Selective drug delivery approaches to lesioned brain through blood brain barrier disruption

Introduction: The development of therapeutics for central nervous system (CNS) disorders is still considered a challenging area in drug development due to insufficient translocation through the blood-brain barrier (BBB). Under normal conditions, BBB restrict the penetration of more than 98% of blood-borne molecules including drugs to the CNS. However, recent research findings have proven that the nature of the BBB is altered in several neurological conditions. This complexity encourages revisiting drug delivery strategies to the CNS as this can give a wide range of opportunities for CNS drug development. Areas covered: This review focuses on nanotechnology-based drug delivery platforms designed for selective recruitment into the lesioned brain by taking advantages of BBB disruption that is associated with certain neurological conditions. Expert opinion: Current CNS therapeutic strategies do not fully address the pathophysiological adaptation of BBB in their design. The lack of selective delivery to the brain lesions has been the culprit behind the failure of many CNS therapeutics. This highlighted the need for smart designs of advanced drug delivery systems that take advantage of BBB structural changes in CNS diseases. Recently, promising examples have been reported in this area, however, more work is still required beyond the preclinical testing

Human cytomegalovirus immediate-early 1 protein rewires upstream STAT3 to downstream STAT1 signaling switching an IL6-type to an IFNγ-like response

MN and CP were supported by the Wellcome Trust (www.wellcome.ac.uk) Institutional Strategic Support Fund and CP was supported by the Deutsche Forschungsgemeinschaft (PA 815/2-1; www.dfg.de).The human cytomegalovirus (hCMV) major immediate-early 1 protein (IE1) is best known for activating transcription to facilitate viral replication. Here we present transcriptome data indicating that IE1 is as significant a repressor as it is an activator of host gene expression. Human cells induced to express IE1 exhibit global repression of IL6- and oncostatin M-responsive STAT3 target genes. This repression is followed by STAT1 phosphorylation and activation of STAT1 target genes normally induced by IFNγ. The observed repression and subsequent activation are both mediated through the same region (amino acids 410 to 445) in the C-terminal domain of IE1, and this region serves as a binding site for STAT3. Depletion of STAT3 phenocopies the STAT1-dependent IFNγ-like response to IE1. In contrast, depletion of the IL6 receptor (IL6ST) or the STAT kinase JAK1 prevents this response. Accordingly, treatment with IL6 leads to prolonged STAT1 instead of STAT3 activation in wild-type IE1 expressing cells, but not in cells expressing a mutant protein (IE1dl410-420) deficient for STAT3 binding. A very similar STAT1-directed response to IL6 is also present in cells infected with a wild-type or revertant hCMV, but not an IE1dl410-420 mutant virus, and this response results in restricted viral replication. We conclude that IE1 is sufficient and necessary to rewire upstream IL6-type to downstream IFNγ-like signaling, two pathways linked to opposing actions, resulting in repressed STAT3- and activated STAT1-responsive genes. These findings relate transcriptional repressor and activator functions of IE1 and suggest unexpected outcomes relevant to viral pathogenesis in response to cytokines or growth factors that signal through the IL6ST-JAK1-STAT3 axis in hCMV-infected cells. Our results also reveal that IE1, a protein considered to be a key activator of the hCMV productive cycle, has an unanticipated role in tempering viral replication.Publisher PDFPeer reviewe

Pooled analysis of WHO Surgical Safety Checklist use and mortality after emergency laparotomy

Background The World Health Organization (WHO) Surgical Safety Checklist has fostered safe practice for 10 years, yet its place in emergency surgery has not been assessed on a global scale. The aim of this study was to evaluate reported checklist use in emergency settings and examine the relationship with perioperative mortality in patients who had emergency laparotomy. Methods In two multinational cohort studies, adults undergoing emergency laparotomy were compared with those having elective gastrointestinal surgery. Relationships between reported checklist use and mortality were determined using multivariable logistic regression and bootstrapped simulation. Results Of 12 296 patients included from 76 countries, 4843 underwent emergency laparotomy. After adjusting for patient and disease factors, checklist use before emergency laparotomy was more common in countries with a high Human Development Index (HDI) (2455 of 2741, 89.6 per cent) compared with that in countries with a middle (753 of 1242, 60.6 per cent; odds ratio (OR) 0.17, 95 per cent c.i. 0.14 to 0.21, P <0001) or low (363 of 860, 422 per cent; OR 008, 007 to 010, P <0.001) HDI. Checklist use was less common in elective surgery than for emergency laparotomy in high-HDI countries (risk difference -94 (95 per cent c.i. -11.9 to -6.9) per cent; P <0001), but the relationship was reversed in low-HDI countries (+121 (+7.0 to +173) per cent; P <0001). In multivariable models, checklist use was associated with a lower 30-day perioperative mortality (OR 0.60, 0.50 to 073; P <0.001). The greatest absolute benefit was seen for emergency surgery in low- and middle-HDI countries. Conclusion Checklist use in emergency laparotomy was associated with a significantly lower perioperative mortality rate. Checklist use in low-HDI countries was half that in high-HDI countries.Peer reviewe

What is the economic evidence for mHealth? A systematic review of economic evaluations of mHealth solutions

Background Mobile health (mHealth) is often reputed to be cost-effective or cost-saving. Despite optimism, the strength of the evidence supporting this assertion has been limited. In this systematic review the body of evidence related to economic evaluations of mHealth interventions is assessed and summarized. Methods Seven electronic bibliographic databases, grey literature, and relevant references were searched. Eligibility criteria included original articles, comparison of costs and consequences of interventions (one categorized as a primary mHealth intervention or mHealth intervention as a component of other interventions), health and economic outcomes and published in English. Full economic evaluations were appraised using the Consolidated Health Economic Evaluation Reporting Standards (CHEERS) checklist and The PRISMA guidelines were followed. Results Searches identified 5902 results, of which 318 were examined at full text, and 39 were included in this review. The 39 studies spanned 19 countries, most of which were conducted in upper and upper-middle income countries (34, 87.2%). Primary mHealth interventions (35, 89.7%), behavior change communication type interventions (e.g., improve attendance rates, medication adherence) (27, 69.2%), and short messaging system (SMS) as the mHealth function (e.g., used to send reminders, information, provide support, conduct surveys or collect data) (22, 56.4%) were most frequent; the most frequent disease or condition focuses were outpatient clinic attendance, cardiovascular disease, and diabetes. The average percent of CHEERS checklist items reported was 79.6% (range 47.62–100, STD 14.18) and the top quartile reported 91.3–100%. In 29 studies (74.3%), researchers reported that the mHealth intervention was cost-effective, economically beneficial, or cost saving at base case. Conclusions Findings highlight a growing body of economic evidence for mHealth interventions. Although all studies included a comparison of intervention effectiveness of a health-related outcome and reported economic data, many did not report all recommended economic outcome items and were lacking in comprehensive analysis. The identified economic evaluations varied by disease or condition focus, economic outcome measurements, perspectives, and were distributed unevenly geographically, limiting formal meta-analysis. Further research is needed in low and low-middle income countries and to understand the impact of different mHealth types. Following established economic reporting guidelines will improve this body of research

Investigating the use of world knowledge during on-line comprehension in adults with autism spectrum disorder

The on-line use of world knowledge during reading was examined in adults with autism spectrum disorder (ASD). Both ASD and typically developed (TD) adults read sentences that included plausible, implausible and anomalous thematic relations, as their eye movements were monitored. No group differences in the speed of detection of the anomalous violations were found, but the ASD group showed a delay in detection of implausible thematic relations. These findings suggest that there are subtle differences in the speed of world knowledge processing during reading in ASD

Global variation in anastomosis and end colostomy formation following left-sided colorectal resection

Background End colostomy rates following colorectal resection vary across institutions in high-income settings, being influenced by patient, disease, surgeon and system factors. This study aimed to assess global variation in end colostomy rates after left-sided colorectal resection. Methods This study comprised an analysis of GlobalSurg-1 and -2 international, prospective, observational cohort studies (2014, 2016), including consecutive adult patients undergoing elective or emergency left-sided colorectal resection within discrete 2-week windows. Countries were grouped into high-, middle- and low-income tertiles according to the United Nations Human Development Index (HDI). Factors associated with colostomy formation versus primary anastomosis were explored using a multilevel, multivariable logistic regression model. Results In total, 1635 patients from 242 hospitals in 57 countries undergoing left-sided colorectal resection were included: 113 (6·9 per cent) from low-HDI, 254 (15·5 per cent) from middle-HDI and 1268 (77·6 per cent) from high-HDI countries. There was a higher proportion of patients with perforated disease (57·5, 40·9 and 35·4 per cent; P < 0·001) and subsequent use of end colostomy (52·2, 24·8 and 18·9 per cent; P < 0·001) in low- compared with middle- and high-HDI settings. The association with colostomy use in low-HDI settings persisted (odds ratio (OR) 3·20, 95 per cent c.i. 1·35 to 7·57; P = 0·008) after risk adjustment for malignant disease (OR 2·34, 1·65 to 3·32; P < 0·001), emergency surgery (OR 4·08, 2·73 to 6·10; P < 0·001), time to operation at least 48 h (OR 1·99, 1·28 to 3·09; P = 0·002) and disease perforation (OR 4·00, 2·81 to 5·69; P < 0·001). Conclusion Global differences existed in the proportion of patients receiving end stomas after left-sided colorectal resection based on income, which went beyond case mix alone

Laboratory and field evaluation of several types of soil nails for different geological conditions

For steep slopes with difficult access or slopes in a corrosive environment, there are various problems associated with the use of conventional steel reinforcement bars as soil nails. For loose-fill slopes or clay slopes, the development of adequate nail bond strength is another practical issue that should be considered. Carbon fiber–reinforced polymer (CFRP) and glass fiber– reinforced polymer (GFRP) in several forms and installation methods have been studied as the alternatives to the classical steel bar. Extensive laboratory tests on the materials and field tests on different types of soil nails with various methods of installation have been carried out in Hong Kong, Korea, and Australia. Test results support the use of these materials with an innovative installation method as soil nails under different geological conditions, and the suitability and performance of these materials under different conditions are assessed in the present study.Department of Civil and Environmental Engineerin

Cognitive perspective-taking during scene perception in autism spectrum disorder: Evidence from eye movements

The present study examined how eye movements during scene viewing are modulated by adopting psychological perspectives in both adults with autism spectrum disorders (ASD) and typically developing adults. In the current study, participants viewed house scenes with either non‐perspective‐taking (look for valuable items/features of the house that need fixing) or perspective‐taking instructions (imagine that you are a burglar/repairman) while their eye movements were recorded. The eye movement measures revealed that for the “look for the valuable items” and burglar perspective task, the ASD group showed typical relevance effects (the preference to look at schema‐relevant compared with schema‐irrelevant targets) in their eye movements. However, we found subtle processing differences between the groups that were related to initial orienting to and processing of schema‐relevant items for the “look for the features that need fixing” and the repairman perspective‐taking task. There was an absence of a relevance effect for the ASD group for the repairman perspective and its non‐perspective‐taking equivalent instruction showing that the identification of items relevant to those schemas was more difficult for the ASD group. The present findings suggest that resolving ambiguity may be a defining feature of complex information processing deficits in ASD

With others and for others: Accounting for decisions about genetic testing in the clinic

Session 12: Communication and Decision-Making in Genetic CounselingWhile there are various factors influencing clients’ decisions about genetic testing; testing for the sake of others is not uncommon (Hallowell et al. 2005, Ho et al. 2003). This paper focuses on decisions about testing (DOT) when a genetic mutation is identified in a Sudden Arrhythmia Death Syndromes (SADS) patient and it is unclear whether the mutation is the cause of the disease. Family members are then asked to consider genetic testing to ascertain the client’s genetic status and future risk. The paper examines, at the interactional level, how genetic counselors, clients and family members negotiate decision-making involving others. The data consists of 23 video-recorded consultations obtained from a Hong Kong hospital. Episodes of decision-making about testing are identified and extracted from the transcribed data. By using theme-oriented discourse analysis (Roberts & Sarangi 2005), the analysis focuses on the discourse strategies that participants employ to foreground the possible benefits when other family members undergo the genetic test. Preliminary findings show a disjuncture of perspectives between genetic counselors and family members in terms of the benefits of testing. While genetic counselors see testing as a means of confirming the diagnosis and managing risk, family members voice concerns about the usefulness of the test for a client’s treatment. To mitigate these different perspectives on DOT, participants use a range of discourse strategies, such as contrast, foregrounding, self-and-other construction (Sarangi 2010) as a way of emphasizing future scenarios. This study, in sum, elucidates how other-oriented decisions are made in the clinical setting

Numerical studies of fracture initiation and propagation in stiff soil

A geo-material failure process analysis, considering the coupling of stress distribution, fluid flow, and element damage evolution, has been used to investigate the mechanisms of crack initiation and propagation around a 2-D cylindrical cavity in heterogeneous stiff soils during grouting. Numerical simulations were performed using the specifically developed computer software F-RFPA2D. The results indicate the analysis is a powerful tool for the studying of soil behavior during fracture grouting. Moreover, they give us a better understanding of the crack initiation and propagation mechanisms during hydrofracturing.link_to_subscribed_fulltex