Letters of concern, condolences, and sympathy from friends and relatives upon the illness and subsequent death of Mr. Fleming on December 20, 1908

Correspondents include: Maggie C. Williams. Letters with accompanying envelopes have written answered on them, 1908-12-16 - 1909-02-1

The AHK-Wales Report Card 2018: Policy Measures - is it possible to ‘score’ qualitative data?

Comprehensive and meaningful policy analysis in the field of physical activity is difficult, not least because of the variable influence of other policy domains. However, in 2011 a Policy Assessment Tool (PAT) was developed by members of the WHO European Network for the Promotion of Health-Enhancing Physical Activity (HEPA Europe) and tested in several different countries. In 2014, Wales joined a global initiative, active healthy kids (AHK) Global Alliance, that supported the development of country level ‘Report Cards’ scoring a range of indicators that influence physical activity amongst children and young people, one of which was labelled ‘Government Strategies and Investments’. For the first two Report Cards this indicator and its associated ‘score’ was informed subjectively by expert consensus. In 2018, it was decided to utilize the Policy Audit Tool Version 2 (PAT v2) developed by HEPA Europe to aid analysis and to develop and test a scoring rubric aligned to the tool. The subsequent process indicated that the tool could be applied and translated into a ‘grade’ that could be used in conjunction with the other indicators of the AHK Report Card to generate overall Report Card grades. The use of both the HEPA PAT v2 and the scoring rubric offers an opportunity to provide greater consistency and potential for developing both comparative and trend data when assessing policy impact on physical activity in children and young people. These tools should be utilized by the AHK Global Alliance in future Report Cards

Decreased expression of the mitochondrial bcat protein correlates with improved patient survival in idh-wt gliomas

Background and research question: Gliomas represent 43% of all solid intracranial tumours, of which glioblastomas have the poorest prognosis. Recently, the human cytosolic branched-chain aminotransferase protein (hBCATc), which metabolises the branched-chain amino acids (BCAA), was identified as a biomarker and therapeutic target for glioblastomas carrying wild-type isocitrate dehydrogenase (IDH-WT) genes. However, the clinical utility of the mitochondrial isoform, hBCATm, which also metabolises BCAAs, was not determined nor its potential role in predicting patient survival.Methods: Glioblastomas, of grades II-IV, from 53 patients were graded by a neuropathologist, where the IDH and MGMT status were assessed. Tumours positive for hBCATm, hBCATc and BCKDC were characterised using immunohistochemistry and Western blot analysis using antibodies specific to these proteins.Results: Here, we report that in IDH-WT tumours, the expression of hBCATm is significantly increased (p=0.034) relative to IDH mutation gliomas, and significantly correlates with patient survival, on Kaplan-Meier analysis, where low hBCATm expression is a positive prognostic factor (p=0.003). Moreover, increased hBCATm expression in these glioblastomas correlated with tumour grade indicating their role as a predictive biomarker of glioma progression. Multiple banding was observed for the branched-chain α-keto acid dehydrogenase complex, which catalyses the committed step in BCAA metabolism, but a significant change in expression was absent (p=0.690). Conclusion: Until now, IDH-WT glioblastomas have a uniformly poor prognosis, however we demonstrate for the first time that relatively low hBCATm may select for a better performing subset within this group and may represent a therapeutic target in these hard to treat patients

Impact of a quadrivalent meningococcal ACWY glycoconjugate or a serogroup B meningococcal vaccine on meningococcal carriage: an observer-blind, phase 3 randomised clinical trial

Background: Meningococcal conjugate vaccines protect individuals directly, but also confer herd protection by interrupting carriage transmission. This Phase III observer-blind, randomised, controlled study evaluated the effects of meningococcal quadrivalent (ACWY) glycoconjugate (MenACWY-CRM) or serogroup B (4CMenB) vaccination on meningococcal carriage rates in young adults. Methods: University students (aged 18–24 years) from ten sites in England were randomised to receive two vaccinations one month apart: two doses of Japanese Encephalitis vaccine (controls), two doses of 4CMenB (4CMenB), or one dose of MenACWY-CRM then placebo (MenACWY-CRM). Meningococci were isolated from oropharyngeal swabs collected before vaccination and at five scheduled intervals over one year. Primary analysis was cross-sectional carriage one month after the vaccine course; secondary analyses included comparison of carriage at any time point after primary analysis until study termination. Findings: 2954 subjects were randomised (control, n=987; 4CMenB, n=988; MenACWY-CRM, n=979); approximately one-third of each group was positive for meningococcal carriage at study entry. By one month, there was no significant difference in carriage between controls and 4CMenB (Odds Ratios (OR) [95% CI]; 1·2 [0·8−1·7]) or MenACWY-CRM (OR [95% CI], 0·9 [0·6–1·3]) groups. From three months after dose two, 4CMenB vaccination resulted in significantly lower carriage of any meningococcal strain (calculated efficacy 18·2% [95% CI: 3·4–30·8]) and capsular groups BCWY (calculated efficacy 26·6% [95% CI: 10·5–39·9]) compared to control vaccination. Significantly lower carriage rates were also observed in the MenACWY-CRM group compared with controls: calculated efficacies 39·0% [95%CI: 17·3-55·0] and 36.2% [95%CI: 15·6-51·7] for serogroups Y and CWY, respectively. Interpretation: MenACWY-CRM and 4CMenB vaccines reduced meningococcal carriage rates over 12 months post-vaccination and, therefore, may affect transmission where widely implemented

Activity Increase Despite Arthritis (AÏDA): design of a Phase II randomised controlled trial evaluating an active management booklet for hip and knee osteoarthritis [ISRCTN24554946]

<p>Abstract</p> <p>Background</p> <p>Hip and knee osteoarthritis is a common cause of pain and disability, which can be improved by exercise interventions. However, regular exercise is uncommon in this group because the low physical activity level in the general population is probably reduced even further by pain related fear of movement. The best method of encouraging increased activity in this patient group is not known. A booklet has been developed for patients with hip or knee osteoarthritis. It focuses on changing disadvantageous beliefs and encouraging increased physical activity.</p> <p>Methods/Design</p> <p>This paper describes the design of a Phase II randomised controlled trial (RCT) to test the effectiveness of this new booklet for patients with hip and knee osteoarthritis in influencing illness and treatment beliefs, and to assess the feasibility of conducting a larger definitive RCT in terms of health status and exercise behaviour. A computerised search of four general medical practice patients' record databases will identify patients older than 50 years of age who have consulted with hip or knee pain in the previous twelve months. A random sample of 120 will be invited to participate in the RCT comparing the new booklet with a control booklet, and we expect 100 to return final questionnaires. This trial will assess the feasibility of recruitment and randomisation, the suitability of the control intervention and outcome measurement tools, and will provide an estimate of effect size. Outcomes will include beliefs about hip and knee pain, beliefs about exercise, fear avoidance, level of physical activity, health status and health service costs. They will be measured at baseline, one month and three months.</p> <p>Discussion</p> <p>We discuss the merits of testing effectiveness in a phase II trial, in terms of intermediate outcome measures, whilst testing the processes for a larger definitive trial. We also discuss the advantages and disadvantages of testing the psychometric properties of the primary outcome measures concurrently with the trial.</p> <p>Trial registration</p> <p>Current Controlled Trials ISRCTN24554946</p

Association of Genetic Variants With Primary Open-Angle Glaucoma Among Individuals With African Ancestry.

Importance:Primary open-angle glaucoma presents with increased prevalence and a higher degree of clinical severity in populations of African ancestry compared with European or Asian ancestry. Despite this, individuals of African ancestry remain understudied in genomic research for blinding disorders. Objectives:To perform a genome-wide association study (GWAS) of African ancestry populations and evaluate potential mechanisms of pathogenesis for loci associated with primary open-angle glaucoma. Design, Settings, and Participants:A 2-stage GWAS with a discovery data set of 2320 individuals with primary open-angle glaucoma and 2121 control individuals without primary open-angle glaucoma. The validation stage included an additional 6937 affected individuals and 14 917 unaffected individuals using multicenter clinic- and population-based participant recruitment approaches. Study participants were recruited from Ghana, Nigeria, South Africa, the United States, Tanzania, Britain, Cameroon, Saudi Arabia, Brazil, the Democratic Republic of the Congo, Morocco, Peru, and Mali from 2003 to 2018. Individuals with primary open-angle glaucoma had open iridocorneal angles and displayed glaucomatous optic neuropathy with visual field defects. Elevated intraocular pressure was not included in the case definition. Control individuals had no elevated intraocular pressure and no signs of glaucoma. Exposures:Genetic variants associated with primary open-angle glaucoma. Main Outcomes and Measures:Presence of primary open-angle glaucoma. Genome-wide significance was defined as P &lt; 5 × 10-8 in the discovery stage and in the meta-analysis of combined discovery and validation data. Results:A total of 2320 individuals with primary open-angle glaucoma (mean [interquartile range] age, 64.6 [56-74] years; 1055 [45.5%] women) and 2121 individuals without primary open-angle glaucoma (mean [interquartile range] age, 63.4 [55-71] years; 1025 [48.3%] women) were included in the discovery GWAS. The GWAS discovery meta-analysis demonstrated association of variants at amyloid-β A4 precursor protein-binding family B member 2 (APBB2; chromosome 4, rs59892895T&gt;C) with primary open-angle glaucoma (odds ratio [OR], 1.32 [95% CI, 1.20-1.46]; P = 2 × 10-8). The association was validated in an analysis of an additional 6937 affected individuals and 14 917 unaffected individuals (OR, 1.15 [95% CI, 1.09-1.21]; P &lt; .001). Each copy of the rs59892895*C risk allele was associated with increased risk of primary open-angle glaucoma when all data were included in a meta-analysis (OR, 1.19 [95% CI, 1.14-1.25]; P = 4 × 10-13). The rs59892895*C risk allele was present at appreciable frequency only in African ancestry populations. In contrast, the rs59892895*C risk allele had a frequency of less than 0.1% in individuals of European or Asian ancestry. Conclusions and Relevance:In this genome-wide association study, variants at the APBB2 locus demonstrated differential association with primary open-angle glaucoma by ancestry. If validated in additional populations this finding may have implications for risk assessment and therapeutic strategies

Reducing repeat pregnancies in adolescence: applying realist principles as part of a mixed-methods systematic review to explore what works, for whom, how and under what circumstances

BACKGROUND: Previous research has demonstrated emotional, psychological and educational harm to young mothers following unintended conceptions. The UK has one of the highest rates of pregnancies in adolescence in Western Europe with a high proportion of these being repeat pregnancies, making it a topic of interest for public health policy makers, and health and social care practitioners. As part of a wider mixed-methods systematic review, realist principles were applied to synthesise evidence about interventions aiming to reduce repeat pregnancies in adolescence.METHODS: A multi-streamed, mixed-methods systematic review was conducted searching 11 major electronic databases and 9 additional databases from 1995 onwards, using key terms such as pregnancy, teen or adolescent. The principles of realist synthesis were applied to all included literature to uncover theories about what works, for whom, how and in what context. Initial theory areas were developed through evidence scoping, group discussion by the authors and stakeholder engagement to uncover context + mechanism = outcome (CMO) configurations and related narratives.RESULTS: The searches identified 8,664 documents initially, and 403 in repeat searches, filtering to 81 included studies, including qualitative studies, randomised controlled trials, quantitative studies and grey literature. Three CMO configurations were developed. The individual experiences of young mothers' triggered self-efficacy, notions of perceived risks, susceptibility and benefits of pregnancy, resulting in the adolescent taking control of their fertility and sexual encounters. The choice between motherhood and other goals triggered notions of motivations, resulting in the adolescent managing their expectations of motherhood and controlling their fertility and sexual encounters. Barriers and facilitators to accessing services triggered notions of connectedness and self-determination; resulting in interventions that are tailored so they are relevant to young persons, and improve access to services and engagement with the issue of pregnancy in adolescence.CONCLUSIONS: Pregnancy in adolescence is a complex issue with many factors to consider. The conceptual platform described here could help guide policy makers and professionals towards a number of areas that need to be attended to in order to increase the likelihood of an intervention working to prevent rapid repeat pregnancy in adolescence.TRIAL REGISTRATION: PROSPERO CRD42012003168

Narrative exposure therapy for PTSD increases top-down processing of aversive stimuli - evidence from a randomized controlled treatment trial

Adenauer H, Catani C, Gola H, et al. Narrative exposure therapy for PTSD increases top-down processing of aversive stimuli - evidence from a randomized controlled treatment trial. BMC Neuroscience. 2011;12(1): 127.BACKGROUND: Little is known about the neurobiological foundations of psychotherapy for Posttraumatic Stress Disorder (PTSD). Prior studies have shown that PTSD is associated with altered processing of threatening and aversive stimuli. It remains unclear whether this functional abnormality can be changed by psychotherapy. This is the first randomized controlled treatment trial that examines whether narrative exposure therapy (NET) causes changes in affective stimulus processing in patients with chronic PTSD. METHODS: 34 refugees with PTSD were randomly assigned to a NET group or to a waitlist control (WLC) group. At pre-test and at four-months follow-up, the diagnostics included the assessment of clinical variables and measurements of neuromagnetic oscillatory brain activity (steady-state visual evoked fields, ssVEF) resulting from exposure to aversive pictures compared to neutral pictures. RESULTS: PTSD as well as depressive symptom severity scores declined in the NET group, whereas symptoms persisted in the WLC group. Only in the NET group, parietal and occipital activity towards threatening pictures increased significantly after therapy. CONCLUSIONS: Our results indicate that NET causes an increase of activity associated with cortical top-down regulation of attention towards aversive pictures. The increase of attention allocation to potential threat cues might allow treated patients to re-appraise the actual danger of the current situation and, thereby, reducing PTSD symptoms. REGISTRATION OF THE CLINICAL TRIAL: Number: NCT00563888Name: "Change of Neural Network Indicators Through Narrative Treatment of PTSD in Torture Victims" ULR: http://www.clinicaltrials.gov/ct2/show/NCT00563888

Lived Experience-Led Research Agenda to Address Early Death in People With a Diagnosis of a Serious Mental Illness: A Consensus Statement

Importance People with serious mental illness (SMI), defined as a diagnosis of schizophrenia spectrum disorder, bipolar disorder, or disabling major depressive disorder) die approximately 10 to 25 years earlier than the general population. Objective To develop the first-ever lived experience–led research agenda to address early mortality in people with SMI. Evidence Review A virtual 2-day roundtable comprising 40 individuals convened on May 24 and May 26, 2022, and used a virtual Delphi method to arrive at expert group consensus. Participants responded to 6 rounds of virtual Delphi discussion via email that prioritized research topics and agreement on recommendations. The roundtable was composed of individuals with lived experience of mental health and/or substance misuse, peer support specialists, recovery coaches, parents and caregivers of people with SMI, researchers and clinician-scientists with and without lived experience, policy makers, and patient-led organizations. Twenty-two of 28 (78.6%) of the authors who provided data represented people with lived experiences. Roundtable members were selected by reviewing the peer-reviewed and gray literature on early mortality and SMI, direct email, and snowball sampling. Findings The following recommendations are presented in order of priority as identified by the roundtable participants: (1) improve the empirical understanding of the direct and indirect social and biological contributions of trauma on morbidity and early mortality; (2) advance the role of family, extended families, and informal supporters; (3) recognize the importance of co-occurring disorders and early mortality; (4) redefine clinical education to reduce stigma and support clinicians through technological advancements to improve diagnostic accuracy; (5) examine outcomes meaningful to people with an SMI diagnosis, such as loneliness and sense of belonging, and stigma and their complex relationship with early mortality; (6) advance the science of pharmaceuticals, drug discovery, and choice in medication use; (7) use precision medicine to inform treatment; and (8) redefine the terms system literacy and health literacy. Conclusions and Relevance The recommendations of this roundtable are a starting point for changing practice and highlighting lived experience–led research priorities as an option to move the field forward.publishedVersio