Risk factors associated with knife-crime in United Kingdom among young people aged 10-24 years: a systematic review

BACKGROUND: Since 2013, the number of violent crimes and offences by sharp instruments have increased continually, following a previous decrease, with majority of cases occurring among young people and in London. There is limited understanding surrounding the drivers influencing this change in trends, with mostly American-based research identifying risk factors. METHODS: The aim of this review is to identify and synthesise evidence from a range of literature to identify risk factors associated with weapon-related crime, for young people (aged 10-24 years) within the UK. A search strategy was generated to conduct a systematic search of published and grey literature within four databases (EMBASE, Medline, PsycINFO, and OpenGrey), identifying papers within a UK-context. Abstracts and full texts were screened by two independent reviewers to assess eligibility for inclusion, namely study focus in line with the objectives of the review. Weight of Evidence approach was utilised to assess paper quality, resulting in inclusion of 16 papers. Thematic analysis was conducted for studies to identity and categorise risk factors according to the WHO ecological model. RESULTS: No association was found between gender or ethnicity and youth violence, contrasting current understanding shown within media. Multiple research papers identified adverse childhood experiences and poor mental health as positively associated with youth and gang violence. It was suggested that community and societal risk factors, such as discrimination and economic inequality, were frequently linked to youth violence. A small number of studies were included within the review as this is a growing field of research, which may have led to a constrained number of risk factors identified. Due to heterogeneity of studies, a meta-analysis could not be conducted. As many studies displayed positive results, publication bias may be present. CONCLUSIONS: Several risk factors were identified, with evidence currently heterogeneous with minimal high-quality studies. However, findings highlight key areas for future research, including the link between poor mental health and knife-crime, and the trajectory into gangs. Risk factors should help identify high-risk individuals, targeting them within mitigation strategies to prevent involvement within crime. This should contribute to efforts aimed at reducing the rising crime rates within UK. SYSTEMATIC REVIEW REGISTRATION NUMBER: CRD42019138545 . Registered at PROSPSERO: 16/08/2019

Compromised BRCA1-PALB2 interaction is associated with breast cancer risk.

The major breast cancer suppressor proteins BRCA1 and BRCA2 play essential roles in homologous recombination (HR)-mediated DNA repair, which is thought to be critical for tumor suppression. The two BRCA proteins are linked by a third tumor suppressor, PALB2, in the HR pathway. While truncating mutations in these genes are generally pathogenic, interpretation of missense variants remains a challenge. To date, patient-derived missense variants that disrupt PALB2 binding have been identified in BRCA1 and BRCA2; however, there has not been sufficient evidence to prove their pathogenicity in humans, and no variants in PALB2 that disrupt either its BRCA1 or BRCA2 binding have been reported. Here we report on the identification of a novel PALB2 variant, c.104T>C (p.L35P), that segregates in a family with a strong history of breast cancer. Functional analyses showed that L35P abrogates the PALB2-BRCA1 interaction and completely disables its abilities to promote HR and confer resistance to platinum salts and PARP inhibitors. Whole-exome sequencing of a breast cancer from a c.104T>C carrier revealed a second, somatic, truncating mutation affecting PALB2, and the tumor displays hallmark genomic features of tumors with BRCA mutations and HR defects, cementing the pathogenicity of L35P. Parallel analyses of other germline variants in the PALB2 N-terminal BRCA1-binding domain identified multiple variants that affect HR function to varying degrees, suggesting their possible contribution to cancer development. Our findings establish L35P as the first pathogenic missense mutation in PALB2 and directly demonstrate the requirement of the PALB2-BRCA1 interaction for breast cancer suppression

Psychosocial impact of undergoing prostate cancer screening for men with BRCA1 or BRCA2 mutations.

OBJECTIVES: To report the baseline results of a longitudinal psychosocial study that forms part of the IMPACT study, a multi-national investigation of targeted prostate cancer (PCa) screening among men with a known pathogenic germline mutation in the BRCA1 or BRCA2 genes. PARTICPANTS AND METHODS: Men enrolled in the IMPACT study were invited to complete a questionnaire at collaborating sites prior to each annual screening visit. The questionnaire included sociodemographic characteristics and the following measures: the Hospital Anxiety and Depression Scale (HADS), Impact of Event Scale (IES), 36-item short-form health survey (SF-36), Memorial Anxiety Scale for Prostate Cancer, Cancer Worry Scale-Revised, risk perception and knowledge. The results of the baseline questionnaire are presented. RESULTS: A total of 432 men completed questionnaires: 98 and 160 had mutations in BRCA1 and BRCA2 genes, respectively, and 174 were controls (familial mutation negative). Participants' perception of PCa risk was influenced by genetic status. Knowledge levels were high and unrelated to genetic status. Mean scores for the HADS and SF-36 were within reported general population norms and mean IES scores were within normal range. IES mean intrusion and avoidance scores were significantly higher in BRCA1/BRCA2 carriers than in controls and were higher in men with increased PCa risk perception. At the multivariate level, risk perception contributed more significantly to variance in IES scores than genetic status. CONCLUSION: This is the first study to report the psychosocial profile of men with BRCA1/BRCA2 mutations undergoing PCa screening. No clinically concerning levels of general or cancer-specific distress or poor quality of life were detected in the cohort as a whole. A small subset of participants reported higher levels of distress, suggesting the need for healthcare professionals offering PCa screening to identify these risk factors and offer additional information and support to men seeking PCa screening

Prostate-specific antigen velocity in a prospective prostate cancer screening study of men with genetic predisposition.

This corrects the article DOI: 10.1038/bjc.2017.429

An observational study of the association between diverse licensed premises types and alcohol-related violence in an inner-London borough

Background: An ecological correlation has been observed between licensed premises and alcohol-related violence (ARV). In the United Kingdom to date, no evidence directly connects alcohol-related harm to a single premises type. Recent policies have called for a diversified alcohol offer yet quantitative evidence in support remains sparse. This study aims to inform policy by determining whether diversification of the alcohol economy is desirable, and to inform the licensing process and submission of public health evidence. Methods: Using 11-years of local licensing data from the London Borough of Southwark, alcohol availability over time was approximated by the number of extant alcohol licences, categorised by outlet type: drinking establishments, eateries, takeaways, off-sales, and ‘other’. Harm was quantified drawing on law enforcement intelligence that recorded ARV. A linked dataset was analysed using negative binomial regression, contrasting cumulative impact zones (CIZ) – a common alcohol control policy – with non-CIZ geographies. Results: Each licensed drinking establishment was associated with a 1.6% (95% CI 0.7% to 2.6%; p=0.001) increase in ARV, respectively. ‘Other’ outlets had a protective effect and were associated with a 1.8% (95% CI 1.0% to 2.5%; p<0.001) decrease in ARV. Conclusion: This study provides direct evidence for an association between alcohol-related harm and licensed premises. The varying associations between outlet type and ARV provide local public health stakeholders with an evidence base upon which to advocate for licensing policies that diversify alcohol availability

Risk factors associated with knife-crime in United Kingdom among young people aged 10-24 years: a systematic review

Background Since 2013, the number of violent crimes and offences by sharp instruments have increased continually, following a previous decrease, with majority of cases occurring among young people and in London. There is limited understanding surrounding the drivers influencing this change in trends, with mostly American-based research identifying risk factors. Methods The aim of this review is to identify and synthesise evidence from a range of literature to identify risk factors associated with weapon-related crime, for young people (aged 10–24 years) within the UK. A search strategy was generated to conduct a systematic search of published and grey literature within four databases (EMBASE, Medline, PsycINFO, and OpenGrey), identifying papers within a UK-context. Abstracts and full texts were screened by two independent reviewers to assess eligibility for inclusion, namely study focus in line with the objectives of the review. Weight of Evidence approach was utilised to assess paper quality, resulting in inclusion of 16 papers. Thematic analysis was conducted for studies to identity and categorise risk factors according to the WHO ecological model. Results No association was found between gender or ethnicity and youth violence, contrasting current understanding shown within media. Multiple research papers identified adverse childhood experiences and poor mental health as positively associated with youth and gang violence. It was suggested that community and societal risk factors, such as discrimination and economic inequality, were frequently linked to youth violence. A small number of studies were included within the review as this is a growing field of research, which may have led to a constrained number of risk factors identified. Due to heterogeneity of studies, a meta-analysis could not be conducted. As many studies displayed positive results, publication bias may be present. Conclusions Several risk factors were identified, with evidence currently heterogeneous with minimal high-quality studies. However, findings highlight key areas for future research, including the link between poor mental health and knife-crime, and the trajectory into gangs. Risk factors should help identify high-risk individuals, targeting them within mitigation strategies to prevent involvement within crime. This should contribute to efforts aimed at reducing the rising crime rates within UK

Germline and somatic FGFR1 abnormalities in dysembryoplastic neuroepithelial tumors

Dysembryoplastic neuroepithelial tumor (DNET) is a benign brain tumor associated with intractable drug-resistant epilepsy. In order to identify underlying genetic alterations and molecular mechanisms, we examined three family members affected by multinodular DNETs as well as 100 sporadic tumors from 96 patients, which had been referred to us as DNETs. We performed whole-exome sequencing on 46 tumors and targeted sequencing for hotspot FGFR1 mutations and BRAF p.V600E was used on the remaining samples. FISH, copy number variation assays and Sanger sequencing were used to validate the findings. By whole-exome sequencing of the familial cases, we identified a novel germline FGFR1 mutation, p.R661P. Somatic activating FGFR1 mutations (p.N546K or p.K656E) were observed in the tumor samples and further evidence for functional relevance was obtained by in silico modeling. The FGFR1 p.K656E mutation was confirmed to be in cis with the germline p.R661P variant. In 43 sporadic cases, in which the diagnosis of DNET could be confirmed on central blinded neuropathology review, FGFR1 alterations were also frequent and mainly comprised intragenic tyrosine kinase FGFR1 duplication and multiple mutants in cis (25/43; 58.1 %) while BRAF p.V600E alterations were absent (0/43). In contrast, in 53 cases, in which the diagnosis of DNET was not confirmed, FGFR1 alterations were less common (10/53; 19 %; p < 0.0001) and hotspot BRAF p.V600E (12/53; 22.6 %) (p < 0.001) prevailed. We observed overexpression of phospho-ERK in FGFR1 p.R661P and p.N546K mutant expressing HEK293 cells as well as FGFR1 mutated tumor samples, supporting enhanced MAP kinase pathway activation under these conditions. In conclusion, constitutional and somatic FGFR1 alterations and MAP kinase pathway activation are key events in the pathogenesis of DNET. These findings point the way towards existing targeted therapies