Clinical Presentation, Treatment Response and Virology Outcomes of Women who Seroconverted in the Dapivirine Vaginal Ring Trials – The Ring Study and DREAM

alexandrossfakianakis shared this article with you from Inoreader Clinical Presentation, Treatment Response and Virology Outcomes of Women who Seroconverted in the Dapivirine Vaginal Ring Trials – The Ring Study and DREAM via Clinical Infectious Diseases Advance Access Abstract Background Participants who HIV seroconverted in The Ring Study, a Phase III trial of Dapivirine Vaginal Ring (DVR), or in the open-label extension trial DREAM, were offered enrollment in an observational cohort study (IPM 007) to assess clinical presentation and response to antiretroviral treatment (ART). Methods Participants' HIV infection was managed at local treatment clinics according to national treatment guidelines. IPM 007 study visits occurred 3 and 6 months after enrollment, and every 6 months thereafter. Assessments included plasma HIV-1 RNA, CD4+ T-cell counts, and recording of HIV/AIDS-associated events and ARV use. Post-hoc virology analyses were performed for participants identified with virologic failure. Results One-hundred-and-fifty-one of 179 eligible participants (84.4%) enrolled into IPM 007; 103 had previously received the DVR in the Ring or DREAM studies; 48 had received placebo in The Ring Stu dy. HIV-1 RNA and CD4+ T-cell counts after 12 months' follow-up were similar for participants who used the DVR in The Ring Study and DREAM, compared to those who received placebo. Of the 78 participants with a study visit approximately 6 months after ART initiation, 59 (75.6%) had HIV-1 RNA <40 copies/mL (The Ring Study: placebo: 13/23; 56.5%; DVR: 32/39; 82.1%; DREAM [DVR]: 14/16; 87.5%). Post-hoc virology analysis indicated that genotypic patterns observed at virologic failure were as expected of an NNRTI-based regimen. Conclusions Seroconversion during DVR use did not negatively affect clinical presentation or treatment outcome. Mutation patterns at virologic failure were in line with individuals failing an NNRTI-based regimen. View on Web

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Impact of respiratory infection and chronic comorbidities on early pediatric antibiotic dispensing in the United States

alexandrossfakianakis shared this article with you from Inoreader Impact of respiratory infection and chronic comorbidities on early pediatric antibiotic dispensing in the United States via Clinical Infectious Diseases Advance Access Abstract Background In the United States, children under age 5 receive high volumes of antibiotics, which may contribute to antibiotic resistance. It has been unclear what role preventable illnesses and chronic comorbidities play in prompting antibiotic prescriptions. Methods We conducted an observational study with a cohort of 124,759 children under age 5 born in the United States between 2008 and 2013 with private medical insurance. Study outcomes included the cumulative number of antibiotic courses dispensed per child by age 5 and the proportion of children for whom at least one antibiotic course was dispensed by age 5. We identified which chronic medical conditions predicted whether a child would be among the top 20% of antibiotic recipients. Results Children received a mean of 6.8 (95% confidence interval [CI] 6.7, 6.9) antibiotic courses by age five, and 91% (95% CI 90, 92) of children had received at least one antibiotic course by age five. Most antibiotic courses (71%, 95% CI 70, 72) were associated with respiratory infections. Presence of a pulmonary/respiratory, otologic, and/or immunological comorbidity substantially increase a child's odds of being in the top 20% of antibiotic recipients. Children with at least one of these conditions received a mean of 10.5 (95% CI 10.4, 10.6) antibiotic courses by age 5. Conclusions Privately insured children in the US receive high volumes of antibiotics early in their lives, largely related to respiratory infections. Antibiotic dispensing is unequally distributed among children, with substantially more antibiotics dispensed to children with select comorbidities. View on Web

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Irinotecan dose schedule for the treatment of Ewing sarcoma

alexandrossfakianakis shared this article with you from Inoreader Irinotecan dose schedule for the treatment of Ewing sarcoma via Pediatric Blood & Cancer Abstract Irinotecan and temozolomide achieve objective responses in patients with Ewing sarcoma that recurs after initial therapy. Optimal dose schedules have not been defined. We reviewed published series of patients treated with irinotecan and temozolomide for Ewing sarcoma that recurred after initial therapy. We compared objective response rates for patients who received 5-day irinotecan treatment schedules to response rates for patients who achieved 10-day irinotecan treatment schedules. Among 89 patients treated with a 10-day irinotecan schedule, there were 47 objective responses (53%). Among 180 patients treated with a 5-day irinotecan schedule, there were 52 responses (29%). In the treatment of recurrent Ewing sarcoma, investigators should consider the use of a 10-day schedule for administration of irinotecan. View on Web

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Anaplastic lymphoma kinase positive histiocytosis presenting as hemocytopenia in an infant

alexandrossfakianakis shared this article with you from Inoreader Anaplastic lymphoma kinase positive histiocytosis presenting as hemocytopenia in an infant via Pediatric Blood & Cancer View on Web

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Relationship between the timing of chemotherapy and surgical complications following surgical biopsy in children with malignant solid tumors

alexandrossfakianakis shared this article with you from Inoreader Relationship between the timing of chemotherapy and surgical complications following surgical biopsy in children with malignant solid tumors via Pediatric Blood & Cancer Abstract Background Biopsies for diagnosis before chemotherapy is common in children with malignant solid tumors. Wound healing is delayed by chemotherapy; however, the ideal interval between biopsy and chemotherapy remains unknown. We aimed to summarize the relationship between chemotherapy timing and postoperative surgical complications. Procedure We retrospectively reviewed patients with malignant solid tumors who underwent chemotherapy after surgical biopsy at our institution between January 2014 and August 2020. The primary outcomes were postoperative surgical complications (within 30 days) and the timing of chemotherapy. Results Forty-three patients were analyzed. The types of tumors were neuroblastoma (n = 20), hepatoblastoma (n = 10), Ewing sarcoma (n = 5), germ cell tumor (n = 3), angiosarcoma (n = 1), clear cell sarcoma (n = 1), ganglioneuroblastoma (n = 1), rhabdoid tumor (n = 1), and rhabdomyosarcoma (n = 1). The operative procedures were thoracoscopy (n = 5), laparotomy (n = 17), laparoscopy (n = 14), and superficial (n = 7). The median time [range] to chemotherapy after biopsy was 4 [0–21] days. No surgical complications occurred before chemotherapy, and two (4.7%) patients experienced complications after chemotherapy. These included postoperative hemorrhage (grade 3) and surgical site infection (grade 1). Chemotherapy was initiated 1 and 6 days after biopsy, respectively, in these cases. Complications occurred 10 and 23 days after biopsy, respectively. Conclusion The rate of postoperative surgical complications related to biopsy seems acceptable, even when chemotherapy was initiated in the early postoperative period. Early initiation of chemotherapy after biopsy may be a suitable option, particularly in children with bulky or symptomatic malignant solid tumors. View on Web

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Imaging of pediatric adrenal tumors: A COG Diagnostic Imaging Committee/SPR Oncology Committee White Paper

alexandrossfakianakis shared this article with you from Inoreader Imaging of pediatric adrenal tumors: A COG Diagnostic Imaging Committee/SPR Oncology Committee White Paper via Pediatric Blood & Cancer Abstract Adrenal tumors other than neuroblastoma are uncommon in children. The most frequently encountered are adrenocortical carcinoma and pheochromocytoma. This paper offers consensus recommendations for imaging of pediatric patients with a known or suspected primary adrenal malignancy other than neuroblastoma at diagnosis and during follow-up. View on Web

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Surgical margins of the oral cavity: is 5 mm really necessary?

alexandrossfakianakis shared this article with you from Inoreader Surgical margins of the oral cavity: is 5 mm really necessary? via Most Recent Articles: Journal of Otolaryngology - Head & Neck Surgery Squamous cell carcinoma is the most common malignancy of the oral cavity. Primary treatment involves surgical resection of the tumour with a surrounding margin. Historically, the most commonly accepted margin ... View on Web

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Characterizing the biology of primary brain tumors and their microenvironment via single-cell profiling methods

alexandrossfakianakis shared this article with you from Inoreader Characterizing the biology of primary brain tumors and their microenvironment via single-cell profiling methods via Neuro-Oncology Advance Access Abstract Genomic and transcriptional heterogeneity is prevalent among the most common and aggressive primary brain tumors in children and adults. Over the past 20 years, advances in bioengineering, biochemistry and bioinformatics have enabled the development of an array of techniques to study tumor biology at single-cell resolution. The application of these techniques to study primary brain tumors has helped advance our understanding of their intra-tumoral heterogeneity and uncover new insights regarding their co-option of developmental programs and signaling from their microenvironment to promote tumor proliferation and invasion. These insights are currently being harnessed to develop new therapeutic approaches. Here we provide an overview of current single-cell techniques and discuss relevant biology and therapeutic insights uncovered by their application to primary brain tumors in children and adults. View on Web

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Oral biofilm dysbiosis during experimental periodontitis

alexandrossfakianakis shared this article with you from Inoreader Oral biofilm dysbiosis during experimental periodontitis via Molecular Oral Microbiology Abstract Objectives We have previously characterized the main osteoimmunological events that occur during ligature periodontitis. This study aims to determine the polymicrobial community shifts that occur during disease development. Methods Periodontitis was induced in C57BL/6 mice using the ligature-induced periodontitis model. Healthy oral mucosa swabs and ligatures were collected every 3-days from 0 to 18 days post-ligature placement. Biofilm samples were evaluated by 16SrRNA gene sequencing (Illumina MiSeq) and QIIME. Timecourse changes were determined by relative abundance, diversity, and rank analyses (PERMANOVA, Bonferroni-adjusted). Results Microbial differences between health and periodontal inflammation were observed at all phylogenic levels. An evident microbial community shift occurred in 25 genera during the advancement of "gingivitis" (3-6d) to periodontitis (9-18d). From day 0–18, dramatic changes were identified Streptococcus levels, with an overall decrease (54.04-0.02%) as well an overall increase of Enterococcus and Lactobacillus (23.7-73.1% and 10.1%-70.2%, respectively). Alpha-diversity decreased to its lowest at 3d, followed by an increase in diversity as disease advancement. Beta-diversity increased after ligature placement, indicating that bone loss develops in response to a greater microbial variability (p = 0.001). Levels of facultative and strict anaerobic bacteria augmented over the course of disease progression, with a total of 8 species significantly different during the 18-day period. Conclusion The data supports that murine gingival inflammation and alveolar bone loss develop in response to microbiome shifts. Bacterial diversity increased during progression to bone loss. These findings further support the utilization of the periodontitis ligature model for microbial shift analysis under different experimental conditions. This article is protected by copyright. All rights reserved View on Web

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Afatinib triggers a Ni2+‐resistant Ca2+ influx pathway in A549 non‐small cell lung cancer cells

alexandrossfakianakis shared this article with you from Inoreader Afatinib triggers a Ni2+‐resistant Ca2+ influx pathway in A549 non‐small cell lung cancer cells via Fundamental & Clinical Pharmacology Abstract Afatinib is used to treat non-small cell lung cancer cells (NSCLC), and its mechanism involves irreversible inhibition of epidermal growth factor receptor (EGFR) tyrosine kinase. In this study, we examined if afatinib had cytotoxic action against NSCLC other than inhibition of tyrosine kinase. Afatinib (1-30 μM) caused apoptotic death in A549 NSCLC in a concentration-dependent manner. Afatinib triggered Ca2+ influx without causing Ca2+ release, and the Ca2+ influx was not unaffected by sodium orthovanadate (SOV, an inhibitor of tyrosine phosphatase), suggesting that afatinib-triggered Ca2+ response was unrelated to its inhibition of tyrosine kinase. Addition of afatinib also promoted Mn2+ influx. Ca2+ influx triggered by afatinib was resistant to SKF96365 and ruthenium red (two general blockers of TRP channels) and, unexpectedly, Ni2+ (a non-specific Ca2+ channel blocker). Afatinib caused an i ncrease in mitochondrial Ca2+ level, an initial mitochondrial hyperpolarization (4 h) and followed by mitochondrial potential collapse (24-48 h). Afatinib-induced cell death was slightly but significantly alleviated in low extracellular Ca2+ condition or under pharmacological block of mitochondrial permeability transition pore (MPTP) opening by cyclosporin A. Therefore, in addition to tyrosine kinase inhibition as a major anti-cancer mechanism of afatinib, stimulation of an atypical Ca2+ influx pathway, mitochondrial Ca2+ overload and potential collapse in part contribute to afatinib-induced cell death. View on Web

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Immunomodulatory effect of IL‐1RA in LPS activated macrophage/dental pulp stem cells co‐culture

alexandrossfakianakis shared this article with you from Inoreader Immunomodulatory effect of IL‐1RA in LPS activated macrophage/dental pulp stem cells co‐culture via International Endodontic Journal Abstract Aims: Lipopolysaccharides (LPS) activated human dental pulp stem cells (hDPSCs) and macrophage co-cultures showed downregulated TNF-α secretion that is modulated by hDPSCs through IDO axis, whereas the secretory levels of IL-1β remained unchanged. Therefore, sustained production of IL-1β could contribute to progressive dental pulp inflammation. However, the role of IL-1 receptor antagonists (IL-1RA) in downregulating the secretion of IL-1β and TNF-α in LPS activated M0/M1/M2 macrophage and hDPSCs co-culture has not been studied yet. Therefore, the aim of the present study is to determine the immunomodulatory role of blocking IL-1 receptors in DPSCs macrophage co-culture activated with LPS. Methodology: Human monocytic cell line THP-1 was polarised to M0, M1, and M2 macrophages and co-cultured with hDPSCs. The viability of the co-cultured cells was assessed by apoptosis assay. Co-cultures were activated with LPS followed by the assessment of gene expression and protein levels of IL-1β and TNF-α with and without IL-1RA blocking via qRT-PCR and cytokine flex assay by flow cytometry. Data from three separate experiments was analysed using One-way ANOVA followed by Tukey's Post-hoc test and a p value of <0.05 was considered statistically significant. Results: THP-1 derived M0, M1, and M2 macrophages co-cultured with hDPSCs showed spindle and round-shaped cells, with > 90% viability when assessed by apoptosis assay. Inflammatory TNF-α and IL-1β profile in stimulated co-cultures showed upregulated IL-1β whereas TNF-α was downregulated (p< 0.05). Anti-inflammatory gene expression levels of IL-10, TGF-β were downregulated (p< 0.05). Blocking with IL-1RA resulted in remarkable decrease of IL-1β at the gene expression and protein production levels while TNF-α levels remained low (p< 0.05). Levels of anti-inflammatory cytokine IL-10 showed no significant difference. Conclusion: Blocking the IL-1 receptor in hDPSCs and macrophage (M0, M1, M2) co-cultures activated with LPS resulted in down regulation of inflammatory cytokines IL-1β and TNF-α. These findings highlight the immunomodulatory effect of IL-1RA in inflammatory conditions of dental pulp infections. View on Web

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