Search

Objective: Medical care for cancer is increasingly directed by genomic laboratory testing for alterations in the tumor genome that are significant for diagnosis, prognosis and therapy. Uniquely in medicine, providers must search the biomedical literature for each patient to determine the clinical significance of these alterations. Access to published scientific literature is frequently subject to high fees, with access limited to institutional subscriptions. We sought to investigate the degree to which the scientific literature is accessible to clinical cancer genomics providers, and the potential role of university and hospital system libraries in information access for cancer care., Methods: We identified 265 journals that were accessed during the interpretation and reporting of clinical test results from 1,842 cancer patients at the University Health Network (Toronto, Canada). We determined the degree of open access for this set of clinically important literature, and for any journals not available through open access we surveyed subscription access at seven academic hospital systems and at their affiliated universities., Results: This study found that nearly half (116/265) of journals have open access mandates that make articles freely available within one year of release. For the remaining subscription access journals, universities provided a uniformly high level of access, but access available through hospital system collections varied widely., Conclusion: This study highlights the importance of different modes of access to the use of the scientific literature in clinical practice and points to challenges that must be overcome as genomic medicine grows in scale and complexity., (Copyright © 2023 Schnell D'Souza, Gregory Downs, Shawn Hendrikx, Rouhi Fazelzad, Gabriel Boldt, Karen Burns, Darlene Chapman, Declan Dawes, Antonia Giannarakos, Lori Anne Oja, Risa Schorr, Maureen Babb, Amada Hodgson, Jessica McEwan, Pamela Jacobs, Tracy Stockley, Tim Tripp, Ian King.)

Interprofessional collaboration (IPC) is fraught with multiple tensions. This is partly due to implicit biases within teams, which can reflect larger social, physical, organizational, and historical contexts. Such biases may influence communication, trust, and how collaboration is enacted within larger contexts. Despite the impact it has on teams, the influence of bias on IPC is relatively under-explored. Therefore, the authors conducted a scoping review on the influence of implicit biases within interprofessional teams. Using scoping review methodology, the authors searched several online databases. From 2792 articles, two reviewers independently conducted title/abstract screening, selecting 159 articles for full-text eligibility. From these, reviewers extracted, coded, and iteratively analyzed key data using a framework derived from socio-material theories. Authors found that many studies demonstrated how biases regarding dominance and expertise were internalized by team members, influencing collaboration in predominantly negative ways. Articles also described how team members dynamically adapted to such biases. Overall, there was a paucity of research that described material influences, often focusing on a single material element instead of the dynamic ways that humans and materials are known to interact and influence each other. In conclusion, implicit biases are relatively under-explored within IPC. The lack of research on material influences and the relationship among racial, age-related, and gender biases are critical gaps in the literature. Future research should consider the longitudinal and reciprocal nature of both positive and negative influences of bias on collaboration in diverse settings.

Objective: To perform a systematic review of the findings of iliopsoas release as it relates to resolution of snapping, improvement of groin pain, and associated complications., Design: Systematic review., Data Sources: Four electronic databases PubMed/MEDLINE, EMBASE, CINAHL, and Web of Science were searched, identifying all literature pertaining to surgical treatment of a snapping hip/coxa saltans, iliopsoas impingement, or iliopsoas tendinitis. A total of 818 studies were identified. Two reviewers independently screened the titles, abstracts, and full-text articles for eligibility., Eligibility Criteria: All studies published in English that reported on iliopsoas release for snapping hip/coxa saltans, iliopsoas impingement, or iliopsoas tendinitis reporting outcomes or associated complications were eligible., Results: A total of 48 articles were included in this review. Three surgical indications were identified for iliopsoas release, internal snapping hip, labral tear secondary to iliopsoas impingement, and iliopsoas tendinopathy after total hip arthroplasty. Arthroscopic techniques seemed to be superior to open techniques with regards to reoccurrence of snapping (5.1% vs 21.7%) and groin pain relief (89.1% vs 85.6%) with fewer complications (4.2% vs 21.1%) overall., Conclusions: Both open and arthroscopic iliopsoas releases have been shown to be successful treatment options regardless of the surgical indications identified in this review. Arthroscopic release demonstrated a decreased failure rate, fewer complications, and improved outcomes when compared with open procedures., Competing Interests: The authors report no conflicts of interest., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)

Telepsychiatry, the use of televideo in psychiatric assessment and treatment, is utilized throughout Canada. Major depressive disorder (MDD) is common, with significant burdens of suffering and cost. This systematic review explores the literature on the use of televideo to diagnose and treat MDD, particularly acceptability and patient satisfaction, efficacy, and cost-effectiveness. A literature search was conducted for years 1946 to 2019. Study eligibility criteria included: MDD as the condition of interest, use of televideo technology, randomized controlled trials (RCTs), Adult (18 years or older) population, any clinical setting, and any healthcare professional providing care. The study must have included at least one of the following measures, satisfaction, efficacy, and cost-effectiveness. Fourteen studies were included. Satisfaction is equivalent to or significantly higher than face-to-face intervention. Both televideo and control groups found relief from depressive symptoms, with differences either statistically insignificant or in favour of televideo. Despite increased cost upfront for televideo due to the technology required, televideo would eventually be more cost-effective due to reducing travel expenses. Limitations include that there is little RCT data, and what exists often uses a collaborative treatment model. Many studies consisted solely of U.S. Veterans, and have limited generalizability. Further research needed to directly compare psychiatrist assessment over televideo versus in-person, and determine if particular patient subgroups benefit more from televideo or in-person intervention.Systematic review registration number: CRD42016048224.

Background: The blood-brain barrier (BBB) is altered in several diseases of the central nervous system. For example, the breakdown of the BBB during cerebral ischemia in stroke or traumatic brain injury is a hallmark of the diseases' progression. This functional damage is one key event which is attempted to be mimicked in in vitro models. Recent studies showed the pivotal role of micro-environmental cells such as astrocytes for this barrier damage in mouse stroke in vitro models. The aim of this study was to evaluate the role of micro-environmental cells for the functional, paracellular breakdown in a human BBB cerebral ischemia in vitro model accompanied by a transcriptional analysis., Methods: Transwell models with human brain endothelial cell line hCMEC/D3 in mono-culture or co-culture with human primary astrocytes and pericytes or rat glioma cell line C6 were subjected to oxygen/glucose deprivation (OGD). Changes of transendothelial electrical resistance (TEER) and FITC-dextran 4000 permeability were recorded as measures for paracellular tightness. In addition, qPCR and high-throughput qPCR Barrier chips were applied to investigate the changes of the mRNA expression of 38 relevant, expressed barrier targets (tight junctions, ABC-transporters) by different treatments., Results: In contrast to the mono-culture, the co-cultivation with human primary astrocytes/pericytes or glioma C6 cells resulted in a significantly increased paracellular permeability after 5 h OGD. This indicated the pivotal role of micro-environmental cells for BBB breakdown in the human model. Hierarchical cluster analysis of qPCR data revealed differently, but also commonly regulated clustered targets dependent on medium exchange, serum reduction, hydrocortisone addition and co-cultivations., Conclusions: The co-cultivation with micro-environmental cells is necessary to achieve a functional breakdown of the BBB in the cerebral ischemia model within an in vivo relevant time window. Comprehensive studies by qPCR revealed that distinct expression clusters of barrier markers exist and that these are regulated by different treatments (even by growth medium change) indicating that controls for single cell culture manipulation steps are crucial to understand the observed effects properly.

Context: Intranasal dexmedetomidine (IND) is an emerging agent for procedural distress in children., Objective: To explore the effectiveness of IND for procedural distress in children., Data Sources: We performed electronic searches of Medline (1946-2019), Embase (1980-2019), Google Scholar (2019), Cumulative Index to Nursing and Allied Health Literature (1981-2019), and Cochrane Central Register., Study Selection: We included randomized trials of IND for procedures in children., Data Extraction: Methodologic quality of evidence was evaluated by using the Cochrane Collaboration's risk of bias tool and the Grading of Recommendations Assessment, Development, and Evaluation system, respectively. The primary outcome was the proportion of participants with adequate sedation., Results: Among 19 trials ( N = 2137), IND was superior to oral chloral hydrate (3 trials), oral midazolam (1 trial), intranasal midazolam (1 trial), and oral dexmedetomidine (1 trial). IND was equivalent to oral chloral hydrate (2 trials), intranasal midazolam (2 trials), and intranasal ketamine (3 trials). IND was inferior to oral ketamine and a combination of IND plus oral ketamine (1 trial). Higher doses of IND were superior to lower doses (4 trials). Adverse effects were reported in 67 of 727 (9.2%) participants in the IND versus 98 of 591 (16.6%) in the comparator group. There were no reports of adverse events requiring resuscitative measures., Limitations: The adequacy of sedation was subjective, which possibly led to biased outcome reporting., Conclusions: Given the methodologic limitations of included trials, IND is likely more effective at sedating children compared to oral chloral hydrate and oral midazolam. However, this must be weighed against the potential for adverse cardiovascular effects., Competing Interests: POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose., (Copyright © 2020 by the American Academy of Pediatrics.)

Rationale: B-1 cell-derived natural IgM antibodies against oxidation-specific epitopes on low-density lipoprotein are anti-inflammatory and atheroprotective. Bone marrow (BM) B-1a cells contribute abundantly to IgM production, yet the unique repertoire of IgM antibodies generated by BM B-1a and the factors maintaining the BM B-1a population remain unexplored. CXCR4 (C-X-C motif chemokine receptor 4) has been implicated in human cardiovascular disease and B-cell homeostasis, yet the role of B-1 cell CXCR4 in regulating atheroprotective IgM levels and human cardiovascular disease is unknown., Objective: To characterize the BM B-1a IgM repertoire and to determine whether CXCR4 regulates B-1 production of atheroprotective IgM in mice and humans., Methods and Results: Single-cell sequencing demonstrated that BM B-1a cells from aged ApoE -/- mice with established atherosclerosis express a unique repertoire of IgM antibodies containing increased nontemplate-encoded nucleotide additions and a greater frequency of unique heavy chain complementarity determining region 3 sequences compared with peritoneal cavity B-1a cells. Some complementarity determining region 3 sequences were common to both compartments suggesting B-1a migration between compartments. Indeed, mature peritoneal cavity B-1a cells migrated to BM in a CXCR4-dependent manner. Furthermore, BM IgM production and plasma IgM levels were reduced in ApoE -/- mice with B-cell-specific knockout of CXCR4, and overexpression of CXCR4 on B-1a cells increased BM localization and plasma IgM against oxidation specific epitopes, including IgM specific for malondialdehyde-modified LDL (low-density lipoprotein). Finally, in a 50-subject human cohort, we find that CXCR4 expression on circulating human B-1 cells positively associates with plasma levels of IgM antibodies specific for malondialdehyde-modified LDL and inversely associates with human coronary artery plaque burden and necrosis., Conclusions: These data provide the first report of a unique BM B-1a cell IgM repertoire and identifies CXCR4 expression as a critical factor selectively governing BM B-1a localization and production of IgM against oxidation specific epitopes. That CXCR4 expression on human B-1 cells was greater in humans with low coronary artery plaque burden suggests a potential targeted approach for immune modulation to limit atherosclerosis.

Calcineurin/NFAT signaling is active in endothelial cells and is proposed to be an essential component of the tumor angiogenic response. Here, we investigated the role of endothelial calcineurin signaling in vivo in physiological and pathological angiogenesis and tumor metastasis. We show that this pathway is dispensable for retinal and tumor angiogenesis, but it is implicated in vessel stabilization. While ablation of endothelial calcineurin does not affect the progression of primary tumors or tumor cell extravasation, it does potentiate the outgrowth of lung metastases. We identify Bmp2 as a downstream target of the calcineurin/NFAT pathway in lung endothelium, potently inhibiting cancer cell growth by stimulating differentiation. We reveal a dual role of calcineurin/NFAT signaling in vascular regression or stabilization and in the tissue-specific production of an angiocrine factor restraining cancer cell outgrowth. Our results suggest that, besides targeting the immune system, post-transplantation immunosuppressive therapy with calcineurin inhibitors directly targets the endothelium, contributing to aggressive cancer progression., (Copyright © 2019 The Author(s). Published by Elsevier Inc. All rights reserved.)

Aim: In children, intravenous anesthetic premedication can be distressing. Intranasal (IN) ketamine offers a less invasive approach., Materials and Methods: We included randomized trials of IN ketamine in anesthetic premedication in children 0-19 years. We performed electronic searches of MEDLINE, EMBASE, Google Scholar, CINAHL, Cochrane Library, Web of Science, Scopus, clinical trial registries and conference proceedings., Results: Among the 23 trials (n = 1680) included, IN ketamine adequately sedated 220/311 (70%) for face mask application, 217/308 (70%) for caregiver separation, 200/371 (54%) for iv. insertion and 19/30 (63%) for monitor application. Vomiting was the most common adverse effect (35/1579 [2.2%])., Conclusion: There is a need for sufficiently powered, methodologically rigorous trials, using psychometrically evaluated, objective outcome measures to meaningfully inform practice.

Nucleic acid-based therapies rely on efficient formulations for nucleic acid protection and delivery. As nonviral strategies, polymeric and lipid-based nanoparticles have been introduced; however, biological efficacy and biocompatibility as well as poor storage properties due to colloidal instability and their unavailability as ready-to-use systems are still major issues. Polyethylenimine is the most widely explored and promising candidate for gene delivery. Polyethylenimine-based polyplexes and their combination with liposomes, lipopolyplexes, are efficient for DNA or siRNA delivery in vitro and in vivo. In this study, a highly potent spray-dried nanoparticle-in-microparticle delivery system is presented for the encapsulation of polyethylenimine-based polyplexes and lipopolyplexes into poly(vinyl alcohol) microparticles, without requiring additional stabilizing agents. This easy-to-handle gene delivery device allows prolonged nanoparticle storage and protection at ambient temperature. Biological analyses reveal further advantages regarding profoundly reduced cytotoxicity and enhanced transfection efficacies of polyethylenimine-based nanoparticles from the nanoparticle-in-microparticle delivery system over their freshly prepared counterparts, as determined in various cell lines. Importantly, this nanoparticle-in-microparticle delivery system is demonstrated as ready-to-use dry powder to be an efficient device for the inhalative delivery of polyethylenimine-based lipopolyplexes in vivo, as shown by transgene expression in mice after only one administration., (© 2018 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

B-1 cells are a unique subset of B cells that are positively selected for expressing autoreactive BCRs. We isolated RNA from peritoneal (B-1a, B-1b, B-2) and splenic (B-1a, marginal zone, follicular) B cells from C57BL/6 mice and used 5'-RACE to amplify the IgH V region using massively parallel sequencing. By analyzing 379,000 functional transcripts, we demonstrate that B-1a cells use a distinct and restricted repertoire. All B-1 cell subsets, especially peritoneal B-1a cells, had a high proportion of sequences without N additions, suggesting predominantly prenatal development. Their transcripts differed markedly and uniquely contained V H 11 and V H 12 genes, which were rearranged only with a restricted selection of D and J genes, unlike other V genes. Compared to peritoneal B-1a, the peritoneal B-1b repertoire was larger, had little overlap with B-1a, and most sequences contained N additions. Similarly, the splenic B-1a repertoire differed from peritoneal B-1a sequences, having more unique sequences and more frequent N additions, suggesting influx of B-1a cells into the spleen from nonperitoneal sites. Two CDR3s, previously described as Abs to bromelain-treated RBCs, comprised 43% of peritoneal B-1a sequences. We show that a single-chain variable fragment designed after the most prevalent B-1a sequence bound oxidation-specific epitopes such as the phosphocholine of oxidized phospholipids. In summary, we provide the IgH V region library of six murine B cell subsets, including, to our knowledge for the first time, a comparison between B-1a and B-1b cells, and we highlight qualities of B-1 cell Abs that indicate unique selection processes., (Copyright © 2018 by The American Association of Immunologists, Inc.)

Biodegradability is a crucial characteristic to improve the clinical potential of sol-gel-derived glass materials. To this end, a set of degradable organic/inorganic class II hybrids from a tetraethoxysilane(TEOS)-derived silica sol and oligovalent cross-linker oligomers containing oligo(d,l-lactide) domains was developed and characterized. A series of 18 oligomers (Mn: 1100-3200Da) with different degrees of ethoxylation and varying length of oligoester units was established and chemical composition was determined. Applicability of an established indirect rapid prototyping method enabled fabrication of a total of 85 different hybrid scaffold formulations from 3-isocyanatopropyltriethoxysilane-functionalized macromers. In vitro degradation was analyzed over 12months and a continuous linear weight loss (0.2-0.5wt%/d) combined with only moderate material swelling was detected which was controlled by oligo(lactide) content and matrix hydrophilicity. Compressive strength (2-30MPa) and compressive modulus (44-716MPa) were determined and total content, oligo(ethylene oxide) content, oligo(lactide) content and molecular weight of the oligomeric cross-linkers as well as material porosity were identified as the main factors determining hybrid mechanics. Cytocompatibility was assessed by cell culture experiments with human adipose tissue-derived stem cells (hASC). Cell migration into the entire scaffold pore network was indicated and continuous proliferation over 14days was found. ALP activity linearly increased over 2weeks indicating osteogenic differentiation. The presented glass-based hybrid concept with precisely adjustable material properties holds promise for regenerative purposes., Statement of Significance: Adaption of degradation kinetics toward physiological relevance is still an unmet challenge of (bio-)glass engineering. We therefore present a glass-derived hybrid material with adjustable degradation. A flexible design concept based on degradable multi-armed oligomers was combined with an established indirect rapid prototyping method to produce a systematic set of porous sol-gel-derived class II hybrid scaffolds. Mechanical properties in the range of cancellous bone were narrowly controlled by hybrid composition. The oligoester introduction resulted in significantly increased compressive moduli. Cytocompatible hybrids degraded in physiologically relevant time frames and a promising linear and controllable weight loss profile was found. To our knowledge, our degradation study represents the most extensive long-term investigation of sol-gel-derived class II hybrids. Due to the broad adjustability of material properties, our concept offers potential for engineering of biodegradable hybrid materials for versatile applications., (Copyright © 2017. Published by Elsevier Ltd.)

Mutations in the gap junction protein connexin47 (Cx47) are associated with lymphedema. However, the role of Cx47 in lymphatic pathophysiology is unknown. We demonstrate that Cx47 is expressed in lymphatic endothelial cells by whole-mount immunostaining and qPCR. To determine if Cx47 plays a role in lymphatic vessel function we analysed Cx47-/- mice. Cx47-deficiency did not affect lymphatic contractility (contractile amplitude or frequency) or lymphatic morphology (vessel diameter or number of valves). Interstitial fluid drainage or dendritic cell migration through lymphatic vessels was also not affected by Cx47-deficiency. Cx47 is dispensable for long-chain fatty acid absorption from the gut but rather promotes serum lipid handling as prolonged elevated triglyceride levels were observed in Cx47-deficient mice after oral lipid tolerance tests. When crossed with Apolipoprotein E-deficient (Apoe-/-) mice, LDL-cholesterol was decreased in young Cx47-/-Apoe-/- adults as compared to Apoe-/- mice, which was inverted later in life. Finally, advanced atherosclerotic plaques in thoracic-abdominal aortas of 15 months-old mice tended to be larger in Cx47-/-Apoe-/- mice. These plaques contained fewer macrophages but similar amounts of T lymphocytes, collagen and lipids than plaques of Apoe-/- mice. In conclusion, Cx47 is expressed in lymphatic endothelium and seems modestly implicated in multiple aspects of lymphatic pathophysiology.

Background: A number of school systems worldwide have proposed and implemented later school start times as a means of avoiding the potentially negative impacts that early morning schedules can have on adolescent students. Even mild sleep deprivation has been associated with significant health and educational concerns: increased risk for accidents and injuries, impaired learning, aggression, memory loss, poor self-esteem, and changes in metabolism. Although researchers have begun to explore the effects of delayed school start time, no one has conducted a rigorous review of evidence to determine whether later school start times support adolescent health, education, and well-being., Objectives: We aimed to assess the effects of a later school start time for supporting health, education, and well-being in high school students.Secondary objectives were to explore possible differential effects of later school start times in student subgroups and in different types of schools; to identify implementation practices, contextual factors, and delivery modes associated with positive and negative effects of later start times; and to assess the effects of later school start times on the broader community (high school faculty and staff, neighborhood, and families)., Search Methods: We conducted the main search for this review on 28 October 2014 and updated it on 8 February 2016. We searched CENTRAL as well as 17 key electronic databases (including MEDLINE, Embase, ERIC, PsycINFO, and Sociological Abstracts), current editions of relevant journals and organizational websites, trial registries, and Google Scholar., Selection Criteria: We included any randomized controlled trials, controlled before-and-after studies, and interrupted time series studies with sufficient data points that pertained to students aged 13 to 19 years and that compared different school start times. Studies that reported either primary outcomes of interest (academic outcomes, amount or quality of sleep, mental health indicators, attendance, or alertness) or secondary outcomes (health behaviors, health and safety indicators, social outcomes, family outcomes, school outcomes, or community outcomes) were eligible., Data Collection and Analysis: At least two review authors independently determined inclusion and exclusion decisions through screening titles, abstracts, and full-text reports. Two review authors independently extracted data for all eligible studies. We presented findings through a narrative synthesis across all studies. When two or more study samples provided sufficient information to permit effect size calculations, we conducted random-effects meta-analyses to synthesize effects across studies., Main Results: Our search located 17 eligible records reporting on 11 unique studies with 297,994 participants; the studies examined academic outcomes, amount and quality of sleep, mental health indicators, attendance, and student alertness. Overall, the quality of the body of evidence was very low, as we rated most studies as being at high or unclear risk of bias with respect to allocation, attrition, absence of randomization, and the collection of baseline data. Therefore, we cannot be confident about the effects of later school start times.Preliminary evidence from the included studies indicated a potential association between later school start times and academic and psychosocial outcomes, but quality and comparability of these data were low and often precluded quantitative synthesis. Four studies examined the association between later school start times and academic outcomes, reporting mixed results. Six studies examined effects on total amount of sleep and reported significant, positive relationships between later school start times and amount of sleep. One study provided information concerning mental health outcomes, reporting an association between decreased depressive symptoms and later school start times. There were mixed results for the association between later school start times and absenteeism. Three studies reported mixed results concerning the association between later school start times and student alertness. There was limited indication of potential adverse effects on logistics, as the qualitative portions of one study reported less interaction between parents and children, and another reported staffing and scheduling difficulties. Because of the insufficient evidence, we cannot draw firm conclusions concerning adverse effects at this time.It is important to note the limitations of this evidence, especially as randomized controlled trials and high-quality primary studies are difficult to conduct; school systems are often unwilling or unable to allow researchers the necessary control over scheduling and data collection. Moreover, this evidence does not speak to the process of implementing later school starts, as the included studies focused on reporting the effects rather than exploring the process., Authors' Conclusions: This systematic review on later school start times suggests several potential benefits for this intervention and points to the need for higher quality primary studies. However, as a result of the limited evidence base, we could not determine the effects of later school start times with any confidence.

Background: Ketamine is commonly used for procedural sedation and analgesia (PSA) in children. Evidence suggests it can be administered intranasally (IN). We sought to review the evidence for IN ketamine for PSA in children., Methods: We performed a systematic review of randomized trials of IN ketamine in PSA that reported any sedation-related outcome in children 0 to 19 years. Trials were identified through electronic searches of MEDLINE (1946-2016), EMBASE (1947-2016), Google Scholar (2016), CINAHL (1981-2016), The Cochrane Library (2016), Web of Science (2016), Scopus (2016), clinical trial registries, and conference proceedings (2000-2016) without language restrictions. The methodological qualities of studies and the overall quality of evidence were evaluated using the Cochrane Collaboration's Risk of Bias tool, and the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) system, respectively., Results: The review included 7 studies (n = 264) of children ranging from 0 to 14 years. Heterogeneity in study design precluded meta-analysis. Most studies were associated with a low or unclear risk of bias and outcome-specific ratings for quality of evidence were low or very low. In four of seven studies, IN ketamine provided superior sedation to comparators and resulted in adequate sedation for 148/175 (85%) of participants. Vomiting was the most common adverse effect; reported by 9/91 (10%) of participants., Conclusions: IN ketamine administration is well tolerated and without serious adverse effects. Although most participants were deemed adequately sedated with IN ketamine, effectiveness of sedation with respect to superiority over comparators was inconsistent, precluding a recommendation for PSA in children.

Nucleic acid-based therapeutics offer enormous potential in the treatment of various pathologies. For DNA or RNA delivery, nanoparticle systems based on lipids or polymers have been developed. However, colloidal instability in solution, poor storage properties especially as dry powder and little stability against an aggressive environment, e.g. after oral application, are major issues. Furthermore, there is an urgent need for sustained release systems that allow for fine-tuned, long-term temporal and spatial nanoparticle release. In this paper, we describe the embedding of polymeric nanoparticles for gene delivery, namely polyethylenimine (PEI)-based polyplexes and their corresponding liposome-modified analogues (lipopolyplexes), into microparticulate poly (vinyl alcohol) (PVA) hydrogels. Various parameters are modified, and major differences are found. PVA is explored with two different molecular weights and at different concentrations, furthermore different emulsifiers and acetone for extraction are employed, and the protocol is performed with or without repetitive freeze/thaw cycles for physical PVA crosslinking. We thereby establish Nanoparticles-in-Microparticle Delivery Systems (NiMDS) that are extensively characterized and shown to allow prolonged storage as easy-to-handle formulation (dry powder) without loss of nanoparticle activity. Unexpectedly, the nanoparticles' PVA encapsulation/release alters important physicochemical nanoparticle properties and biological activities in a favourable way. Furthermore, we also demonstrate the nanoparticle release to be dependent on the microstructure of the PVA matrix, which is determined by the degree of physical crosslinking through a defined number of freeze/thaw cycles. We show that these defined physically crosslinked PVA hydrogels thus represent sustained release devices for fine-tuned, long-term nanoparticle release in possible therapeutic applications., Statement of Significance: The present paper for the first time describes the embedding of polymeric PEI-based polyplexes and lipopolyplexes into poly(vinyl alcohol) (PVA) hydrogels, to establish novel Nanoparticles-in-Microparticle Delivery Systems (NiMDS). Through modification of various parameters including different PVA molecular weights and concentrations, different emulsifiers and defined numbers of freeze-thaw cycles for physical PVA crosslinking, sustained release devices are also obtained. Beyond favourable alterations of important physicochemical/biological nanoparticle properties and the possibility for prolonged storage as easy-to-handle formulation (dry powder), we show that these NiMDS also allow the tailormade, fine-tuned, long-term release of fully active nanoparticles in possible therapeutic applications., (Copyright © 2016 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.)

Review Question/objective: The objective of this review is to identify the evidence on the use of integrated knowledge translation (iKT) strategies in acute care. This information will assist in the identification of the strategies used to engage stakeholders, such as patients and decision makers, in the research process and how their involvement has influenced the implementation or integration of research into practice. The extent to which these iKT activities have occurred in the context of care of the elderly, intensively ill patient will be examined. The question that will guide this review is: What iKT strategies have been used within the acute care environment for the care of an older person, specifically: (a) where have these strategies been used, and (b) how have iKT strategies been implemented?

We present a series of organic/inorganic hybrid sol-gel derived glasses, made from a tetraethoxysilane-derived silica sol (100% SiO2) and oligovalent organic crosslinkers functionalized with 3-isocyanatopropyltriethoxysilane. The material was susceptible to heat sterilization. The hybrids were processed into pore-interconnected scaffolds by an indirect rapid prototyping method, described here for the first time for sol-gel glass materials. A large panel of polyethylene oxide-derived 2- to 4-armed crosslinkers of molecular weights ranging between 170 and 8000Da were incorporated and their effect on scaffold mechanical properties was investigated. By multiple linear regression, 'organic content' and the 'content of ethylene oxide units in the hybrid' were identified as the main factors that determined compressive strength and modulus, respectively. In general, 3- and 4-armed crosslinkers performed better than linear molecules. Compression tests and cell culture experiments with osteoblast-like SaOS-2 cells showed that macroporous scaffolds can be produced with compressive strengths of up to 33±2MPa and with a pore structure that allows cells to grow deep into the scaffolds and form mineral deposits. Compressive moduli between 27±7MPa and 568±98MPa were obtained depending on the hybrid composition and problems associated with the inherent brittleness of sol-gel glass materials could be overcome. SaOS-2 cells showed cytocompatibility on hybrid glass scaffolds and mineral accumulation started as early as day 7. On day 14, we also found mineral accumulation on control hybrid glass scaffolds without cells, indicating a positive effect of the hybrid glass on mineral accumulation., Statement of Significance: We produced a hybrid sol-gel glass material with significantly improved mechanical properties towards an application in bone regeneration and processed the material into macroporous scaffolds of controlled architecture by indirect rapid prototyping. We were able to produce macroporous materials of relevant porosity and pore size with compressive moduli, covering the range reported for cancellous bone while an even higher compressive strength was maintained. By multiple linear regression, we identified crosslinker parameters, namely organic content and the content of ethylene oxide units in the hybrids that predominantly determined the mechanics of the hybrid materials. The scaffolds proved to be cytocompatible and induced mineralization in SaOS-2 cells. This provides new insight on the critical parameters for the design of the organic components of covalent hybrid sol-gel glasses., (Copyright © 2016 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.)

Overcoming resistance to chemotherapy is a major challenge in colorectal cancer (CRC) treatment, especially since the underlying molecular mechanisms remain unclear. We show that silencing of the prolyl hydroxylase domain protein PHD1, but not PHD2 or PHD3, prevents p53 activation upon chemotherapy in different CRC cell lines, thereby inhibiting DNA repair and favoring cell death. Mechanistically, PHD1 activity reinforces p53 binding to p38α kinase in a hydroxylation-dependent manner. Following p53-p38α interaction and chemotherapeutic damage, p53 can be phosphorylated at serine 15 and thus activated. Active p53 allows nucleotide excision repair by interacting with the DNA helicase XPB, thereby protecting from chemotherapy-induced apoptosis. In accord with this observation, PHD1 knockdown greatly sensitizes CRC to 5-FU in mice. We propose that PHD1 is part of the resistance machinery in CRC, supporting rational drug design of PHD1-specific inhibitors and their use in combination with chemotherapy., (© 2015 The Authors. Published under the terms of the CC BY 4.0 license.)

Background: Tremor and headache are two of the most prevalent neurological conditions. This review addresses possible associations between various types of tremor and headache, and provides a differential diagnosis for patients presenting with both tremor and headache., Methods: Data were identified by searching MEDLINE in February 2015, with the terms "tremor" and terms representing the primary headache syndromes., Results: Evidence for an association between migraine and essential tremor is conflicting. Other primary headaches are not associated with tremor. Conditions that may present with both tremor and headache include cervical dystonia, infectious diseases, hydrocephalus, spontaneous cerebrospinal fluid leaks, space-occupying lesions, and metabolic disease. Furthermore, both can be seen as a side effect of medication and in the use of recreational drugs., Discussion: No clear association between primary headaches and tremor has been found. Many conditions may feature both headache and tremor, but rarely as core clinical symptoms at presentation.

Two patients, a man aged 45 years and a woman aged 61 years, were diagnosed with syringomyelia. They later developed Charcot's arthropathy of the elbow and shoulder, respectively. The second patient was misdiagnosed with multiple sclerosis during the pre-MRI era. The 3 hallmarks of syringomyelia are impairment of vital or non-vital sensory perception, muscle weakness with atrophy and areflexia of the arms. Syringomyelia often occurs in association with other disorders, such as Chiari's malformation type I or tumours of the spinal column. Diagnosis should include scanning of the entire spinal column and the region surrounding the foramen magnum. Various treatment options exist: watchful waiting is possible or surgery, including decompression of the foramen magnum or placement of a syringosubarachnoidal or syringoperitoneal shunt. In the first patient, the elbow became infected, necessitating surgery. The joint later became non-functional. In the second patient, a conservative approach was followed.