Implementing a whole-school relationships and sex education intervention to prevent dating and relationship violence: evidence from a pilot trial in English secondary schools

Adolescent dating and relationship violence is associated with health harms and is an important topic for sex education. School-based interventions addressing this have been effective in the USA, but schools in England confront pressures that might hinder implementation. We assessed the feasibility of, and contextual enablers/barriers to implementing Project Respect, a whole-school intervention. We conducted a pilot trial with process evaluation in six English secondary schools. Intervention comprised: training; policy-review; mapping and patrolling ‘hotspots’; parent information; help-seeking app; and a curriculum (including student-led campaigns) targeting dating violence. Process evaluation included assessments of fidelity and interviews with the trainer and school staff. Schools delivered training and lessons partially or completely and made parent and app information available. Two schools conducted policy reviews; none patrolled hotspots or implemented campaigns. Implementation was strengthened where staff saw dating violence as a priority. Delivery was undermined where staff were insufficiently involved, lacked time for planning or struggled to timetable lessons, and where new school challenges undermined engagement. School-based health interventions must work to build staff buy-in and ensure they do not overburden schools. Dating and relationship violence might best be addressed in this context as a broader aspect of sex education

Antimicrobial activity of phytic acid: an emerging agent in dentistry

Background: Phytic acid (IP6) is a promising and emerging agent, and because of its unique structure and distinctive properties, it lends itself to several applications in dentistry. Recently, IP6 was proposed as a potential chelating agent in endodontics. However, there is limited knowledge regarding its antimicrobial and antibiofilm effectiveness. The aims of this study, were therefore to evaluate the antimicrobial and antibiofilm activities of IP6 against a range of microbial species and compare these with ethylenediaminetetraacetic acid (EDTA) and sodium hypochlorite (NaOCl). The contact time required for IP6 to exert its bactericidal effect on Enterococcus faecalis was also determined. Methods: The inhibitory and biocidal activities of IP6, EDTA and NaOCl were assessed using a broth microdilution assay against 11 clinical and reference strains of bacteria and a reference strain of Candida albicans. The contact time required for various IP6 concentrations to eliminate planktonic cultures of E. faecalis was determined using a membrane filtration method according to BS-EN-1040:2005. IP6 bactericidal activity was also evaluated using fluorescent microscopy, and the antibiofilm activity of the test agents was also determined. Results: IP6 was biocidal against all tested microorganisms. At concentrations of 0.5%, 1% and 2%, IP6 required 5 min to exert a bactericidal effect on E. faecalis, while 5% IP6 was bactericidal after 30 s. IP6 also eradicated biofilms of the tested microorganisms. In conclusion, IP6 had notable antimicrobial effects on planktonic and biofilm cultures and exhibited rapid bactericidal effects on E. faecalis. This research highlighted, for the first time the antimicrobial and antibiofilm properties of IP6, which could be exploited, not only in dental applications, but also other fields where novel strategies to counter antimicrobial resistance are required

A school intervention for 13- to 15-year-olds to prevent dating and relationship violence: the Project Respect pilot cluster RCT

Background ‘Dating and relationship violence’ is intimate partner violence during adolescence. Among dating adolescents in England, 66–75% of girls and 32–50% of boys report victimisation. Multicomponent school-based interventions might reduce dating and relationship violence. We optimised and piloted Project Respect, a new intervention in secondary schools in England, and study methods, to assess the value of a Phase III randomised controlled trial. Objectives To optimise Project Respect and to then conduct a pilot randomised controlled trial in southern England, addressing whether or not progression to a Phase III trial is justified in terms of prespecified criteria. To assess which of two dating and relationship violence scales is optimal, to assess response rates and to consider any necessary refinements. Design Optimisation activities aimed at intervention development and a pilot randomised controlled trial. Setting Optimisation in four secondary schools across southern England, varying by region and local deprivation. A pilot cluster randomised controlled trial in six other such schools (four intervention schools and two control schools), varying by region, attainment and local deprivation. Participants School students in years 8–10 at baseline and staff. Interventions Schools were randomised to the intervention or control arm in a 2 : 1 ratio; intervention comprised staff training, mapping ‘hotspots’ in school for dating and relationship violence, modifying staff patrols, school policy review, informing parents and carers, an application supporting student help-seeking, and a classroom curriculum for students in years 9 and 10 (including student-led campaigns). Main outcome measures Prespecified criteria for progression to Phase III of the trial, concerning acceptability, feasibility, fidelity and response rates. Primary health outcomes were assessed using the Safe Dates and short Conflicts in Adolescent Dating Relationships Inventory measures collected and analysed by individuals who were masked to allocation. Feasibility of economic analysis was assessed. Data sources Baseline and follow-up student and staff surveys, interviews, observations and logbooks. Results The intervention was optimised and approved by the Study Steering Committee. The student response rates in intervention and control groups were 1057 (84.8%) and 369 (76.6%) at baseline, and 1177 (76.8%) and 352 (83.4%) at follow-up, respectively. Safe Dates and the short Conflicts in Adolescent Dating Relationships Inventory had high levels of completion and reliability. At follow-up, prevalence of past-year dating and relationship violence victimisation was around 35% (Safe Dates scale and short Conflicts in Adolescent Dating Relationships Inventory). Staff response rates were very low. Training occurred in all four schools, with suboptimal fidelity. The curriculum was delivered with optimal fidelity in three schools. Other components were delivered inconsistently. Dating and relationship violence was addressed in control schools via violence prevention and responses, but not systematically. Intervention acceptability among students and staff was mixed. An economic evaluation would be feasible. Limitations One school did not undertake baseline surveys. Staff survey response rates were low and completion of the logbook was patchy. Conclusions Our findings suggest that progression to a Phase III trial of this intervention is not indicated because of limited fidelity and acceptability. Future work High prevalence of dating and relationship violence highlights the ongoing need for effective intervention. Potential intervention refinements would include more external support for schools and enhanced curriculum materials. Any future randomised controlled trials could consider having a longer lead-in from randomisation to intervention commencement, using the short Conflicts in Adolescent Dating Relationships Inventory as the primary outcome and not relying on staff surveys. Trial registration Current Controlled Trials ISRCTN65324176. Funding This project was funded by the National Institute for Health Research (NIHR) Public Health Research programme and will be published in full in Public Health Research; Vol. 8, No. 5. See the NIHR Journals Library website for further project information

Shared Genetic Risk Factors of Intracranial, Abdominal, and Thoracic Aneurysms

Background: Intracranial aneurysms (IAs), abdominal aortic aneurysms (AAAs), and thoracic aortic aneurysms (TAAs) all have a familial predisposition. Given that aneurysm types are known to co‐occur, we hypothesized that there may be shared genetic risk factors for IAs, AAAs, and TAAs. Methods and Results: We performed a mega‐analysis of 1000 Genomes Project‐imputed genome‐wide association study (GWAS) data of 4 previously published aneurysm cohorts: 2 IA cohorts (in total 1516 cases, 4305 controls), 1 AAA cohort (818 cases, 3004 controls), and 1 TAA cohort (760 cases, 2212 controls), and observed associations of 4 known IA, AAA, and/or TAA risk loci (9p21, 18q11, 15q21, and 2q33) with consistent effect directions in all 4 cohorts. We calculated polygenic scores based on IA‐, AAA‐, and TAA‐associated SNPs and tested these scores for association to case‐control status in the other aneurysm cohorts; this revealed no shared polygenic effects. Similarly, linkage disequilibrium–score regression analyses did not show significant correlations between any pair of aneurysm subtypes. Last, we evaluated the evidence for 14 previously published aneurysm risk single‐nucleotide polymorphisms through collaboration in extended aneurysm cohorts, with a total of 6548 cases and 16 843 controls (IA) and 4391 cases and 37 904 controls (AAA), and found nominally significant associations for IA risk locus 18q11 near RBBP8 to AAA (odds ratio [OR]=1.11; P=4.1×10−5) and for TAA risk locus 15q21 near FBN1 to AAA (OR=1.07; P=1.1×10−3). Conclusions: Although there was no evidence for polygenic overlap between IAs, AAAs, and TAAs, we found nominally significant effects of two established risk loci for IAs and TAAs in AAAs. These two loci will require further replication

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

Influences on defense procurement expenditures in California during the Reagan presidency.

http://archive.org/details/influencesondefe00wil

Targeting glutamine metabolism improves sarcoma response to radiation therapy in vivo

Abstract Diverse tumor metabolic phenotypes are influenced by the environment and genetic lesions. Whether these phenotypes extend to rhabdomyosarcoma (RMS) and how they might be leveraged to design new therapeutic approaches remains an open question. Thus, we utilized a Pax7 Cre-ER-T2/+ ; Nras LSL-G12D/+ ; p53 fl/fl (P7NP) murine model of sarcoma with mutations that most frequently occur in human embryonal RMS. To study metabolism, we infuse 13C-labeled glucose or glutamine into mice with sarcomas and show that sarcomas consume more glucose and glutamine than healthy muscle tissue. However, we reveal a marked shift from glucose consumption to glutamine metabolism after radiation therapy (RT). In addition, we show that inhibiting glutamine, either through genetic deletion of glutaminase (Gls1) or through pharmacological inhibition of glutaminase, leads to significant radiosensitization in vivo. This causes a significant increase in overall survival for mice with Gls1-deficient compared to Gls1-proficient sarcomas. Finally, Gls1-deficient sarcomas post-RT elevate levels of proteins involved in natural killer cell and interferon alpha/gamma responses, suggesting a possible role of innate immunity in the radiosensitization of Gls1-deficient sarcomas. Thus, our results indicate that glutamine contributes to radiation response in a mouse model of RMS

The Effect of <i>Atm</i> Loss on Radiosensitivity of a Primary Mouse Model of <i>Pten</i>-Deleted Brainstem Glioma

Diffuse midline gliomas arise in the brainstem and other midline brain structures and cause a large proportion of childhood brain tumor deaths. Radiation therapy is the most effective treatment option, but these tumors ultimately progress. Inhibition of the phosphoinositide-3-kinase (PI3K)-like kinase, ataxia–telangiectasia mutated (ATM), which orchestrates the cellular response to radiation-induced DNA damage, may enhance the efficacy of radiation therapy. Diffuse midline gliomas in the brainstem contain loss-of-function mutations in the tumor suppressor PTEN, or functionally similar alterations in the phosphoinositide-3-kinase (PI3K) pathway, at moderate frequency. Here, we sought to determine if ATM inactivation could radiosensitize a primary mouse model of brainstem glioma driven by Pten loss. Using Cre/loxP recombinase technology and the RCAS/TVA retroviral gene delivery system, we established a mouse model of brainstem glioma driven by Pten deletion. We find that Pten-null brainstem gliomas are relatively radiosensitive at baseline. In addition, we show that deletion of Atm in the tumor cells does not extend survival of mice bearing Pten-null brainstem gliomas after focal brain irradiation. These results characterize a novel primary mouse model of PTEN-mutated brainstem glioma and provide insights into the mechanism of radiosensitization by ATM deletion, which may guide the design of future clinical trials

Temporary Knockdown of p53 During Focal Limb Irradiation Increases the Development of Sarcomas.

UNLABELLED: Approximately half of patients with cancer receive radiotherapy and, as cancer survivorship increases, the low rate of radiation-associated sarcomas is rising. Pharmacologic inhibition of p53 has been proposed as an approach to ameliorate acute injury of normal tissues from genotoxic therapies, but how this might impact the risk of therapy-induced cancer and normal tissue injuries remains unclear. We utilized mice that express a doxycycline (dox)-inducible p53 short hairpin RNA to reduce Trp53 expression temporarily during irradiation. Mice were placed on a dox diet 10 days prior to receiving 30 or 40 Gy hind limb irradiation in a single fraction and then returned to normal chow. Mice were examined weekly for sarcoma development and scored for radiation-induced normal tissue injuries. Radiation-induced sarcomas were subjected to RNA sequencing. Following single high-dose irradiation, 21% of animals with temporary p53 knockdown during irradiation developed a sarcoma in the radiation field compared with 2% of control animals. Following high-dose irradiation, p53 knockdown preserves muscle stem cells, and increases sarcoma development. Mice with severe acute radiation-induced injuries exhibit an increased risk of developing late persistent wounds, which were associated with sarcomagenesis. RNA sequencing revealed radiation-induced sarcomas upregulate genes related to translation, epithelial-mesenchymal transition (EMT), inflammation, and the cell cycle. Comparison of the transcriptomes of human and mouse sarcomas that arose in irradiated tissues revealed regulation of common gene programs, including elevated EMT pathway gene expression. These results suggest that blocking p53 during radiotherapy could minimize acute toxicity while exacerbating late effects including second cancers. SIGNIFICANCE: Strategies to prevent or mitigate acute radiation toxicities include pharmacologic inhibition of p53 and other cell death pathways. Our data show that temporarily reducing p53 during irradiation increases late effects including sarcomagenesis

Characterizing the potency and impact of carbon ion therapy in a primary mouse model of soft tissue sarcoma

Carbon ion therapy (CIT) offers several potential advantages for treating cancers compared with X-ray and proton radiotherapy including increased biological efficacy and more conformal dosimetry. However, CIT potency has not been characterized in primary tumor animal models. Here, we calculate the relative biological effectiveness (RBE) of carbon ions compared to X-rays in an autochthonous mouse model of soft tissue sarcoma. We used Cre/loxP technology to generate primary sarcomas in KrasLSL-G12D/+; p53fl/fl mice. Primary tumors were irradiated with a single fraction of carbon ions (10 Gy), X-rays (20 Gy, 25 Gy, or 30 Gy), or observed as controls. The RBE was calculated by determining the dose of X-rays that resulted in similar time to post-treatment tumor volume quintupling and exponential growth rate as 10 Gy carbon ions. The median tumor volume quintupling time and exponential growth rate of sarcomas treated with 10 Gy carbon ions and 30 Gy X-rays were similar: 27.3 days and 28.1 days, and 0.060 mm3/day and 0.059 mm3/day, respectively. Tumors treated with lower doses of X-rays had faster regrowth. Thus, the RBE of carbon ions in this primary tumor model is 3. When isoeffective treatments of carbon ions and X-rays were compared, we observed significant differences in tumor growth kinetics, proliferative indices, and immune infiltrates. We found that carbon ions were three times as potent as X-rays in this aggressive tumor model and identified unanticipated differences in radiation response that may have clinical implications