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Background The aim of this randomized control trial is to test the impact of providing additional training and support to volunteers who are paired with youth of color in the Big Brothers Big Sisters (BBBS) community-based mentoring program. The aim of the intervention activities is to enhance the capacity of mentors to have more culturally responsive and informed interactions with their mentees of color, thereby strengthening the youth’s ethnic/racial identity and abilities to both cope with experiences of racism and contribute to causes that advance social justice. Methods Recruitment started in June 2022, with a goal of enrolling 240 dyads (i.e., “matches”), each consisting of a volunteer mentor and a youth of color aged 9- to 17-years old with whom they were paired through BBBS. Each match is assigned randomly to receive either standard BBBS services or to services that incorporate the intervention activities (i.e., approximately 3 h of initial training that is then supplemented with booster emails and in the context of the contacts that case managers have with mentors routinely in the program). The BBBS staff who are responsible for delivering the enhancements receive preparatory training as well as ongoing support with implementation. The study has a mixed-methods design. Survey data, on outcomes (e.g., ethnic/racial identity, sense of mattering, efficacy) aligned with the theory of change, are collected at multiple time points within 12 months from mentors, youth and their parent/guardian, and BBBS staff. Multiple qualitative interviews are conducted with a subset of youth, mentors, parents and BBBS staff to examine how the intervention works and how it impacts relationship development and youth outcomes over time. Integration of quantitative and qualitative data will aim to better understand whether and how the intervention works with respect to its potential influence on mentor attitudes (e.g., cultural humility), mentor-youth interactions, and emergent identities and capacities that have well-documented importance for the resilience and well-being of youth of color. Discussion This culturally tailored training and support intervention for volunteer mentors may be one way to increase the effectiveness of mentoring programs for youth of color. Study findings will have implications for youth mentoring programs and for other settings (e.g., schools, after school programs) in which children and adolescents form relationships with adults. Trial registration www.clinicaltrials.gov —Clinical Trial #NCT05391711; original 05.21.2022; Amendment 07.01.2022: study status was updated and more details were provided on outcome measures; Amendment 11/13/2022: sample size was modified, a few mentor outcome measures were added in the 12-months survey, the timing of a mentor measure was updated.

The current paper presents lessons learned from a research-to-practice partnership between mentoring program practitioners and researchers that focused on the development and implementation of a cultural humility training for volunteer mentors. Using multiple data sources (e.g., training materials, field notes, mentor surveys), we present a description of the research-to-practice partnership and the Culturally Smart Relationships pilot training content. We generate practice-oriented lessons to inform future cultural humility training work with staff and volunteers in youth programs. Our lessons reflect recommendations that emerged from five project phases: (a) organizational commitment to justice, equity, diversity, inclusion; (b) training curriculum and logistical planning; (c) “To Zoom, or not to Zoom''; (d) facilitation of the training; and (e) post-training and ongoing support. The pilot training content and lessons learned have implications for youth programs by elucidating training as one component of a broader approach for equity in youth developmental program practice.

Background The Enterobacter cloacae complex (Ecc) encompasses opportunistic Gram-negative bacteria demonstrating considerable phenotypic and genotypic diversity. Bloodstream, respiratory and urinary tract infections by Ecc bacteria are associated with morbidity and mortality worldwide. These infections are often difficult to treat since Ecc bacteria are resistant to penicillins, quinolones, aminoglycosides, and third-generation cephalosporins. Resistance also extends to carbapenems, leaving only polymyxins, such as colistin, as a last resort antibiotic for treatment. However, colistin resistance in Ecc isolates is also unexpectedly frequent. Despite extensive information on antibiotic resistance by Enterobacter species, much less is known about their infection biology. There are few reports on the survival and persistence of selected Enterobacter species in macrophages and epithelial cells, but how Enterobacter isolates interact with innate immune host cells upon engulfment remains unexplored. In this study, we have investigated the intracellular trafficking of a subset of antimicrobial resistant Ecc clinical isolates, including colistin-resistant strains, within human macrophages, and determined the macrophage response to the intracellular infection. Methods Phagocytosis of 11 clinical Ecc isolates, including E. cloacae, E. bugandensis, E. kobei, E. xiangfangensis, E. roggenkampii, E. hoffmannii, and E. ludwigii was investigated in THP-1 and human monocyte derived macrophages (HMDMs). Confocal fluorescence microscopy was used to ascertain intracellular trafficking via co-localisation of cell markers with fluorescent bacteria. Intracellular bacterial replication was assessed by bacterial enumeration in cell lysates after killing extracellular bacteria and by a fluorescence dilution approach to follow the synthesis of the bacterial cell wall over time. Macrophage cell cytotoxicity was investigated by quantifying the release of lactate dehydrogenase during infection with all isolates. Two prototypic isolates, the E. cloacae ATCC13047 type strain and the E. bugandensis 104107, were used to explore in more detail the response of macrophages to the intracellular infection by determining cleavage of the proinflammatory markers caspase-1, gasdermin D and pro-interleukin-1β. Findings We found that Ecc isolates do not replicate in human macrophages but survive within a modified late phagolysosome compartment. Survival occurred in all species investigated and did not correlate with colistin resistance, lipopolysaccharide modifications, or bacterial pathogenicity in the Galleria mellonella infection model. All isolates induced macrophage cell cytotoxicity at significantly lower levels than controls treated with lipopolysaccharide and nigericin treatment (to induce a proinflammatory response). Low cytotoxicity also correlated with absence of cleavage of proinflammatory markers in infected macrophages. Interpretation Ecc species can survive without replication inside human macrophages with minimal effects on cell viability and inflammation. These observations could have implications in the clinical outcome of patients that cannot readily clear infecting Ecc bacteria. This can potentially lead to prolonged intracellular survival and infection relapse.Competing Interest StatementThe authors have declared no competing interest.

Based on a consensus conference of experts in the evolution and ecology of cancer, this article proposes a framework for classifying tumours that includes four evolutionary and ecological processes: neoplastic cell diversity and changes over time in that diversity, hazards to cell survival and available resources. Neoplasms change over time through a process of cell-level evolution, driven by genetic and epigenetic alterations. However, the ecology of the microenvironment of a neoplastic cell determines which changes provide adaptive benefits. There is widespread recognition of the importance of these evolutionary and ecological processes in cancer, but to date, no system has been proposed for drawing clinically relevant distinctions between how different tumours are evolving. On the basis of a consensus conference of experts in the fields of cancer evolution and cancer ecology, we propose a framework for classifying tumours that is based on four relevant components. These are the diversity of neoplastic cells (intratumoural heterogeneity) and changes over time in that diversity, which make up an evolutionary index (Evo-index), as well as the hazards to neoplastic cell survival and the resources available to neoplastic cells, which make up an ecological index (Eco-index). We review evidence demonstrating the importance of each of these factors and describe multiple methods that can be used to measure them. Development of this classification system holds promise for enabling clinicians to personalize optimal interventions based on the evolvability of the patient's tumour. The Evo- and Eco-indices provide a common lexicon for communicating about how neoplasms change in response to interventions, with potential implications for clinical trials, personalized medicine and basic cancer research.

In a randomized phase 3 trial involving patients with acute intermittent porphyria, the use of givosiran, an oligonucleotide drug designed to target messenger RNA encoding aminolevulinic acid synthase, led to a 74% lower annualized porphyria attack rate than the use of placebo at 6 months.

Treatment-resistant major depression is common and potentially life-threatening in elderly people, in whom little is known about the benefits and risks of augmentation pharmacotherapy. We aimed to assess whether aripiprazole is associated with a higher probability of remission than is placebo. We did a randomised, double-blind, placebo-controlled trial at three centres in the USA and Canada to test the efficacy and safety of aripiprazole augmentation for adults aged older than 60 years with treatment-resistant depression (Montgomery Asberg Depression Rating Scale [MADRS] score of ≥15). Patients who did not achieve remission during a pre-trial with venlafaxine extended-release (150–300 mg/day) were randomly assigned (1:1) to the addition of aripiprazole (target dose 10 mg [maximum 15 mg] daily) daily or placebo for 12 weeks. The computer-generated randomisation was done in blocks and stratified by site. Only the database administrator and research pharmacists had knowledge of treatment assignment. The primary endpoint was remission, defined as an MADRS score of 10 or less (and at least 2 points below the score at the start of the randomised phase) at both of the final two consecutive visits, analysed by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00892047. From July 20, 2009, to Dec 30, 2013, we recruited 468 eligible participants, 181 (39%) of whom did not remit and were randomly assigned to aripiprazole (n=91) or placebo (n=90). A greater proportion of participants in the aripiprazole group achieved remission than did those in the placebo group (40 [44%] vs 26 [29%] participants; odds ratio [OR] 2·0 [95% CI 1·1–3·7], p=0·03; number needed to treat [NNT] 6·6 [95% CI 3·5–81·8]). Akathisia was the most common adverse effect of aripiprazole (reported in 24 [26%] of 91 participants on aripiprazole vs 11 [12%] of 90 on placebo). Compared with placebo, aripiprazole was also associated with more Parkinsonism (15 [17%] of 86 vs two [2%] of 81 participants), but not with treatment-emergent suicidal ideation (13 [21%] of 61 vs 19 [29%] of 65 participants) or other measured safety variables. In adults aged 60 years or older who do not achieve remission from depression with a first-line antidepressant, the addition of aripiprazole is effective in achieving and sustaining remission. Tolerability concerns include the potential for akathisia and Parkinsonism. National Institute of Mental Health, UPMC Endowment in Geriatric Psychiatry, Taylor Family Institute for Innovative Psychiatric Research, National Center for Advancing Translational Sciences, and the Campbell Family Mental Health Research Institute.

AbstractObjectiveTo assess the immediate impact of the introduction of minimum unit pricing in Scotland on household alcohol purchases.DesignControlled interrupted time series analysis.SettingPurchase data from Kantar Worldpanel’s household shopping panel for 2015-18.Participants5325 Scottish households, 54 807 English households as controls, and 10 040 households in northern England to control for potential cross border effects.InterventionsIntroduction of a minimum price of 50p (€0.55; $0.61) per UK unit (6.25p per gram) for the sale of alcohol in Scotland on 1 May 2018.Main outcome measuresPrice per gram of alcohol, number of grams of alcohol purchased from off-trade by households, and weekly household expenditure on alcohol.ResultsThe introduction of minimum unit pricing in Scotland was associated with an increase in purchase price of 0.64p per gram of alcohol (95% confidence interval 0.54 to 0.75), a reduction in weekly purchases of 9.5 g of alcohol per adult per household (5.1 to 13.9), and a non-significant increase in weekly expenditure on alcohol per household of 61p (−5 to 127). The increase in purchase price was higher in lower income households and in households that purchased the largest amount of alcohol. The reduction in purchased grams of alcohol was greater in lower income households and only occurred in the top fifth of households by income that purchased the greatest amount of alcohol, where the reduction was 15 g of alcohol per week (6 to 24). Changes in weekly expenditure were not systematically related to household income but increased with increasing household purchases.ConclusionsIn terms of immediate impact, the introduction of minimum unit pricing appears to have been successful in reducing the amount of alcohol purchased by households in Scotland. The action was targeted, in that reductions of purchased alcohol only occurred in the households that bought the most alcohol.