The conformational state of Tes regulates its zyxin-dependent recruitment to focal adhesions

The function of the human Tes protein, which has extensive similarity to zyxin in both sequence and domain organization, is currently unknown. We now show that Tes is a component of focal adhesions that, when expressed, negatively regulates proliferation of T47D breast carcinoma cells. Coimmunoprecipitations demonstrate that in vivo Tes is complexed with actin, Mena, and vasodilator-stimulated phosphoprotein (VASP). Interestingly, the isolated NH2-terminal half of Tes pulls out α-actinin and paxillin from cell extracts in addition to actin. The COOH-terminal half recruits zyxin as well as Mena and VASP from cell extracts. These differences suggest that the ability of Tes to associate with α-actinin, paxillin, and zyxin is dependent on the conformational state of the molecule. Consistent with this hypothesis, we demonstrate that the two halves of Tes interact with each other in vitro and in vivo. Using fibroblasts lacking Mena and VASP, we show that these proteins are not required to recruit Tes to focal adhesions. However, using RNAi ablation, we demonstrate that zyxin is required to recruit Tes, as well as Mena and VASP, but not vinculin or paxillin, to focal adhesions

The effects of visual priming on information processing in child sexual offenders

Child sexual offenders are hypothesized to hold offence-supportive beliefs that set them apart from others. The current study seeks support for this view via a cognitive-experimental approach. Child sexual offenders and offender controls were exposed to pictures of semi-clothed children (priming condition) or clothed, mature adults (control condition). Participants then read ambiguous sentences describing children\u27s actions that could be interpreted in a sexualized manner. Next, participants completed a surprise recognition test in which half the sentences were re-presented in an unambiguously sexual form, and half in an unambiguously non-sexual form. Contrary to hypotheses, primed and/or control child sexual offenders did not show a memory bias for sexualized sentences, suggesting that they did not interpret the original sentences in line with offence-supportive beliefs. Results raise questions about whether child sexual offenders universally hold abnormal beliefs that facilitate their offending. Results also highlight the need for further experimental research within this field

Altering the availability or proximity of food, alcohol, and tobacco products to change their selection and consumption.

BACKGROUND: Overconsumption of food, alcohol, and tobacco products increases the risk of non-communicable diseases. Interventions to change characteristics of physical micro-environments where people may select or consume these products - including shops, restaurants, workplaces, and schools - are of considerable public health policy and research interest. This review addresses two types of intervention within such environments: altering the availability (the range and/or amount of options) of these products, or their proximity (the distance at which they are positioned) to potential consumers. OBJECTIVES: 1. To assess the impact on selection and consumption of altering the availability or proximity of (a) food (including non-alcoholic beverages), (b) alcohol, and (c) tobacco products.2. To assess the extent to which the impact of these interventions is modified by characteristics of: i. studies, ii. interventions, and iii. SEARCH METHODS: We searched CENTRAL, MEDLINE, Embase, PsycINFO, and seven other published or grey literature databases, as well as trial registries and key websites, up to 23 July 2018, followed by citation searches. SELECTION CRITERIA: We included randomised controlled trials with between-participants (parallel group) or within-participants (cross-over) designs. Eligible studies compared effects of exposure to at least two different levels of availability of a product or its proximity, and included a measure of selection or consumption of the manipulated product. DATA COLLECTION AND ANALYSIS: We used a novel semi-automated screening workflow and applied standard Cochrane methods to select eligible studies, collect data, and assess risk of bias. In separate analyses for availability interventions and proximity interventions, we combined results using random-effects meta-analysis and meta-regression models to estimate summary effect sizes (as standardised mean differences (SMDs)) and to investigate associations between summary effect sizes and selected study, intervention, or participant characteristics. We rated the certainty of evidence for each outcome using GRADE. MAIN RESULTS: We included 24 studies, with the majority (20/24) giving concerns about risk of bias. All of the included studies investigated food products; none investigated alcohol or tobacco. The majority were conducted in laboratory settings (14/24), with adult participants (17/24), and used between-participants designs (19/24). All studies were conducted in high-income countries, predominantly in the USA (14/24).Six studies investigated availability interventions, of which two changed the absolute number of different options available, and four altered the relative proportion of less-healthy (to healthier) options. Most studies (4/6) manipulated snack foods or drinks. For selection outcomes, meta-analysis of three comparisons from three studies (n = 154) found that exposure to fewer options resulted in a large reduction in selection of the targeted food(s): SMD -1.13 (95% confidence interval (CI) -1.90 to -0.37) (low certainty evidence). For consumption outcomes, meta-analysis of three comparisons from two studies (n = 150) found that exposure to fewer options resulted in a moderate reduction in consumption of those foods, but with considerable uncertainty: SMD -0.55 (95% CI -1.27 to 0.18) (low certainty evidence).Eighteen studies investigated proximity interventions. Most (14/18) changed the distance at which a snack food or drink was placed from the participants, whilst four studies changed the order of meal components encountered along a line. For selection outcomes, only one study with one comparison (n = 41) was identified, which found that food placed farther away resulted in a moderate reduction in its selection: SMD -0.65 (95% CI -1.29 to -0.01) (very low certainty evidence). For consumption outcomes, meta-analysis of 15 comparisons from 12 studies (n = 1098) found that exposure to food placed farther away resulted in a moderate reduction in its consumption: SMD -0.60 (95% CI -0.84 to -0.36) (low certainty evidence). Meta-regression analyses indicated that this effect was greater: the farther away the product was placed; when only the targeted product(s) was available; when participants were of low deprivation status; and when the study was at high risk of bias. AUTHORS' CONCLUSIONS: The current evidence suggests that changing the number of available food options or altering the positioning of foods could contribute to meaningful changes in behaviour, justifying policy actions to promote such changes within food environments. However, the certainty of this evidence as assessed by GRADE is low or very low. To enable more certain and generalisable conclusions about these potentially important effects, further research is warranted in real-world settings, intervening across a wider range of foods - as well as alcohol and tobacco products - and over sustained time periods

Does specialized psychological treatment for offending reduce recidivism? a meta-analysis examining staff and program variables as predictors of treatment effectiveness

A meta-analysis was conducted to examine whether specialized psychological offense treatments were associated with reductions in offense specific and non-offense specific recidivism. Staff and treatment program moderators were also explored. The review examined 68 studies and 55,604 individuals who had offended. Three specialized treatments were examined: sexual offense, domestic violence, and general violence programs. Across all programs, offense specific recidivism was 13.4% for treated individuals and 19.4% for untreated comparisons over an average follow up of 66.1 months. Relative reductions in offense specific recidivism were 32.6% for sexual offense programs, 36.0% for domestic violence programs, and 24.3% for general violence programs. All programs were also associated with significant reductions in non-offense specific recidivism. Overall, treatment effectiveness appeared improved when programs received consistent hands-on input from a qualified registered psychologist and facilitating staff were provided with clinical supervision. Numerous program variables appeared important for optimizing the effectiveness of specialized psychological offense programs (e.g., arousal reconditioning for sexual offense programs, treatment approach for domestic violence programs). The findings show that such treatments are associated with robust reductions in offense specific and nonoffense specific recidivism. We urge treatment providers to pay particular attention to staffing and program implementation variables for optimal recidivism reductions

Effect of Hydrocortisone on Mortality and Organ Support in Patients With Severe COVID-19: The REMAP-CAP COVID-19 Corticosteroid Domain Randomized Clinical Trial.

Importance: Evidence regarding corticosteroid use for severe coronavirus disease 2019 (COVID-19) is limited. Objective: To determine whether hydrocortisone improves outcome for patients with severe COVID-19. Design, Setting, and Participants: An ongoing adaptive platform trial testing multiple interventions within multiple therapeutic domains, for example, antiviral agents, corticosteroids, or immunoglobulin. Between March 9 and June 17, 2020, 614 adult patients with suspected or confirmed COVID-19 were enrolled and randomized within at least 1 domain following admission to an intensive care unit (ICU) for respiratory or cardiovascular organ support at 121 sites in 8 countries. Of these, 403 were randomized to open-label interventions within the corticosteroid domain. The domain was halted after results from another trial were released. Follow-up ended August 12, 2020. Interventions: The corticosteroid domain randomized participants to a fixed 7-day course of intravenous hydrocortisone (50 mg or 100 mg every 6 hours) (n = 143), a shock-dependent course (50 mg every 6 hours when shock was clinically evident) (n = 152), or no hydrocortisone (n = 108). Main Outcomes and Measures: The primary end point was organ support-free days (days alive and free of ICU-based respiratory or cardiovascular support) within 21 days, where patients who died were assigned -1 day. The primary analysis was a bayesian cumulative logistic model that included all patients enrolled with severe COVID-19, adjusting for age, sex, site, region, time, assignment to interventions within other domains, and domain and intervention eligibility. Superiority was defined as the posterior probability of an odds ratio greater than 1 (threshold for trial conclusion of superiority >99%). Results: After excluding 19 participants who withdrew consent, there were 384 patients (mean age, 60 years; 29% female) randomized to the fixed-dose (n = 137), shock-dependent (n = 146), and no (n = 101) hydrocortisone groups; 379 (99%) completed the study and were included in the analysis. The mean age for the 3 groups ranged between 59.5 and 60.4 years; most patients were male (range, 70.6%-71.5%); mean body mass index ranged between 29.7 and 30.9; and patients receiving mechanical ventilation ranged between 50.0% and 63.5%. For the fixed-dose, shock-dependent, and no hydrocortisone groups, respectively, the median organ support-free days were 0 (IQR, -1 to 15), 0 (IQR, -1 to 13), and 0 (-1 to 11) days (composed of 30%, 26%, and 33% mortality rates and 11.5, 9.5, and 6 median organ support-free days among survivors). The median adjusted odds ratio and bayesian probability of superiority were 1.43 (95% credible interval, 0.91-2.27) and 93% for fixed-dose hydrocortisone, respectively, and were 1.22 (95% credible interval, 0.76-1.94) and 80% for shock-dependent hydrocortisone compared with no hydrocortisone. Serious adverse events were reported in 4 (3%), 5 (3%), and 1 (1%) patients in the fixed-dose, shock-dependent, and no hydrocortisone groups, respectively. Conclusions and Relevance: Among patients with severe COVID-19, treatment with a 7-day fixed-dose course of hydrocortisone or shock-dependent dosing of hydrocortisone, compared with no hydrocortisone, resulted in 93% and 80% probabilities of superiority with regard to the odds of improvement in organ support-free days within 21 days. However, the trial was stopped early and no treatment strategy met prespecified criteria for statistical superiority, precluding definitive conclusions. Trial Registration: ClinicalTrials.gov Identifier: NCT02735707

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570

Mutation of a putative ADP-ribosylation motif in the Pasteurella multocida toxin does not affect mitogenic activity

AbstractPasteurella multocida toxin (PMT) is a potent mitogen for Swiss 3T3 fibroblasts and cytotoxic to embryonic bovine lung cells. Site-directed mutagenesis was used to investigate the functional significance of a three amino acid motif in PMT that is present in five other bacterial protein toxins which exhibit ADP-ribosyl transferase activity. Crude lysates of mutant clones were fully cytotoxic for embryonic bovine lung cells. Purified mutant toxin was also as effective at stimulating inositol phosphate turnover and nucleic acid synthesis as wild type toxin. We conclude that this motif has no functional significance in Pasteurella multocida toxin