Dysregulated ADAM10-Mediated Processing of APP during a Critical Time Window Leads to Synaptic Deficits in Fragile X Syndrome.

The Fragile X mental retardation protein (FMRP) regulates neuronal RNA metabolism, and its absence or mutations leads to the Fragile X syndrome (FXS). The β-amyloid precursor protein (APP) is involved in Alzheimer's disease, plays a role in synapse formation, and is upregulated in intellectual disabilities. Here, we show that during mouse synaptogenesis and in human FXS fibroblasts, a dual dysregulation of APP and the α-secretase ADAM10 leads to the production of an excess of soluble APPα (sAPPα). In FXS, sAPPα signals through the metabotropic receptor that, activating the MAP kinase pathway, leads to synaptic and behavioral deficits. Modulation of ADAM10 activity in FXS reduces sAPPα levels, restoring translational control, synaptic morphology, and behavioral plasticity. Thus, proper control of ADAM10-mediated APP processing during a specific developmental postnatal stage is crucial for healthy spine formation and function(s). Downregulation of ADAM10 activity at synapses may be an effective strategy for ameliorating FXS phenotypes.

Repetitive Deliberate Fires: Critical Review of the Situation and Proposal of a Follow-Up Process and Systematic Analysis

Deliberate fires appear to be borderless and timeless events creating a serious security problem. There have been many attempts to develop approaches to tackle this problem, but unfortunately acting effectively against deliberate fires has proven a complex challenge. This article reviews the current situation relating to deliberate fires: what do we know, how serious is the situation, how is it being dealt with, and what challenges are faced when developing a systematic and global methodology to tackle the issues? The repetitive nature of some types of deliberate fires will also be discussed. Finally, drawing on the reality of repetition within deliberate fires and encouraged by successes obtained in previous repetitive crimes (such as property crimes or drug trafficking), we will argue that the use of the intelligence process cycle as a framework to allow a follow-up and systematic analysis of fire events is a relevant approach. This is the first article of a series of three articles. This first part is introducing the context and discussing the background issues in order to provide a better underpinning knowledge to managers and policy makers planning on tackling this issue. The second part will present a methodology developed to detect and identify repetitive fire events from a set of data, and the third part will discuss the analyses of these data to produce intelligence.

Premature Discontinuation of Randomized Trials in Critical and Emergency Care: A Retrospective Cohort Study.

OBJECTIVES: Randomized clinical trials that enroll patients in critical or emergency care (acute care) setting are challenging because of narrow time windows for recruitment and the inability of many patients to provide informed consent. To assess the extent that recruitment challenges lead to randomized clinical trial discontinuation, we compared the discontinuation of acute care and nonacute care randomized clinical trials. DESIGN: Retrospective cohort of 894 randomized clinical trials approved by six institutional review boards in Switzerland, Germany, and Canada between 2000 and 2003. SETTING: Randomized clinical trials involving patients in an acute or nonacute care setting. SUBJECTS AND INTERVENTIONS: We recorded trial characteristics, self-reported trial discontinuation, and self-reported reasons for discontinuation from protocols, corresponding publications, institutional review board files, and a survey of investigators. MEASUREMENTS AND MAIN RESULTS: Of 894 randomized clinical trials, 64 (7%) were acute care randomized clinical trials (29 critical care and 35 emergency care). Compared with the 830 nonacute care randomized clinical trials, acute care randomized clinical trials were more frequently discontinued (28 of 64, 44% vs 221 of 830, 27%; p = 0.004). Slow recruitment was the most frequent reason for discontinuation, both in acute care (13 of 64, 20%) and in nonacute care randomized clinical trials (7 of 64, 11%). Logistic regression analyses suggested the acute care setting as an independent risk factor for randomized clinical trial discontinuation specifically as a result of slow recruitment (odds ratio, 4.00; 95% CI, 1.72-9.31) after adjusting for other established risk factors, including nonindustry sponsorship and small sample size. CONCLUSIONS: Acute care randomized clinical trials are more vulnerable to premature discontinuation than nonacute care randomized clinical trials and have an approximately four-fold higher risk of discontinuation due to slow recruitment. These results highlight the need for strategies to reliably prevent and resolve slow patient recruitment in randomized clinical trials conducted in the critical and emergency care setting.

Patient-centered Care in Maternity Services: A Critical Appraisal and Synthesis of the Literature.

BACKGROUND: Patient-centered care (PCC) has been recognized as a marker of quality in health service delivery. In policy documents, PCC is often used interchangeably with other models of care. There is a wide literature about PCC, but there is a lack of evidence about which model is the most appropriate for maternity services specifically. AIM: We sought to identify and critically appraise the literature to identify which definition of PCC is most relevant for maternity services. METHODS: The four-step approach used to identify definitions of PCC was to 1) search electronic databases using key terms (1995-2011), 2) cross-reference key papers, 3) search of specific journals, and 4) search the grey literature. Four papers and two books met our inclusion criteria. ANALYSIS: A four-criteria critical appraisal tool developed for the review was used to appraise the papers and books. MAIN RESULTS: From the six identified definitions, the Shaller's definition met the majority of the four criteria outlined and seems to be the most relevant to maternity services because it includes physiologic conditions as well as pathology, psychological aspects, a nonmedical approach to care, the greater involvement of family and friends, and strategies to implement PCC. CONCLUSION: This review highlights Shaller's definitions of PCC as the one that would be the most inclusive of all women using maternity services. Future research should concentrate on evaluating programs that support PCC in maternity services, and testing/validating this model of care.

A cast of shadow on adjuvant radiotherapy for prostate cancer: A critical review based on a methodological perspective.

OBJECTIVE: To perform a critical review focusing on the applicability in clinical daily practice of data from three randomized controlled trials (RCTs): SWOG 8794, EORTC 22911, and ARO/AUO 96-02. METHODS AND MATERIALS: An analytical framework, based on the identified population, interventions, comparators, and outcomes (PICO) was used to refine the search of the evidence from the three large randomized trials regarding the use of radiation therapy after prostatectomy as adjuvant therapy (ART). RESULTS: With regard to the inclusion criteria: (1) POPULATION: in the time since they were designed, in two among three trial (SWOG 8794 and EORTC 22911) patients had a detectable PSA at the time of randomization, thus representing de facto a substantial proportion of patients who eventually received salvage RT (SRT) at non-normalised PSA levels rather than ART. (2) INTERVENTIONS: although all the trials showed the benefit of postoperative ART compared to a wait-and-see approach, the dose herein employed would be now considered inadequate; (3) COMPARATORS: the comparison arm in all the 3 RCTs was an uncontrolled observation arm, where patients who subsequently developed biochemical failure were treated in various ways, with up to half of them receiving SRT at PSA well above 1ng/mL, a level that would be now deemed inappropriate; (4) OUTCOMES: only in one trial (SWOG 8794) ART was found to significantly improve overall survival compared to observation, with a ten-year overall survival rate of 74% vs. 66%, although this might be partly the result of imbalanced risk factors due to competing event risk stratification. CONCLUSIONS: ART has a high level of evidence due to three RCTs with at least 10-year follow-up recording a benefit in biochemical PFS, but its penetrance in present daily clinics should be reconsidered. While the benefit of ART or SRT is eagerly expected from ongoing randomized trials, a dynamic risk-stratified approach should drive the decisions making process.

Are alcohol outlet densities strongly associated with alcohol-related outcomes? A critical review of recent evidence.

ISSUES: There have been reviews on the association between density of alcohol outlets and harm including studies published up to December 2008. Since then the number of publications has increased dramatically. The study reviews the more recent studies with regard to their utility to inform policy. APPROACH: A systematic review found more than 160 relevant studies (published between January 2009 and October 2014). The review focused on: (i) outlet density and assaultive or intimate partner violence; (ii) studies including individual level data; or (iii) 'natural experiments'. KEY FINDINGS: Despite overall evidence for an association between density and harm, there is little evidence on causal direction (i.e. whether demand leads to more supply or increased availability increases alcohol use and harm). When outlet types (e.g. bars, supermarkets) are analysed separately, studies are too methodologically diverse and partly contradictory to permit firm conclusions besides those pertaining to high outlet densities in areas such as entertainment districts. Outlet density commonly had little effect on individual-level alcohol use, and the few 'natural experiments' on restricting densities showed little or no effects. IMPLICATIONS AND CONCLUSIONS: Although outlet densities are likely to be positively related to alcohol use and harm, few policy recommendations can be given as effects vary across study areas, outlet types and outlet cluster size. Future studies should examine in detail outlet types, compare different outcomes associated with different strengths of association with alcohol, analyse non-linear effects and compare different methodologies. Purely aggregate-level studies examining total outlet density only should be abandoned. [Gmel G, Holmes J, Studer J. Are alcohol outlet densities strongly associated with alcohol-related outcomes? A critical review of recent evidence. Drug Alcohol Rev 2015].

Image guided critical screw placement precision in the cervical spine : important or incidental? : results of a series of 91 consecutive cases using OVEM

Study design: A retrospective study of image guided cervical implant placement precision. Objective: To describe a simple and precise classification of cervical critical screw placement. Summary of Background Data: "Critical" screw placement is defined as implant insertion into a bone corridor which is surrounded circumferentially by neurovascular structures. While the use of image guidance has improved accuracy, there is currently no classification which provides sufficient precision to assess the navigation success of critical cervical screw placement. Methods: Based on postoperative clinical evaluation and CT imaging, the orthogonal view evaluation method (OVEM) is used to classify screw accuracy into grade I (no cortical breach), grade la (screw thread cortical breach), grade II (internal diameter cortical breach) and grade III (major cortical breach causing neural or vascular injury). Grades II and III are considered to be navigation failures, after accounting for bone corridor / screw mismatch (minimal diameter of targeted bone corridor being smaller than an outer screw diameter). Results: A total of 276 screws from 91 patients were classified into grade I (64.9%), grade la (18.1%), and grade II (17.0%). No grade III screw was observed. The overall rate of navigation failure was 13%. Multiple logistic regression indicated that navigational failure was significantly associated with the level of instrumentation and the navigation system used. Navigational failure was rare (1.6%) when the margin around the screw in the bone corridor was larger than 1.5 mm. Conclusions: OVEM evaluation appears to be a useful tool to assess the precision of critical screw placement in the cervical spine. The OVEM validity and reliability need to be addressed. Further correlation with clinical outcomes will be addressed in future studies.

The cutting of cocaine and heroin: a critical review

The illicit drug cutting represents a complex problem that requires the sharing of knowledge from addiction studies, toxicology, criminology and criminalistics. Therefore, cutting is not well known by the forensic community. Thus, this review aims at deciphering the different aspects of cutting, by gathering information mainly from criminology and criminalistics. It tackles essentially specificities of cocaine and heroin cutting. The article presents the detected cutting agents (adulterants and diluents), their evolution in time and space and the analytical methodology implemented by forensic laboratories. Furthermore, it discusses when, in the history of the illicit drug, cutting may take place. Moreover, researches studying how much cutting occurs in the country of destination are analysed. Lastly, the reasons for cutting are addressed. According to the literature, adulterants are added during production of the illicit drug or at a relatively high level of its distribution chain (e.g. before the product arrives in the country of destination or just after its importation in the latter). Their addition seems hardly justified by the only desire to increase profits or to harm consumers' health. Instead, adulteration would be performed to enhance or to mimic the illicit drug effects or to facilitate administration of the drug. Nowadays, caffeine, diltiazem, hydroxyzine, levamisole, lidocaïne and phenacetin are frequently detected in cocaine specimens, while paracetamol and caffeine are almost exclusively identified in heroin specimens. This may reveal differences in the respective structures of production and/or distribution of cocaine and heroin. As the relevant information about cutting is spread across different scientific fields, a close collaboration should be set up to collect essential and unified data to improve knowledge and provide information for monitoring, control and harm reduction purposes. More research, on several areas of investigation, should be carried out to gather relevant information.