Exploration of Tilmicosin Cardiotoxicity in Rats and the Protecting Role of the Rhodiola rosea Extract: Potential Roles of Cytokines, Antioxidant, Apoptotic, and Anti-Fibrotic Pathways.

Tilmicosin (TIL) is a common macrolide antibiotic in veterinary medicine. High doses of TIL can have adverse cardiovascular effects. This study examined the effects of Rhodiola rosea (RHO) that have anti-inflammatory, antioxidant, and anti-fibrotic effects on tilmicosin (TIL)-induced cardiac injury targeting anti-inflammatory, antioxidant, apoptotic, and anti-apoptotic signaling pathways with anti-fibrotic outcomes. Thirty-six male Wistar albino rats were randomly divided into groups of six rats each. Rats received saline as a negative control, CARV 1 mL orally (10 mg/kg BW), and RHO 1 mL orally at 400 mg/kg BW daily for 12 consecutive days. The TIL group once received a single subcutaneous injection (SC) dose of TIL (75 mg/kg BW) on the sixth day of the experiment to induce cardiac damage. The standard group (CARV + TIL) received CARV daily for 12 consecutive days with a single TIL SC injection 1 h after CARV administration only on the sixth day of study and continued for another six successive days on CARV. The protective group (RHO + TIL) received RHO daily for the same period as in CARV + TIL-treated rats and with the dosage mentioned before. Serum was extracted at the time of the rat's scarification at 13 days of study and examined for biochemical assessments in serum lactate dehydrogenase (LDH), cardiac troponin I (cTI), and creatine phosphokinase (CK-MB). Protein carbonyl (PC) contents, malondialdehyde (MDA), and total antioxidant capacity (TAC) in cardiac homogenate were used to measure these oxidative stress markers. Quantitative RT-PCR was used to express interferon-gamma (INF-γ), cyclooxygenase-2 (COX-2), OGG1, BAX, caspase-3, B-cell lymphoma-2 (Bcl-2), and superoxide dismutase (SOD) genes in cardiac tissues, which are correlated with inflammation, antioxidants, and apoptosis. Alpha-smooth muscle actin (α-SMA), calmodulin (CaMKII), and other genes associated with Ca2+ hemostasis and fibrosis were examined using IHC analysis in cardiac cells (myocardium). TIL administration significantly increased the examined cardiac markers, LDH, cTI, and CK-MB. TIL administration also increased ROS, PC, and MDA while decreasing antioxidant activities (TAC and SOD mRNA) in cardiac tissues. Serum inflammatory cytokines and genes of inflammatory markers, DNA damage (INF-γ, COX-2), and apoptotic genes (caspase-3 and BAX) were upregulated with downregulation of the anti-apoptotic gene Bcl-2 as well as the DNA repair OGG1 in cardiac tissues. Furthermore, CaMKII and α-SMA genes were upregulated at cellular levels using cardiac tissue IHC analysis. On the contrary, pretreatment with RHO and CARV alone significantly decreased the cardiac injury markers induced by TIL, inflammatory and anti-inflammatory cytokines, and tissue oxidative-antioxidant parameters. INF-γ, COX-2, OGG1, BAX, and caspase-3 mRNA were downregulated, as observed by real-time PCR, while SOD and Bcl-2 mRNA were upregulated. Furthermore, the CaMKII and α-SMA genes' immune reactivities were significantly decreased in the RHO-pretreated rats.

Magnesium Sulfate in Pediatric Abdominal Cancer Surgery: Safety and Efficacy in Ultrasound-Guided Transversus Abdominis Plane (US-TAP) Block in Conjugation with Levobupivacaine.

Purpose: Magnesium sulfate (MgSO4) may enhance the effects of local anesthetics when used as an adjuvant in peripheral nerve blocks. Our objective was to evaluate efficiency and safety of utilizing MgSO4 alongside levobupivacaine in bilateral ultrasound-guided transversus abdominis plane (US-TAP) block for postoperative pain in pediatric cancer patients who underwent abdominal surgery. Methodology: A randomized double-blinded controlled trial at South Egypt Cancer Institute, Assiut University, Assiut, Egypt, included that 40 pediatric patients with Wilms' tumor or neuroblastoma were randomly allocated to get bilateral (US-TAP) block and divided into two groups; M group: received US-TAP with 0.6 mL/kg levobupivacaine 0.25% + 2 mg/kg MgSO4 and C group: received with 0.6 mL/kg levobupivacaine 0.25% only. FLACC scores (Face, Leg, Activity, Cry, Consolability) were used to evaluate post-operative pain, first analgesic request, total analgesic consumption, adverse effects, as well as hemodynamics were monitored for 24 h and recorded at time points (2, 4, 6, 8, 12, 18, and 24h). Parent's satisfaction at discharge, also, was evaluated. Results: FLACC score in M group was significantly lower than in C group from 4 h to 24 h with the first analgesic request being longer (15.95 ± 1.99 vs 7.70 ± 0.80 (h); p < 0.001) and lower total analgesic consumption (231.75 ± 36.57 vs 576.00 ± 170.71 (mg); p < 0.001) when comparing M group to C group, respectively. Both groups had insignificant differences regarding hemodynamics, parent satisfaction, postoperative agitation, and side effects except vomiting occurred in two patients in the C group and one patient in the M group. Conclusion: We conclude that adding magnesium sulphate as an adjuvant to local anaesthetic in US-TAP block for pain management in pediatric abdominal cancer surgeries resulted in better and longer analgesia, with less consumption of rescue analgesics with no serious side effects.

Evaluating steroid hormone receptor interactions using the live-cell NanoBRET proximity assay.

Steroid hormone receptors play a crucial role in the development and characterization of the majority of breast cancers. These receptors canonically function through homodimerization, but physical interactions between different hormone receptors play a key role in cell functions as well. The estrogen receptor (ERα) and progesterone receptor (PR), for example, are involved in a complex set of interactions known as ERα/PR crosstalk. Here, we developed a valuable panel of nuclear receptor expression plasmids specifically for use in NanoBRET assays to assess nuclear receptor homo- and heterodimerization. We demonstrate the utility of this assay system by assessing ERα/PR physical interaction in the context of the endocrine therapy resistance-associated ERα Y537S mutation. We identify a role of the ERα Y537S mutation beyond that of constitutive activity of the receptor; it also increases ERα/PR crosstalk. In total, the NanoBRET assay provides a novel avenue for investigating hormone receptor crosstalk. Future research may use this system to assess the effects of other clinically significant hormone receptor mutations on hormone receptor crosstalk.

Cancer stem cells as the source of tumor associated myoepithelial cells in the tumor microenvironment developing ductal carcinoma in situ.

The heterogeneous cell population in the stromal microenvironment is considered to be attributed to the multiple sources from which the cells originate. Tumor associated myoepithelial cells (TAMEs) are one of the most important populations in the tumor microenvironment (TME) especially in breast cancer. On the other hand, cancer stem cells (CSCs) have previously been described to be the origin of tumor-associated cellular components in the TME. We prepared a cancer stem cell model converting mouse-induced pluripotent stem cells (miPSCs) in the presence of conditioned medium of breast cancer cell line MDA-MB-231 cells. The converted cells developed tumors progressing into invasive carcinoma with ductal carcinoma in situ (DCIS) like structure when transplanted into mouse mammary fat pads. The primary cultured cells from the tumor further exhibited markers of CSC such as Sox2, Oct3/4, - CD133 and EpCAM, and mammary gland-related TAME markers such as α-smooth muscle actin, cytokeratin 8, whey acidic protein, prolactin receptor and progesterone receptor as well. These results indicated that the CSCs could be an origin of TAMEs contributing to mammary gland epithelial cell differentiation and the progression to invasive carcinoma during tumor development. The gene expression profiles confirmed the enhanced signaling pathways of PI3K/AKT and MAPK, which have been demonstrated to be enriched in the CSC models, together with the estrogen receptor signaling which was peculiar to mammary gland-derived character.

Activation of SIRT-1 Pathway by Nanoceria Sheds Light on Its Ameliorative Effect on Doxorubicin-Induced Cognitive Impairment (Chemobrain): Restraining Its Neuroinflammation, Synaptic Dysplasticity and Apoptosis.

Chemo fog is one of the most serious health concerns encountered by cancer survivors receiving doxorubicin (DOX)-based chemotherapy. Oxidative stress, neuroinflammation, apoptosis and impairment of synaptic plasticity are regarded as the key factors implicated in DOX-induced cognitive impairment. This research aimed to assess the possible neuroprotective effect of cerium oxide nanoparticles (CeNPs) against DOX-induced neurotoxicity. Forty-eight rats were divided into four groups (12 rats/group): control group, CeNPs group (received oral CeNPs solution (35 mg/kg) daily for 4 weeks), and DOX group (were administered DOX intraperitoneally (2 mg/kg, once/week for 4 weeks)) and DOX+ CeNPs group. The findings revealed that CeNPs mitigated behavioral alterations in DOX-induced cognitive deficit. Additionally, CeNPs alleviated the histopathological abnormalities in hippocampus and ameliorated DOX-induced neuroinflammation by downregulating the expression of NF-κB, TNF-α, IL-1ß and IL6. In addition, CeNPs antagonized the apoptosis through reducing the protein expression of cytochrome c and caspase 3. In addition, it stimulated the antioxidant defense, as indicated by upregulating the expression of the Nrf2, HO-1 and PGC-1α genes. CeNPs improved synaptic plasticity via acting on the BDNF. These actions were related through the modification of SIRT-1 expression. Based on the aforementioned results, CeNPs antagonized the doxorubicin-induced neurodegeneration by its antioxidant, anti-inflammatory and antiapoptotic effects, alongside its SIRT-1 mediated mechanisms.

Functional and Molecular Characters of Cancer Stem Cells Through Development to Establishment.

Cancer stem cells (CSCs) are small subpopulation sharing similar properties like normal stem such as self-renewal and differentiation potential to direct tumor growth. Last few years, scientists considered CSCs as the cause of phenotypic heterogeneity in diverse cancer types. Also, CSCs contribute to cancer metastasis and recurrence. The cellular and molecular regulators influence on the CSCs' phenotype changing their behaviors in different stages of cancer progression. CSC markers play significance roles in cancer diagnosis and characterization. We delineate the cross-talks between CSCs and the tumor microenvironment that supports their intrinsic properties including survival, stemness, quiescence and their cellular and molecular adaptation. An insight into the markers of CSCs specific to organs is described.

Microenvironment of mammary fat pads affected the characteristics of the tumors derived from the induced cancer stem cells.

Breast cancer is the first common cause of cancer-related death in women worldwide. Since the malignancy and aggressiveness of breast cancer have been correlated with the presence of breast cancer stem cells, the establishment of a disease model with cancer stem cells is required for the development of a novel therapeutic strategy. Here, we aimed to evaluate the availability of cancer stem cell models developed from mouse induced pluripotent stem cells with the conditioned medium of different subtypes of breast cancer cell lines, the hormonal-responsive T47D cell line and the triple-negative breast cancer BT549 cell line, to generate in vivo tumor models. When transplanted into the mammary fat pads of BALB/c nude mice, these two model cells formed malignant tumors exhibiting pronounced histopathological characteristics similar to breast cancers. Serial transplantation of the primary cultured cells into mammary fat pads evoked the same features of breast cancer, while this result was perturbed following subcutaneous transplantation. The tumors formed in the mammary fat pads exhibited immune reactivities to prolactin receptor, progesterone receptor, green florescent protein, Ki67, CD44, estrogen receptor α/ß and cytokeratin 8, while all of the tumors and their derived primary cells exhibited immunoreactivity to estrogen receptor α/ß and cytokeratin 8. Cancer stem cells can be developed from pluripotent stem cells via the secretory factors of cancer-derived cells with the capacity to inherit tissue specificity. However, cancer stem cells should be plastic enough to be affected by the microenvironment of specific tissues. In summary, we successfully established a breast cancer tumor model using mouse induced pluripotent stem cells developed from normal fibroblasts without genetic manipulation.

Increase in polymorphonuclear myeloid-derived suppressor cells and regulatory T-cells in children with B-cell acute lymphoblastic leukemia.

Our study aimed to evaluate the levels of MDSCs and Tregs in pediatric B-cell acute lymphoblastic leukemia (B-ALL), their relation to patients' clinical and laboratory features, and the impact of these cells on the induction response. This study included 31 pediatric B-ALL patients and 27 healthy controls. All patients were treated according to the protocols of the modified St. Jude Children's Research Hospital total therapy study XIIIB for ALL. Levels of MDSCs and Tregs were analyzed using flow cytometry. We observed a reduction in the levels of CD4 + T-cells and an increase in both the polymorphonuclear MDSCs (PMN-MDSCs) and Tregs. The frequencies of PMN-MDSCs and Tregs were directly related to the levels of peripheral and bone marrow blast cells and CD34 + cells. Complete postinduction remission was associated with reduced percentages of PMN-MDSCs and Tregs, with the level of PMN-MDCs in this subpopulation approaching that of healthy controls. PMN-MDSCs and Tregs jointly play a critical role in maintaining an immune-suppressive state suitable for B-ALL tumor progression. Thereby, they could be independent predictors of B-ALL progress, and finely targeting both PMN-MDSCs and Tregs may be a promising approach for the treatment of B-ALL.

Tumor-associated macrophages derived from cancer stem cells.

Macrophages are the most abundant immune cells in the microenvironment of solid tumors. The present study displayed histological and immunohistochemical analyses of a malignant tumor model developed from cancer stem cells (CSCs) converted from human induced pluripotent stem cells (hiPSCs) in a cancer microenvironment prepared from the conditioned medium (CM) of a pancreatic cancer cell line. We focused on the localization and the origin of tumor-associated macrophages (TAMs), To the best of our knowledge this may be the first study to suggest the potential differentiation of CSCs to TAMs. hiPSCs were converted into CSCs in the presence of CM from PK8 cells. CSCs were then transplanted in vivo and formed primary tumors. Primary cultures for these tumors were serially transplanted again to obtain secondary tumors. Secondary tumors exhibited histopathological features of malignancy. Cells derived from tumors maintained the expression of endogenous stemness markers and pancreatic CSCs markers. Simultaneously, high immunoreactivity to anti-mouse CD68, anti-human CD68, CD206 and CD11b antibodies were detected revealing that the tumor tissue derived from CSCs was enriched for macrophages which can originate from both human and mouse cells. The model of CSCs highlighted the possibility of CSCs to differentiate into TAMs.

Analgesic Effect of Intrathecal Fentanyl vs Dexmedetomidine as Adjuvants to Bupivacaine Following Abdominal Surgery for Cancer in Children, a Randomized Trial.

BACKGROUND: Intrathecal fentanyl in spinal anesthesia improves intra- and postoperative analgesia. Dexmedetomidine is a fascinating adjuvant with regards to neuraxial anesthesia in children experiencing surgery for abdominal malignancy. PATIENTS AND METHODS: After endorsement by the institutional reviewing board (IRB) and guardians' written informed consent, this research was carried out on 60 pediatric malignancy patients scheduled for major abdominal surgery. Children were randomly distributed into three groups (20 patients each): Group C: given 2 mL of bupivacaine 0.5% (0.4 mg/kg) intrathecally, injected gradually over 20 seconds. Group F: the same as group C, plus fentanyl 0.2 µg/kg. Group D: the same as group C, plus dexmedetomidine 0.2 µg/kg. Pain at zero, two, four, six, 12, 18, and 24 hours postoperatively was evaluated by Face, Legs, Activity, Crying, and Consolability (FLACC) score. First analgesic request and postoperative unfavorable effects were recorded for 24 hours postoperatively. RESULTS: A significant decrease was recognized in the mean FLACC score in groups D and F at six, eight, and 12 hours postoperatively, in contrast to group C (P ≤ 0.05). First analgesic request was significantly prolonged in group D (7.67 ± 0.57 hours), in contrast to groups F and C (5.40 ± 1.09 hours and 4.23 ± 3.27 hours, respectively, P < 0.04). Paracetamol utilization was significantly decreased in group D (316.67 ± 28.86 mg), in contrast to group C (391.00 ± 52.00 mg, P < 0.03), without a significant difference between group F (354.44 ± 46.67 mg) and groups D and C (P > 0.05). CONCLUSIONS: Adding dexmedetomidine and fentanyl to intrathecal bupivacaine improved postoperative analgesia following abdominal surgery for cancer in children, with better overall analgesia of dexmedetomidine compared with fentanyl.

Paclitaxel and Sorafenib: The Effective Combination of Suppressing the Self-Renewal of Cancer Stem Cells.

"Combination therapy", which is a treatment modality combining two or more therapeutic agents, is considered a cornerstone of cancer therapy. The combination of anticancer drugs, of which functions are different from the other, enhances the efficiency compared to the monotherapy because it targets cancer cells in a synergistic or an additive manner. In this study, the combination of paclitaxel and sorafenib in low concentration was evaluated to target cancer stem cells, miPS-BT549cmP and miPS-Huh7cmP cells, developed from mouse induced pluripotent stem cells. The synergistic effect of paclitaxel and sorafenib on cancer stem cells was assessed by the inhibition of proliferation, self-renewal, colony formation, and differentiation. While the IC50 values of paclitaxel and sorafenib were approximately ranging between 250 and 300 nM and between 6.5 and 8 µM, respectively, IC50 of paclitaxel reduced to 20 and 25 nM, which was not toxic in a single dose, in the presence of 1 µM sorafenib, which was not toxic to the cells. Then, the synergistic effect was further assessed for the potential of self-renewal of cancer stem cells by sphere formation ability. As a result, 1 µM of sorafenib significantly enhanced the effect of paclitaxel to suppress the number of spheres. Simultaneously, paclitaxel ranging in 1 to 4 nM significantly suppressed not only the colony formation but also the tube formation of the cancer stem cells in the presence of 1 µM sorafenib. These results suggest the combination therapy of paclitaxel and sorafenib in low doses should be an attractive approach to target cancer stem cells with fewer side effects.

Revisiting Cancer Stem Cells as the Origin of Cancer-Associated Cells in the Tumor Microenvironment: A Hypothetical View from the Potential of iPSCs.

The tumor microenvironment (TME) has an essential role in tumor initiation and development. Tumor cells are considered to actively create their microenvironment during tumorigenesis and tumor development. The TME contains multiple types of stromal cells, cancer-associated fibroblasts (CAFs), Tumor endothelial cells (TECs), tumor-associated adipocytes (TAAs), tumor-associated macrophages (TAMs) and others. These cells work together and with the extracellular matrix (ECM) and many other factors to coordinately contribute to tumor growth and maintenance. Although the types and functions of TME cells are well understood, the origin of these cells is still obscure. Many scientists have tried to demonstrate the origin of these cells. Some researchers postulated that TME cells originated from surrounding normal tissues, and others demonstrated that the origin is cancer cells. Recent evidence demonstrates that cancer stem cells (CSCs) have differentiation abilities to generate the original lineage cells for promoting tumor growth and metastasis. The differentiation of CSCs into tumor stromal cells provides a new dimension that explains tumor heterogeneity. Using induced pluripotent stem cells (iPSCs), our group postulates that CSCs could be one of the key sources of CAFs, TECs, TAAs, and TAMs as well as the descendants, which support the self-renewal potential of the cells and exhibit heterogeneity. In this review, we summarize TME components, their interactions within the TME and their insight into cancer therapy. Especially, we focus on the TME cells and their possible origin and also discuss the multi-lineage differentiation potentials of CSCs exploiting iPSCs to create a society of cells in cancer tissues including TME.

Metastasis of Cancer Stem Cells Developed in the Microenvironment of Hepatocellular Carcinoma.

Metastasis develops when cancer cells spread from the primary site of a malignant tumor to the surrounding and distant tissues, and it is the most critical problem in cancer treatment. Our group developed cancer stem cells (CSCs) from induced pluripotent stem cells (iPSCs) in the presence of a conditioned medium (CM) of cancer-derived cells. The CSCs were characterized by the formation of malignant tumors in vivo, followed by metastasis. In this study, CSCs converted from mouse iPSCs in the presence of CM from hepatocellular carcinoma (HCC) cell line Huh7 cells. These converted cells (miPS-Huh7cm cells) were established as the metastatic cells. The generated CSCs were injected into the liver or spleen of nude mice. Almost one month after transplantation, the tumors were excised, and the primary cultured cells derived from the malignant tumors and metastatic nodules were evaluated by stemness and metastatic markers to compare their differences. The miPS-Huh7cm cells exhibited metastatic potential, and efficiently formed malignant tumors with lung and/or liver lesions in vivo, whereas the injected miPS formed teratoma. The primary cultured cells derived from the malignant tumors and metastatic nodules sustained the expression of stemness markers, such as Nanog, Klf4 and c-Myc, and acquired cancer stem markers, such as CD90, CD44 and ALDH1. Simultaneously, the expression of metastatic markers, such as Slug, Twist1 and vimentin, in primary cells derived from the malignant tumors, was higher than in metastatic nodules. The CSCs derived from iPSCs, forming malignant tumors and displaying high metastasis, will provide a good animal model to study the mechanisms of metastasis.

Risk factors for multiple tobacco product use among high school youth.

PURPOSE: To examine how youth multiple tobacco product (MTP) users differ relative to non-users and to single-product users on risk factors at multiple levels of influence. METHODS: We analyzed data on high school students from the North Carolina Youth Tobacco Survey, 2015 (n = 2922). Single- and MTP use were defined as use of one, or two or more tobacco products in the past month, respectively. Multinomial regressions estimated the association between risk factors and MTP use compared to single-product use and non-use of tobacco. Risk factors included intra-personal (e.g., harm perceptions), and interpersonal (e.g., household, peer tobacco use, secondhand smoke or vapor, and advertising) factors. RESULTS: Of students, 12% and 13% were single product and MTP users, respectively. Many differences emerged between MTP users and non-tobacco users, with MTP users showing lower harm perceptions, higher perceived social benefits of smoking, significantly higher relative risk of having friends who use tobacco (RRR = 4.79, 95% CI 3.42, 6.70), of exposure to secondhand e-cigarette vapor (RRR = 1.35, 95% CI 1.23, 1.48), and of being receptive to tobacco marketing (RRR = 4.01, 95% CI 2.87, 5.61). Fewer differences emerged between MTP and single product users with MTP users having significantly higher relative risk of having friends who use tobacco (RRR = 2.31 95% CI 1.73, 3.07), of exposure to secondhand vapor (RRR = 1.10, 95% CI 1.02, 1.18), and of being receptive to tobacco marketing (RRR = 1.71, 95% CI 1.17, 2.50). CONCLUSIONS: Efforts that target multiple tobacco product use should increase youth tobacco-related harm perceptions, and protect youth from social, peer, and industry influences.

Preemptive nebulized ketamine for pain control after tonsillectomy in children: randomized controlled trial / Uso preventivo de cetamina nebulizada para controle da dor após amigdalectomia em crianças: estudo randômico e controlado

Abstract Objectives The administration of ketamine as nebulized inhalation is relatively new and studies on nebulized ketamine are scarce. We aimed to investigate the analgesic efficacy of nebulized ketamine (1 and 2 mg.kg-1) administered 30 min before general anesthesia in children undergoing elective tonsillectomy in comparison with intravenous ketamine (0.5 mg.kg-1) and saline placebo. Methods One hundred children aged (7-12) years were randomly allocated in four groups (n = 25) receive; Saline Placebo (Group C), Intravenous Ketamine 0.5 mg.kg-1 (Group K-IV), Nebulized Ketamine 1 mg.kg-1 (Group K-N1) or 2 mg.kg-1 (Group K-N2). The primary endpoint was the total consumption of rescue analgesics in the first 24 h postoperative. Results The mean time to first request for rescue analgesics was prolonged in K-N1 (400.9 ± 60.5 min, 95% CI 375.9-425.87) and K-N2 (455.5 ± 44.6 min, 95% CI 437.1-473.9) groups compared with Group K-IV (318.5 ± 86.1 min, 95% CI 282.9-354.1) and Group C (68.3 ± 21.9 min, 95% CI 59.5-77.1; p < 0.001), with a significant difference between K-N1 and K-N2 Groups (p < 0.001). The total consumption of IV paracetamol in the first 24 h postoperative was reduced in Group K-IV (672.6 ± 272.8 mg, 95% CI 559.9-785.2), Group K-N1 (715.6 ± 103.2 mg, 95% CI 590.4-840.8) and Group K-N2 (696.6 ± 133.3 mg, 95% CI 558.8-834.4) compared with Control Group (1153.8 ± 312.4 mg, 95% CI 1024.8-1282.8; p < 0.001). With no difference between intravenous and Nebulized Ketamine Groups (p = 0.312). Patients in intravenous and Nebulized Ketamine Groups showed lower postoperative VRS scores compared with Group C (p < 0.001), no differences between K-IV, K-N1 or K-N2 group and without significant adverse effects. Conclusion Preemptive nebulized ketamine was effective for post-tonsillectomy pain relief. It can be considered as an effective alternative route to IV ketamine.

Resumo Objetivos A administração de cetamina por via inalatória através de nebulizador é relativamente nova e os estudos sobre este assunto são escassos. Nosso objetivo foi investigar a eficácia analgésica da cetamina nebulizada (1 e 2 mg.kg-1) administrada 30 minutos antes da anestesia geral em crianças submetidas à amigdalectomia eletiva, em comparação com cetamina intravenosa (0,5 mg.kg-1) e placebo (soro fisiológico). Métodos Cem crianças entre 7-12 anos foram randomicamente alocadas em quatro grupos (n = 25) e receberam: soro fisiológico para controle (Grupo C); 0,5 mg.kg-1 de cetamina intravenosa (Grupo C-IV); 1 mg.kg-1 de cetamina nebulizada (Grupo C-N1); 2 mg.kg-1 de cetamina nebulizada (Grupo C-N2). O desfecho primário foi o consumo total de analgésicos de resgate nas primeiras 24 horas de pós-operatório. Resultados O tempo médio para a primeira solicitação de analgésicos de resgate foi prolongado nos grupos C-N1 (400,9 ± 60,5 min, IC 95% 375,9-425,87) e C-N2 (455,5 ± 44,6 min, IC 95% 437,1-473,9) em comparação com o Grupo C-IV (318,5 ± 86,1 min, IC 95% 282,9-354,1) e o Grupo C (68,3 ± 21,9 min, IC 95% 59,5-77,1; p < 0,001), com uma diferença significativa entre os grupos C-N1 e C-N2 (p < 0,001). O consumo total de paracetamol IV nas primeiras 24 horas de pós-operatório foi reduzido no Grupo C-IV (672,6 ± 272,8 mg, IC 95% 559,9-785,2), Grupo C-N1 (715,6 ± 103,2 mg, IC 95% 590,4-840,8) e Grupo C-N2 (696,6 ± 133,3 mg, IC 95% 558,8-834,4) em comparação com o Grupo C (1153,8 ± 312,4 mg, IC 95% 1024,8-1282,8; p < 0,001). Não houve diferença entre os grupos de cetamina intravenosa e nebulizada (p = 0,312). Os pacientes dos grupos de cetamina intravenosa e nebulizada apresentaram escores VRS pós-operatórios menores, em comparação com o Grupo C (p < 0,001), sem diferenças entre os grupos C-IV, C-N1 ou C-N2 e sem efeitos adversos significativos. Conclusão A administração preventiva de cetamina nebulizada foi eficaz no alívio da dor pós-amigdalectomia. Cetamina nebulizada pode ser considerada como uma via alternativa eficaz à cetamina IV.

Receipt of direct tobacco mail/email coupons and coupon redemption: Demographic and socioeconomic disparities among adult smokers in the United States.

A key marketing strategy used by tobacco companies to lower tobacco product prices is the distribution of tobacco coupons via direct marketing channels such as mail or email. We analyzed data on adult smokers from Wave 1 of the Population Assessment of Tobacco and Health (PATH) Study (n = 10,994) to examine the prevalence and correlates of coupon receipt via both channels, and associations with cigarette coupon redemption. Overall, 22% and 32% of smokers received tobacco coupons via email and mail, respectively, and 22% redeemed cigarette coupons. White, 25-44 year old, female, sexual minority, and more nicotine dependent smokers were more likely to receive coupons via both channels and to redeem coupons, as were smokers with mid-levels education (GED to associate degree) and those unable to pay important bills (OR email receipt = 1.37, 95% CI 1.22-1.54; OR mail receipt = 1.38, 95% CI 1.24-1.55; and OR coupon redemption = 1.44, 95% CI 1.26-1.64). Smokers who received coupons via mail only or via both channels, had three times (OR = 2.97, 95% CI 2.31-3.83) and five times (OR = 4.56, 95% CI 3.61-5.76) higher odds to redeem cigarette coupons compared to those who received them via email only. Major demographic and socioeconomic disparities exist in receipt and redemption of direct email\mail tobacco coupons among US smokers. Cigarette coupons received via direct mail are more likely to be redeemed than coupons received via email. Restrictions on tobacco coupon redemption, implemented jointly with increasing access to affordable cessation resources, may incentivize smokers vulnerable to tobacco marketing tactics to quit.

Vaping cannabis among adolescents: prevalence and associations with tobacco use from a cross-sectional study in the USA.

OBJECTIVE: Previous research suggests that some adolescents are using e-cigarette devices to vaporise ('vaping') cannabis in the form of hash oil, tetrahydrocannabinol (THC) wax or oil, or dried cannabis buds or leaves. However, it is unclear how adolescents who vape cannabis use other tobacco products. This study examined the extent to which adolescents reported ever vaping cannabis and investigated how demographic variables and tobacco behaviours were associated with use. DESIGN: We used cross-sectional data from adolescents (total response rate 64.5%) who participated in the 2017 North Carolina Youth Tobacco Survey. SAS logistic regression survey procedures were used to account for the complex survey design and sampling weights. SETTING: North Carolina, USA. PARTICIPANTS: Adolescents in high school (n=2835). PRIMARY OUTCOME AND MEASURE: Adolescents were asked to indicate whether they had ever used an e-cigarette device with marijuana, THC or hash oil, or THC wax. RESULTS: Approximately 1 in 10 high school students reported ever vaping cannabis in the overall sample (9.6%). In multivariable models, adolescents who reported using cigars (adjusted OR (aOR) 3.76, 95% CI 2.33 to 6.07), waterpipe (aOR 2.32, 95% CI 1.37 to 3.93) or e-cigarettes (aOR 3.18, 95% CI 2.38 to 4.25) in the past 30 days had higher odds of reporting ever vaping cannabis compared with their counterparts. There was no significant association between use of smokeless tobacco (aOR 0.89, 95% CI 0.42 to 1.91) or use of cigarettes (aOR 1.27, 95% CI 0.71 to 2.29) in the past 30 days and odds of reporting ever vaping cannabis. CONCLUSIONS: These findings provide evidence that large numbers of high school students who use tobacco products have vaped cannabis. As tobacco control policies-such as communication campaigns or smoke-free laws-increasingly focus on e-cigarettes, attention to understanding how adolescents use e-cigarettes to vape substances other than nicotine is essential.

Adolescents' first tobacco products: Associations with current multiple tobacco product use.

Understanding which tobacco products adolescents use first can lead to insights for tobacco prevention interventions and policies. We used cross-sectional data from high school students who reported ever using a tobacco product from the 2017 North Carolina Youth Tobacco Survey (n = 1,053). In multivariable regressions, we examined how demographic and psychosocial factors were associated with adolescents' first product tried and how first product tried was associated with current tobacco use (i.e., no use, use of a single product, use of multiple products) and frequency of tobacco use. Cigarettes (34.8%) and e-cigarettes (33.7%) were the most frequently reported first products tried, followed by cigars (15.6%), smokeless tobacco (10.7%), waterpipe (4.0%), and other tobacco products (i.e., pipe tobacco or some other tobacco product) (1.2%). Demographic differences in adolescents' first product tried existed, with Black adolescents having higher odds of initiating tobacco use via cigars (aOR: 6.17, 95% CI: 3.75, 10.14). Adolescents who initiated tobacco use via cigars (aOR: 2.33, 95% CI: 1.31, 4.13) or smokeless tobacco (aOR: 2.45, 95% CI: 1.18, 5.04) had higher odds of being a multiple current tobacco product user, whereas adolescents who initiated tobacco use via e-cigarettes (aOR: 0.57, 95% CI: 0.34, 0.93) had lower odds of being a multiple current tobacco product user. Additionally, adolescents who initiated tobacco use via smokeless tobacco had higher odds of currently using at least one tobacco product frequently (aOR: 1.90, 95% CI: 1.04, 3.48), while adolescents who initiated tobacco use via e-cigarettes had lower odds of currently using at least one tobacco product frequently (aOR: 0.40, 95% CI: 0.23, 0.70). These findings suggest that most adolescents reported initiating tobacco use via cigarettes or e-cigarettes and that trying certain products first (e.g., cigars, smokeless tobacco) was associated with higher odds of multiple current tobacco product use.

Similarities and Differences in Tobacco Control Research Findings From Convenience and Probability Samples.

BACKGROUND: Online convenience samples are a quick and low-cost way to study health behavior, but the comparability to findings from probability samples is not yet well understood. PURPOSE: We sought to compare convenience and probability samples' findings for experiments, correlates, and prevalence in the context of tobacco control research. METHODS: Participants were a probability sample of 5,014 U.S. adults recruited by phone from September 2014 through May 2015 (cost ~U.S.$620,000) and an online convenience sample of 4,137 U.S. adults recruited through Amazon Mechanical Turk (MTurk) in December 2014 (cost ~U.S.$17,000). Participants completed a survey with experiments, measures of tobacco product use and demographic characteristics. RESULTS: MTurk convenience and probability samples showed the same pattern of statistical significance and direction in almost all experiments (21 of 24 analyses did not differ) and observational studies (19 of 25 associations did not differ). Demographic characteristics of the samples differed substantially (1 of 17 estimates did not differ), with the convenience sample being younger, having more years of education, and including more Whites and Asians. Tobacco product use also differed substantially (1 of 22 prevalence estimates did not differ), with the convenience sample reporting more cigarette and e-cigarette use (median error 19%). CONCLUSIONS: Using MTurk convenience samples can yield generalizable findings for experiments and observational studies. Prevalence estimates from MTurk convenience samples are likely to be over- or underestimates.

The RICO Verdict and Corrective Statements: Catalysts for Policy Change?

OBJECTIVES: A federal court ruled tobacco companies violated racketeering laws and ordered them to publish corrective statements. This study assesses effects of exposure to the statements and related court findings on attitudes toward tobacco-related policies and tobacco company influences on policymaking. METHODS: We conducted a cross-sectional survey of US adults (N = 2010) prior to publication of the statements. Participants were randomly assigned to the "unexposed" group (N = 1004), which answered attitude questions before reading the statements and court findings, or the "exposed" group (N = 1006), which answered attitude questions after reading the statements and court findings. RESULTS: The exposed group was less likely to think lawmakers should trust tobacco companies as much as other companies (ß = -.24, p < .001) or that lawmakers should trust tobacco company lobbyists to provide accurate information (ß = -.17, p = .019), compared to the unexposed group. The exposed group also was more likely to support requiring graphic warning labels (ß = .15, p = .014) and point-of-sale quitline signs (ß = .13, p = .028). CONCLUSIONS: Exposure to the statements and court findings may aid tobacco industry denormalization and tobacco-related policy initiatives.