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Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Background: Currently, over half of drug overdose deaths are due to opioids. Opioid alternatives may be prescribed to help curb the opioid epidemic. However, little is known about their efficacy for acute postoperative pain., Methods: We studied patients who underwent low-risk outpatient surgery. Perioperatively, all patients were started on an anti-inflammatory bundle consisting of multimodal pain remedies. Opioids were available to the patients postoperatively. Pain scores and opioid use were recorded., Results: Over 18 months, 120 patients underwent low-risk outpatient surgery and all used the anti-inflammatory bundle. All patients had a significant decrease in postoperative pain scores (p = 0.001). There was no significant difference in postoperative pain scores between those who followed the anti-inflammatory bundle alone and those who also used opioids (mean 2.2 vs 3.1/10). Twenty-five (21%) patients were using opioids preoperatively and 50 (42%) postoperatively. Of those using opioids preoperatively, six (24%) patients used the anti-inflammatory bundle alone and avoided opioids postoperatively., Conclusions: For 58% of our patients, an anti-inflammatory bundle alone provided adequate pain control after a low-risk outpatient operation, such as hernia repair. Our practice uses the anti-inflammatory bundle for all patients. Our goal is to reduce both the need for opioids and the surgeon's contribution to the opioid epidemic.

Together with the Africa Continental Branch of the International Society of Paediatric Oncology (SIOP Africa), the Uganda Cancer Institute, a tertiary governmental institution for specialised cancer care services, research and training, hosted the 14th continental meeting of SIOP Africa from the 16-18 March 2022. Under the conference theme, 'Innovate for Africa', the hybrid conference brought together close to 400 international delegates to discuss innovations and experiences, as well as share the latest research in the field of paediatric oncology. The World Health Organisation 2030 Global Initiative for Childhood Cancer provided the main starting point for the conference with a comprehensive pre-conference workshop programme, from multiple stakeholders and organisations and the themes for the plenaries towards improving survival to the main breakout sessions. Delegates discussed various ways of improving outcomes in Africa, despite the challenges faced individually and collectively ranging from education, management systems and treatment guidelines to future governmental and NGO involvement in African cancer care. The main achievements of the conference were various commitments for collaboration, investing in junior investigators, development of registries and systems for improved childhood care on the African continent, while working towards greater access to advanced management options such as targeted therapies and bone marrow transplant services., Competing Interests: The authors declare that they have no conflict of interests., (© the authors; licensee ecancermedicalscience.)

Background: The flank approach to lumbar spine surgery is considered a new minimally invasive alternative to the anterior abdominal approach. Flank incisional hernia is one complication, but it has been poorly studied., Methods: Retrospective review of patients referred for evaluation of abdominal bulging after Lateral Interbody Fusion (LIF), 2013-2020., Results: Seventeen patients were evaluated for abdominal bulging after LIF: 14 were diagnosed with incisional hernias. Three with denervation injury without hernia defect were excluded., Conclusions: This is the largest study addressing incisional flank hernias after LIF, an under-represented complication in the spine literature. We show that the patients present early, within months of their operation, and yet most hernias are not diagnosed for over a year. Although LIF is considered a minimally invasive procedure, the morbidity from hernia complications cannot be overlooked. These flank hernias are difficult to repair with suboptimal outcomes. We prefer robotic approach with primary closure of the defect and extraperitoneal sublay mesh, whenever possible. Prevention is key. To help reduce risk of hernia, we recommend closure of all muscle layers with slowly absorbable suture; this is different than was originally described in the spine literature., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: There are no effective treatments for Burkholderia cenocepacia in patients with cystic fibrosis (CF) due to bacterial multi-drug resistance and defective host killing. We demonstrated that decreased bacterial killing in CF is caused by reduced macrophage autophagy due to defective cystic fibrosis transmembrane conductance regulator (CFTR) function. AR-12 is a small molecule autophagy inducer that kills intracellular pathogens such as Francisella. We evaluated the efficacy of AR-12 and a new analogue AR-13 in reducing bacterial burden in CF phagocytes., Methods: Human CF and non-CF peripheral blood monocyte-derived macrophages, neutrophils, and nasal epithelial cells were exposed to CF bacterial strains in conjunction with treatment with antibiotics and/or AR compounds., Results: AR-13 and not AR-12 had growth inhibition on B. cenocepacia and methicillin-resistantStaphylococcus aureus (MRSA) in media alone. There was a 99% reduction in MRSA in CF macrophages, 71% reduction in Pseudomonas aeruginosa in CF neutrophils, and 70% reduction in non-CF neutrophils using AR-13. Conversely, there was no reduction in B. cenocepacia in infected CF and non-CF macrophages using AR-13 alone, but AR-13 and antibiotics synergistically reduced B. cenocepacia in CF macrophages. AR-13 improved autophagy in CF macrophages and CF patient-derived epithelial cells, and increased CFTR protein expression and channel function in CF epithelial cells., Conclusions: The novel AR-12 analogue AR-13, in combination with antibiotics, reduced antibiotic-resistant bacterial burden in CF phagocytes, which correlated with increased autophagy and CFTR expression. AR-13 is a novel therapeutic for patients infected with B. cenocepacia and other resistant organisms that lack effective therapies., (Copyright © 2018 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.)

Macrophage intracellular pathogen killing is defective in cystic fibrosis (CF), despite abundant production of reactive oxygen species (ROS) in lung tissue. Burkholderia species can cause serious infection in CF and themselves affect key oxidase components in murine non-CF cells. However, it is unknown whether human CF macrophages have an independent defect in the oxidative burst and whether Burkholderia contributes to this defect in terms of assembly of the NADPH oxidase complex and subsequent ROS production. In this article, we analyze CF and non-CF human monocyte-derived macrophages (MDMs) for ROS production, NADPH assembly capacity, protein kinase C expression, and calcium release in response to PMA and CF pathogens. CF MDMs demonstrate a nearly 60% reduction in superoxide production after PMA stimulation compared with non-CF MDMs. Although CF MDMs generally have increased total NADPH component protein expression, they demonstrate decreased expression of the calcium-dependent protein kinase C conventional subclass α/β leading to reduced phosphorylation of NADPH oxidase components p47 phox and p40 phox in comparison with non-CF MDMs. Ingestion of B. cenocepacia independently contributes to and worsens the overall oxidative burst deficits in CF MDMs compared with non-CF MDMs. Together, these results provide evidence for inherent deficits in the CF macrophage oxidative burst caused by decreased phosphorylation of NADPH oxidase cytosolic components that are augmented by Burkholderia These findings implicate a critical role for defective macrophage oxidative responses in persistent bacterial infections in CF and create new opportunities for boosting the macrophage immune response to limit infection., (Copyright © 2017 by The American Association of Immunologists, Inc.)

Afibrinogenemia is a rare dyscrasia characterized by a congenital fibrinogen deficiency It is transmitted in an autosomal recessive manner. Hemorrhagic manifestations are variable and can be life-threatening. A little more than 250 cases have been published up till now. We here report a new case of congenital afibrinogenemia in a 3 1/2-year old child hospitalized for medium abundance hematemesis. This case study aims to highlight numerous aspects of this condition from a clinical, biological, genetic and therapeutic points of view., Competing Interests: Les auteurs ne déclarent aucun conflit d’intérêt.

Background: Acinetobacter species are associated with increasing mortality due to emerging drug-resistance. Pediatric Acinetobacter infections are largely undefined in developed countries and clinical laboratory identification methods do not reliably differentiate between members of the Acinetobacter calcoaceticus-baumannii complex, leading to improper identification. Therefore we aimed to determine risk factors for invasive Acinetobacter infections within an academic, pediatric setting as well as defining microbiologic characteristics of predominant strains., Methods: Twenty-four invasive Acinetobacter isolates were collected from 2009-2013. Comparative sequence analysis of the rpoB gene was performed coupled with phenotypic characterization of antibiotic resistance, motility, biofilm production and clinical correlation., Results: Affected patients had a median age of 3.5 years, and 71 % had a central catheter infection source. rpoB gene sequencing revealed a predominance of A. pittii (45.8 %) and A. baumannii (33.3 %) strains. There was increasing incidence of A. pittii over the study. Two fatalities occurred in the A. pittii group. Seventeen percent of isolates were multi-drug resistant. A pittii and A. baumannii strains were similar in motility, but A pittii strains had significantly more biofilm production (P value = 0.018)., Conclusions: A. pittii was the most isolated species highlighting the need for proper species identification. The isolated strains had limited acute mortality in children, but the occurrence of more multi-drug resistant strains in the future is a distinct possibility, justifying continued research and accurate species identification.

Autophagy is a biological process characterized by self-digestion and involves induction of autophagosome formation, leading to degradation of autophagic cargo. Aging is associated with the reduction of autophagy activity leading to neurodegenerative disorders, chronic inflammation, and susceptibility to infection; however, the underlying mechanism is unclear. DNA methylation by DNA methyltransferases reduces the expression of corresponding genes. Since macrophages are major players in inflammation and defense against infection we determined the differences in methylation of autophagy genes in macrophages derived from young and aged mice. We found that promoter regions of Atg5 and LC3B are hypermethylated in macrophages from aged mice and this is accompanied by low gene expression. Treatment of aged mice and their derived macrophages with methyltransferase inhibitor (2)-epigallocatechin-3-gallate (EGCG) or specific DNA methyltransferase 2 (DNMT2) siRNA restored the expression of Atg5 and LC3 in vivo and in vitro. Our study builds a foundation for the development of novel therapeutics aimed to improve autophagy in the elderly population and suggests a role for DNMT2 in DNA methylation activities.

Autophagy describes an intracellular process responsible for the lysosome-dependent degradation of cytosolic components. The ULK1/2 complex comprising the kinase ULK1/2 and the accessory proteins ATG13, RB1CC1, and ATG101 has been identified as a central player in the autophagy network, and it represents the main entry point for autophagy-regulating kinases such as MTOR and AMPK. It is generally accepted that the ULK1 complex is constitutively assembled independent of nutrient supply. Here we report the characterization of the ATG13 region required for the binding of ULK1/2. This binding site is established by an extremely short peptide motif at the C terminus of ATG13. This motif is mandatory for the recruitment of ULK1 into the autophagy-initiating high-molecular mass complex. Expression of a ULK1/2 binding-deficient ATG13 variant in ATG13-deficient cells resulted in diminished but not completely abolished autophagic activity. Collectively, we propose that autophagy can be executed by mechanisms that are dependent or independent of the ULK1/2-ATG13 interaction.

The neurodegenerative effects of Parkinson's disease (PD) are marked by a selective loss of dopaminergic (DA) neurons. Epidemiological studies suggest that chronic exposure to the pesticide paraquat may increase the risk for PD and DA cell loss. However, combined exposure with additional fungicide(s) including maneb and/or ziram may be required for pathogenesis. To explore potential pathogenic mechanisms, we have developed a Drosophila model of chronic paraquat exposure. We find that while chronic paraquat exposure alone decreased organismal survival and motor function, combined chronic exposure to both paraquat and maneb was required for DA cell death in the fly. To initiate mechanistic studies of this interaction, we used additional genetic reagents to target the ubiquitin proteasome system, which has been implicated in some rare familial forms of PD and the toxic effects of ziram. Genetic inhibition of E1 ubiquitin ligase, but not the proteasome itself, increased DA cell death in combination with maneb but not paraquat. These studies establish a model for long-term exposure to multiple pesticides, and support the idea that pesticide interactions relevant to PD may involve inhibition of protein ubiquitination., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Burkholderia cenocepacia is a virulent pathogen that causes significant morbidity and mortality in patients with cystic fibrosis (CF), survives intracellularly in macrophages, and uniquely causes systemic infections in CF. Autophagy is a physiologic process that involves engulfing non-functional organelles and proteins and delivering them for lysosomal degradation, but also plays a role in eliminating intracellular pathogens, including B. cenocepacia. Autophagy is defective in CF but can be stimulated in murine CF models leading to increased clearance of B. cenocepacia, but little is known about autophagy stimulation in human CF macrophages. IFN-γ activates macrophages and increases antigen presentation while also inducing autophagy in macrophages. We therefore, hypothesized that treatment with IFN-γ would increase autophagy and macrophage activation in patients with CF. Peripheral blood monocyte derived macrophages (MDMs) were obtained from CF and non-CF donors and subsequently infected with B. cenocepacia. Basal serum levels of IFN-γ were similar between CF and non-CF patients, however after B. cenocepacia infection there is deficient IFN-γ production in CF MDMs. IFN-γ treated CF MDMs demonstrate increased co-localization with the autophagy molecule p62, increased autophagosome formation, and increased trafficking to lysosomes compared to untreated CF MDMs. Electron microscopy confirmed IFN-γ promotes double membrane vacuole formation around bacteria in CF MDMs, while only single membrane vacuoles form in untreated CF cells. Bacterial burden is significantly reduced in autophagy stimulated CF MDMs, comparable to non-CF levels. IL-1β production is decreased in CF MDMs after IFN-γ treatment. Together, these results demonstrate that IFN-γ promotes autophagy-mediated clearance of B. cenocepacia in human CF macrophages.