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The translation of pre‐clinical anti‐cancer therapies to regulatory approval has been promising, but slower than hoped. While innovative and effective treatments continue to achieve or seek approval, setbacks are often attributed to a lack of efficacy, failure to achieve clinical endpoints, and dose‐limiting toxicities. Successful efforts have been characterized by the development of therapeutics designed to specifically deliver optimal and effective dosing to tumour cells while minimizing off‐target toxicity. Much effort has been devoted to the rational design and application of synthetic nanoparticles to serve as targeted therapeutic delivery vehicles. Several challenges to the successful application of this modality as delivery vehicles include the induction of a protracted immune response that results in their rapid systemic clearance, manufacturing cost, lack of stability, and their biocompatibility. Extracellular vesicles (EVs) are a heterogeneous class of endogenous biologically produced lipid bilayer nanoparticles that mediate intercellular communication by carrying bioactive macromolecules capable of modifying cellular phenotypes to local and distant cells. By genetic, chemical, or metabolic methods, extracellular vesicles (EVs) can be engineered to display targeting moieties on their surface while transporting specific cargo to modulate pathological processes following uptake by target cell populations. This review will survey the types of EVs, their composition and cargoes, strategies employed to increase their targeting, uptake, and cargo release, and their potential as targeted anti‐cancer therapeutic delivery vehicles.

Continuous glucose monitoring (CGM) and continuous subcutaneous insulin infusions (CSIIs) are the current standard treatment devices for type 1 diabetes (T1D) management. With a high prevalence of T1D beginning in pediatrics and carrying into adulthood, insufficient glycemic control leads to poor patient outcomes. Dermatologic complications such as contact dermatitis, lipodystrophies, and inflammatory lesions are among those associated with CGM and CSII, which reduce glycemic control and patient compliance. This systematic review aims to explore the current literature surrounding dermatologic complications of CGM and CSII as well as the impact on patient outcomes. A systematic review of the literature was carried out using PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) 2020 guidelines using 5 online databases. Included articles were those containing primary data relevant to human participants and adverse reactions to CGM and CSII devices in pediatric populations, of which greater than 50% of the sample size were aged 0-21 years. Qualitative analysis was chosen due to the heterogeneity of outcomes. Following the application of exclusion criteria, 25 studies were analyzed and discussed. An additional 5 studies were identified after the initial search and inclusion. The most common complication covered is contact dermatitis, with 13 identified studies. Further, 7 studies concerned lipodystrophies, 5 covered nonspecific cutaneous changes, 3 covered unique cutaneous findings such as granulomatous reactions and panniculitis, and 2 discussed user acceptability. The dermatologic complications of CGM and CSII pose a potential risk to long-term glycemic control in T1D, especially in young patients where skin lesions can lead to discontinuation. Increased manufacturer transparency is critical and further studies are needed to expand upon the current preventative measures such as device site rotation and steroid creams, which lack consistent effectiveness.

Introduction Minimally invasive surgery (MIS), such as laparoscopic and robotic techniques, has become standard in kidney surgery due to its benefits in offering faster recovery while maintaining comparable oncologic outcomes when compared to open surgery. However, some cases still require unexpected conversion to open surgery, which can increase the risk of postoperative complications and increase the 30-day readmission risk. Predictors and risk factors for these conversions remain underexplored. This study uses the American College of Surgeons National Surgical Quality Improvement Program (ACS NSQIP) database to identify predictors and outcomes in nephrectomy patients, therefore improving patient selection for open surgeries. Methods Using the 2019-2020 NSQIP data, this retrospective study analyzed 14,186 patients, 4,862 of whom met the inclusion criteria of nephrectomy for kidney cancer. Patients were subcategorized into planned MIS (n=4,756) and unplanned conversion to open (UCO) (n=106). The Wilcoxon signed-rank test was utilized for continuous variables, and Fisher's exact test was performed for categorical variables, including chi-squared analysis. Statistical significance was set at a P-value of <0.05. Results Unplanned conversion to open rate was 2.2%. There was an increased incidence of unplanned conversion to open in T3 and T4 tumors (30.2% and 8.5%) compared to the planned group (21.2% and 0.50%). Patients in the American Society of Anesthesiologists (ASA) classification 3 and 4 categories were more likely to be within the unplanned group. Outcomes (readmission, blood transfusion, mean operative time, the length of stay, prolonged nil per os/nasogastric tube {NPO/NGT}, and lymphocele/lymphatic leak) were compared between the groups. Conclusion Higher tumor stage, higher ASA classification, deranged kidney function, and raised prothrombin time/international normalized ratio (PT/INR) were predictive factors for unplanned conversions, with worse outcomes such as prolonged hospitalizations and postoperative complications.

\"Native Son\" days require a comparatively small amount of the recruiter's time and cost far less than other methods, but they can do much to keep local talent at home

Background Airborne fine particulate matter with diameter < 2.5 μm (PM2.5), can reach the alveolar regions of the lungs, and is associated with over 4 million premature deaths per year worldwide. However, the source-specific consequences of PM2.5 exposure remain poorly understood. A major, but unregulated source is car brake wear, which exhaust emission reduction measures have not diminished. Methods We used an interdisciplinary approach to investigate the consequences of brake-wear PM2.5 exposure upon lung alveolar cellular homeostasis using diesel exhaust PM as a comparator. This involved RNA-Seq to analyse global transcriptomic changes, metabolic analyses to investigate glycolytic reprogramming, mass spectrometry to determine PM composition, and reporter assays to provide mechanistic insight into differential effects. Results We identified brake-wear PM from copper-enriched non-asbestos organic, and ceramic brake pads as inducing the greatest oxidative stress, inflammation, and pseudohypoxic HIF activation (a pathway implicated in diseases associated with air pollution exposure, including cancer, and pulmonary fibrosis), as well as perturbation of metabolism, and metal homeostasis compared with brake wear PM from low- or semi-metallic pads, and also, importantly, diesel exhaust PM. Compositional and metal chelator analyses identified that differential effects were driven by copper. Conclusions We demonstrate here that brake-wear PM may perturb cellular homeostasis more than diesel exhaust PM. Our findings demonstrate the potential differences in effects, not only for non-exhaust vs exhaust PM, but also amongst different sources of non-exhaust PM. This has implications for our understanding of the potential health effects of road vehicle-associated PM. More broadly, our findings illustrate the importance of PM composition on potential health effects, highlighting the need for targeted legislation to protect public health.

ObjectivesThis study investigates perceived barriers towards the implementation of multiprofessional team briefings (MPTB) in operating theatres, as well as ways to overcome these perceived barriers. Previous research shows that MPTB can enhance teamwork and communication, but are underused in operating theatres. By adopting a multilevel systems perspective, this study examines perceived barriers and solutions for MPTB implementation.DesignParticipants completed open-ended survey questions. Responses were coded via qualitative content analysis. The analysis focused on themes in the responses and the systems level at which each barrier and solution operates.SettingFour tertiary hospitals in Australia.Participants103 operating theatre staff, including nurses, surgeons, anaesthetists, technicians and administrators.ResultsParticipants identified barriers and solutions at the organisational (15.81% of barriers; 74.10% of solutions), work group (61.39% of barriers; 25.09% of solutions) and individual level (22.33% of barriers; 0% of solutions). Of all the perceived barriers to MPTB occurrence, a key one is getting everyone into the room at the same time . Matching of perceived barriers and solutions shows that higher systems-level solutions can address lower level barriers, thereby showing the relevance of implementing such wider reaching solutions to MPTB occurrence (including work practices at occupational level and above) as well as addressing more local issues.ConclusionsSuccessful MPTB implementation requires changes at various systems levels. Practitioners can strategically prepare and plan for systems-based strategies to overcome barriers to MPTB implementation. Future research can build on this study’s findings by directly examining higher systems-level barriers and solutions via detailed case analyses.

Tumor hypoxia (oxygen deficiency) is a major contributor to radiotherapy resistance. Ultrasound-sensitive microbubbles containing oxygen have been explored as a mechanism for overcoming tumor hypoxia locally prior to radiotherapy. Previously, our group demonstrated the ability to encapsulate and deliver a pharmacological inhibitor of tumor mitochondrial respiration (lonidamine (LND)), which resulted in ultrasound-sensitive microbubbles loaded with O2 and LND providing prolonged oxygenation relative to oxygenated microbubbles alone. This follow-up study aimed to evaluate the therapeutic response to radiation following the administration of oxygen microbubbles combined with tumor mitochondrial respiration inhibitors in a head and neck squamous cell carcinoma (HNSCC) tumor model. The influences of different radiation dose rates and treatment combinations were also explored. The results demonstrated that the co-delivery of O2 and LND successfully sensitized HNSCC tumors to radiation, and this was also enhanced with oral metformin, significantly slowing tumor growth relative to unsensitized controls (p < 0.01). Microbubble sensitization was also shown to improve overall animal survival. Importantly, effects were found to be radiation dose-rate-dependent, reflecting the transient nature of tumor oxygenation.

Abstract BACKGROUND Brain cavernous angiomas with symptomatic hemorrhage (CASH) are uncommon but exact a heavy burden of neurological disability from recurrent bleeding, for which there is no proven therapy. Candidate drugs to stabilize the CASH lesion and prevent rebleeding will ultimately require testing of safety and efficacy in multisite clinical trials. Much progress has been made in understanding the epidemiology of CASH, and novel biomarkers have been linked to the biological mechanisms and clinical activity in lesions. Yet, the ability to enroll and risk-stratify CASH subjects has never been assessed prospectively at multiple sites. Biomarkers and other outcomes have not been evaluated for their sensitivity and reliability, nor have they been harmonized across sites. OBJECTIVE To address knowledge gaps and establish a research network as infrastructure for future clinical trials, through the Trial Readiness grant mechanism, funded by National Institute of Neurological Disorders and Stroke/National Institutes of Health. METHODS This project includes an observational cohort study to assess (1) the feasibility of screening, enrollment rates, baseline disease categorization, and follow-up of CASH using common data elements at multiple sites, (2) the reliability of imaging biomarkers including quantitative susceptibility mapping and permeability measures that have been shown to correlate with lesion activity, and (3) the rates of recurrent hemorrhage and change in functional status and biomarker measurements during prospective follow-up. EXPECTED OUTCOMES We propose a harmonized multisite assessment of enrollment rates of CASH, baseline features relevant to stratification in clinical trials, and follow-up assessments of functional outcomes in relation to clinical bleeds. We introduce novel biomarkers of vascular leak and hemorrhage, with firm mechanistic foundations, which have been linked to clinical disease activity. We shall test their reliability and validity at multiple sites, and assess their changes over time, with and without clinical rebleeds, hence their fitness as outcome instruments in clinical trials. DISCUSSION The timing cannot be more opportune, with therapeutic targets identified, exceptional collaboration among researchers and the patient community, along with several drugs ready to benefit from development of a path to clinical testing using this network in the next 5 years.

Micropollutants are increasingly prevalent in the aquatic environment. A major part of these originates from wastewater treatment plants since traditional treatment technologies do not remove micropollutants sufficiently. Moving bed biofilm reactors (MBBRs), however, have been shown to aid in micropollutant removal when applied to conventional wastewater treatment as a polishing step. Here, we used Total RNA sequencing to investigate both the active microbial community and functional dynamics of MBBR biofilms when these were exposed to increasing micropollutant concentrations over time. Concurrently, we conducted batch culture experiments using biofilm carriers from the MBBRs to assess micropollutant degradation potential. Our study showed that biofilm eukaryotes, in particular protozoa, were negatively influenced by micropollutant exposure, in contrast to prokaryotes that increased in relative abundance. Further, we found several functional genes that were differentially expressed between the MBBR with added micropollutants and the control. These include genes involved in aromatic and xenobiotic compound degradation. Moreover, the biofilm carrier batch experiment showed vastly different alterations in benzotriazole and diclofenac degradation following the increased micropollutant concentrations in the MBBR. Ultimately, this study provides essential insights into the microbial community and functional dynamics of MBBRs and how an increased load of micropollutants influences these dynamics.

Culturable bacterial pathogens (Campylobacter, Salmonella, Listeria, Yersinia) and indicators (E. coli, enterococci, Clostridium perfringens) were quantified at six water resource recovery facilities that land apply anaerobically digested biosolids in Ontario, Canada. Cryptosporidium parvum and Giardia lamblia were also quantified by polymerase chain reaction (PCR). Salmonella and Listeria were frequently detected in sludge and liquid biosolids (70–100% of samples) but less often in fresh dewatered cake biosolids (50–60%); with low levels in fresh cake (<100 cells/g dw). Yersinia were in 20 to 30% of samples, typically at very low levels (<10 cell/g dw). Giardia and Cryptosporidium were detected in 80 and 20% of cake biosolids at geometric means of 270 cysts/g dw and 70 oocysts/g dw, respectively. E. coli reduction was typically >2-log10 while pathogen reduction was variable. “Sudden increase” of pathogens was not observed, however, Salmonella and E. coli showed regrowth (at 1 to 3 orders of magnitude) after 2-to 3-day storage at 30 °C.