bleeds (OR 1.66; 95% CI 1.31-2.10), hospitalizations at a large hospital (OR 1.17; 95% CI 1.00-1.37), and an urban teaching hospital (OR 1.23; 95% CI 1.02-1.48). Increasing age was associated with longer LOS, which also translated into higher COH (Table 2). Comorbidities such as GI bleed (2.5 days, 95% CI 2.1-2.9; $9,391, 95% CI 8,210-10,572), hematuria (1.1 days, 95% CI 0.6-1.6; $3,586, 95% CI 1,941-5,230), and other bleeding (1.1 days, 95% CI 0.7-1.5; $5,931, 95% CI 4,565-7,296) were also associated with longer LOS and higher COH. LOS decreased from 2007 to 2016 [-0.2 days, 95% CI (-0.3)-(-0.1)], however, the COH did not change. Conclusion: The overall incidence of ICH among ITP hospitalizations is low and remained stable from 2007-2016, which is reassuring. Nonetheless, a quarter of these hospitalizations resulted in mortality. ICH also significantly increased healthcare utilization in ITP hospitalizations through high LOS and COH. Older age and male gender were associated with higher ICH incidence and mortality. Future studies should reassess the ICH trends to study the impact of novel therapeutic options such as thrombopoietin receptor agonists. Disclosures No relevant conflicts of interest to declare.

Monoamine oxidase (MAO) enzyme inhibition is a crucial target for the management of depression and Alzheimer disease and inhibitors of MAO are the most important drugs for their management. Coumarins are a large family of compounds, of natural and synthetic origin, that exhibit a variety of pharmacological activities, including MAO inhibition. The current review highlights the design and synthetic methods of coumarin derivatives as well as coumarins obtained from plant source as MAO inhibitors for treatment of depression and Alzheimer disease with salient finding related to structure-activity relationship. The aim of present review is to find out natural as well as synthetic coumarins as MAO inhibitors.

Objective. To determine if a positive result on pneumography, diagnosis of gastroesophageal reflux disease (GERD), or nontreatment of those diagnosed with GERD with antireflux medications predicts an increased recurrence risk of apparent life-threatening event (ALTE) over the first 4 weeks of follow-up. Methods. Secondary analysis of a prospective, observational study of 300 infants diagnosed with ALTE. Results. The relative risk of recurrent ALTE was 1.26 (95% confidence interval = 0.47-3.38) among infants with an abnormal versus normal result on pneumography, 1.98 (1.02-3.86) among those diagnosed with GERD versus those not, and 0.46 (0.20-1.03) among those with GERD and started on antireflux medications versus those not started on such medications. Conclusions. Positive pneumography for apnea or reflux does not predict an increase in recurrence rate of an ALTE. Infants diagnosed with GERD are more likely to have recurrent ALTE; treatment with antireflux medications may reduce this risk.

Antitumor immunity is strongly influenced by the balance of tumor antigen-specific effector T cells (Teff) and regulatory T cells (Treg). However, the impact that vaccine adjuvants have in regulating the balance of antigen-specific T-cell populations is not well understood. We found that antigen-specific Tregs were induced following subcutaneous vaccination with either OVA or melanoma-derived peptides, with a restricted expansion of Teffs. Addition of the adjuvants CpG-ODN or Poly(I:C) preferentially amplified Teffs over Tregs, dramatically increasing the antigen-specific Teff:Treg ratios and inducing polyfunctional effector cells. In contrast, two other adjuvants, imiquimod and Quil A saponin, favored an expansion of antigen-specific Tregs and failed to increase Teff:Treg ratios. Following therapeutic vaccination of tumor-bearing mice, high ratios of tumor-specific Teffs:Tregs in draining lymph nodes were associated with enhanced CD8+ T-cell infiltration at the tumor site and a durable rejection of tumors. Vaccine formulations of peptide+CpG-ODN or Poly(I:C) induced selective production of proinflammatory type I cytokines early after vaccination. This environment promoted CD8+ and CD4+ Teff expansion over that of antigen-specific Tregs, tipping the Teff to Treg balance to favor effector cells. Our findings advance understanding of the influence of different adjuvants on T-cell populations, facilitating the rational design of more effective cancer vaccines. Cancer Res; 73(22); 6597–608. ©2013 AACR.

A major limiting factor in the success of immunotherapy is tumor infiltration by CD8(+) T cells, a process that remains poorly understood. In the present study, we characterized homing receptors expressed by human melanoma-specific CD8(+) T cells. Our data reveal that P-selectin binding and expression of the retention integrin, very late antigen (VLA)-1, by vaccine-induced T cells correlate with longer patient survival. Furthermore, we demonstrate that CD8(+)VLA-1(+) tumor-infiltrating lymphocytes (TILs) are highly enriched in melanoma metastases in diverse tissues. VLA-1-expressing TIL frequently co-express CD69 and CD103, indicating tissue-resident memory T cells (TRM) differentiation. We employed a mouse model of melanoma to further characterize VLA-1-expressing TIL. Our data show that VLA-1(+) TRM develop in murine tumors within 2 weeks, where they exhibit increased activation status, as well as superior effector functions. In addition, in vivo blockade of either VLA-1 or CD103 significantly impaired control of subcutaneous tumors. Together, our data indicate that VLA-1(+) TRM develop in tumors and play an important role in tumor immunity, presenting novel targets for the optimization of cancer immunotherapy.

Growth in preterm infants is compromised during the transition phase of nutrition, when parenteral nutrition (PN) volumes are weaned with advancing enteral nutrition (EN) feeds, likely due to suboptimal nutrient intakes during this time. We implemented new PN guidelines designed to maintain optimal nutrient intakes during the transition phase and compared growth outcomes of this cohort with a control group.A chart review was conducted on infants born32 weeks' gestation, before (control group) and after (study group) a new transition PN protocol was implemented in the neonatal intensive care unit. Weight parameters and nutrient intakes were calculated for the transition phase and compared between the 2 groups.Demographic and clinical characteristics of the 2 groups were comparable except for higher rates of sepsis in control group. Weight-for-age z scores at birth, at 1 week of life, and at the start of the transition phase were similar. At the end of the transition phase, infants in the study group had significantly higher z scores compared with the control group, even when corrected for sepsis, a difference that persisted at 35 weeks' gestation. During the transition phase, study infants gained 16.1 ± 4.6 g/kg/d compared with 13.2 ± 5.4 g/kg/d in control group ( P.001). Similar results were observed in the subset of expressed breastmilk-only fed infants (15.9 ± 4.6 g/kg/d in the study group compared with 13.2 ± 5.4 g/kg/d in the control group, P.004).Optimizing nutrition by the use of concentrated PN during the transition phase to maintain appropriate nutrient intakes improves growth rates in preterm infants.