Identifying potential outcomes of patient engagement in primary care quality improvement: a modified Delphi study.

Rationale: A barrier to dedicating resources towards patient engagement in primary care quality improvement is the lack of clearly identified outcomes that might result from these initiatives.

Aims And Objectives: We sought to identify these potential outcomes at three healthcare levels as defined by the Institute of Medicine: 1) Micro/Direct Care; 2) Meso/Microsystem; and 3) Macro/Clinic/System using a Modified Delphi technique.

Method: Two focus groups of patients and primary care clinician leaders generated a first set of outcomes.

Young people's views and experience of diet-related inequalities in England (UK): a qualitative study.

Inequalities in diets contribute to overall inequalities in health. Economic inequality and inequalities in access to healthy food are key drivers of poor diet and ill health among young people (YP). Despite mounting evidence of structural barriers to healthy eating, less is known about how YP view and experience these inequalities where they live, and how to address them.

'It depends on where you were born…here in the North East, there's not really many job opportunities compared to in the South': young people's perspectives on a North-South health divide and its drivers in England, UK.

Background: Improving the public's understanding of how regional and socioeconomic inequalities create and perpetuate inequalities in health, is argued to be necessary for building support for policies geared towards creating a more equal society. However, research exploring public perceptions of health inequalities, and how they are generated, is limited. This is particularly so for young people.

Autophagy suppression in DNA damaged cells occurs through a newly identified p53-proteasome-LC3 axis.

Macroautophagy is thought to have a critical role in shaping and refining cellular proteostasis in eukaryotic cells recovering from DNA damage. Here, we report a mechanism by which autophagy is suppressed in cells exposed to bacterial toxin-, chemical-, or radiation-mediated sources of genotoxicity. Autophagy suppression is directly linked to cellular responses to DNA damage, and specifically the stabilization of the tumor suppressor p53, which is both required and sufficient for regulating the ubiquitination and proteasome-dependent reduction in cellular pools of microtubule-associated protein 1 light chain 3 (LC3A/B), a key precursor of autophagosome biogenesis and maturation, in both epithelial cells and an organoid model.

Machine Learning Models Identify Inhibitors of New Delhi Metallo-β-lactamase.

The worldwide spread of the metallo-β-lactamases (MBL), especially New Delhi metallo-β-lactamase-1 (NDM-1), is threatening the efficacy of β-lactams, which are the most potent and prescribed class of antibiotics in the clinic. Currently, FDA-approved MBL inhibitors are lacking in the clinic even though many strategies have been used in inhibitor development, including quantitative high-throughput screening (qHTS), fragment-based drug discovery (FBDD), and molecular docking. Herein, a machine learning-based prediction tool is described, which was generated using results from HTS of a large chemical library and previously published inhibition data.

Young people's experiences of physical activity insecurity: a qualitative study highlighting intersectional disadvantage in the UK.

Background: Intersecting socioeconomic and demographic reasons for physical activity (PA) inequalities are not well understood for young people at risk of experiencing marginalisation and living with disadvantage. This study explored young people's experiences of PA in their local area, and the associated impacts on opportunities for good physical and emotional health and wellbeing.

Methods: Seven local youth groups were purposefully sampled from disadvantaged areas across urban, rural and coastal areas of England, including two that were specifically for LGBTQ + young people.

Multiple and Optimal Screening Subset: a method selecting global characteristic congeners for robust foodomics analysis.

Metabolomics and foodomics shed light on the molecular processes within living organisms and the complex food composition by leveraging sophisticated analytical techniques to systematically analyze the vast array of molecular features. The traditional feature-picking method often results in arbitrary selections of the model, feature ranking, and cut-off, which may lead to suboptimal results. Thus, a Multiple and Optimal Screening Subset (MOSS) approach was developed in this study to achieve a balance between a minimal number of predictors and high predictive accuracy during statistical model setup.

Revisiting bacterial cytolethal distending toxin structure and function.

Cytolethal distending toxins (CDTs) are intracellular-acting bacterial genotoxins generated by a diverse group of mucocutaneous human pathogens. CDTs must successfully bind to the plasma membrane of host cells in order to exert their modulatory effects. Maximal toxin activity requires all three toxin subunits, CdtA, CdtB, and CdtC, which, based primarily on high-resolution structural data, are believed to preassemble into a tripartite complex necessary for toxin activity.

Taxifolin as a Metallo-β-Lactamase Inhibitor in Combination with Augmentin against Verona Imipenemase 2 Expressing .

Among the various mechanisms that bacteria use to develop antibiotic resistance, the multiple expression of β-lactamases is particularly problematic, threatening public health and increasing patient mortality rates. Even if a combination therapy-in which a β-lactamase inhibitor is administered together with a β-lactam antibiotic-has proven effective against serine-β-lactamases, there are no currently approved metallo-β-lactamase inhibitors. Herein, we demonstrate that quercetin and its analogs are promising starting points for the further development of safe and effective metallo-β-lactamase inhibitors.

The directed evolution of NDM-1.

β-Lactam antibiotics are among the most frequently prescribed therapeutic agents. A common mechanism of resistance toward β-lactam antibiotics is the production of β-lactamases. These enzymes are capable of hydrolyzing the β-lactam bond, rendering the drug inactive.

Characterizing bourbon whiskey via the combination of LC-MS and GC-MS based molecular fingerprinting.

To discover molecular fingerprints that vary by bourbon's age or color, 121 commercial bourbon samples were analyzed using both gas chromatography and liquid chromatography combined with mass spectrometry. In total, 81 non-volatile compounds and 102 volatile compounds were identified. A subset of samples containing age information was divided into training (n = 70) and testing (n = 12) groups to build and validate the Partial Least Square - Discriminant Analysis models for age-based classification.

Protein kinase D1 (Prkd1) deletion in brown adipose tissue leads to altered myogenic gene expression after cold exposure, while thermogenesis remains intact.

Brown adipose tissue (BAT) has in recent times been rediscovered in adult humans, and together with work from preclinical models, has shown to have the potential of providing a variety of positive metabolic benefits. These include lower plasma glucose, improved insulin sensitivity, and reduced susceptibility to obesity and its comorbidities. As such, its continued study could offer insights to therapeutically modulate this tissue to improve metabolic health.

Optimization of 1,2,4-Triazole-3-thiones toward Broad-Spectrum Metallo-β-lactamase Inhibitors Showing Potent Synergistic Activity on VIM- and NDM-1-Producing Clinical Isolates.

Metallo-β-lactamases (MBLs) contribute to the resistance of Gram-negative bacteria to carbapenems, last-resort antibiotics at hospital, and MBL inhibitors are urgently needed to preserve these important antibacterial drugs. Here, we describe a series of 1,2,4-triazole-3-thione-based inhibitors displaying an α-amino acid substituent, which amine was mono- or disubstituted by (hetero)aryl groups. Compounds disubstituted by certain nitrogen-containing heterocycles showed submicromolar activities against VIM-type enzymes and strong NDM-1 inhibition ( = 10-30 nM).

Exploring young people's perspectives on mental health support: A qualitative study across three geographical areas in England, UK.

Improving young people's (YP) mental health and well-being is a global public health priority. Despite continued commitment within the UK policy agenda to improve the mental health and well-being of YP, the incidence of mental health issues continues to rise. This has been further compounded by the outbreak of COVID-19 which has disproportionately affected YP in the most socioeconomically disadvantaged areas.

Student self-ratings of social-emotional competencies: Dimensional structure and outcome associations of the WCSD-SECA among Hispanic and non-Hispanic White boys and girls in elementary through high school.

School-based assessments of students' self-reported social-emotional competencies (SECs) are an essential part of social and emotional learning (SEL) initiatives. Few studies, however, have investigated whether such assessments align with the frameworks that inform SEL practices, especially for diverse populations. In the present study we investigated the dimensional structure of the 40-item Washoe County School District Social-Emotional Competency Assessment (WCSD-SECA), which was designed to measure the five domains of SECs defined by the widely used Collaborative for Academic Social and Emotional Learning framework (CASEL 5).

Developing catalyst films of health experiences: an analysis of a robust multi-stakeholder involvement journey.

Background: Those whose lives are most directly impacted by health care-patients, caregivers, and frontline staff-are ideally situated to improve patient health care services and care quality. Despite a proliferation of literature on both Patient and Public Involvement (PPI) and clinical quality improvement (QI), concrete strategies regarding how to involve patients remain elusive.

Aim: Research suggests catalyst films, comprised of rigorously-analyzed interview data from diverse patients about their experiences with health and health care ("catalyst films") are a promising way to bring actionable patient feedback to QI.

Discovery of an Effective Small-Molecule Allosteric Inhibitor of New Delhi Metallo-β-lactamase (NDM).

To identify novel inhibitors of the carbapenemase New Delhi metallo-β-lactamase (NDM) as possible therapeutic compounds, we conducted a high-throughput screen of a 43,358-compound library. One of these compounds, a 2-quinazolinone linked through a diacylhydrazine to a phenyl ring (QDP-1) (IC = 7.9 ± 0.

'It All Kind of Links Really': Young People's Perspectives on the Relationship between Socioeconomic Circumstances and Health.

Meaningful inclusion of young people's perceptions and experiences of inequalities is argued to be critical in the development of pro-equity policies. Our study explored young people's perceptions of what influences their opportunities to be healthy within their local area and their understandings of health inequalities. Three interlinked qualitative focus group discussions, each lasting 90 to 100 min, with the same six groups of young people ( = 42) aged 13-21, were conducted between February and June 2021.

Sudden Death in High School Athletes: A Case Series Examining the Influence of Sickle Cell Trait.

Athletes with sickle cell trait (SCT) have up to a 37-fold increased risk of exercise-related death. Exertional collapse associated with sickle cell trait (ECAST) is uncommon but can lead to exercise-related death due to exertional sickling. We present a case series of fatal ECAST in high school athletes aged 14 to 16 years.

Recommendations to disclose sexual assault are motivated by retribution among women who endorse honor values.

Rape arrests are higher in US states wherein residents more typically endorse honor values. Because honor values reflect an association between reputation and self-worth, which is based on one's ability to uphold traditional gender norms, one should expect that women who endorse honor values are motivated to conceal a sexual assault. However, honor values also engender the expectation that women defend their reputations if threatened.

1,2,4-Triazole-3-thione compounds with a 4-ethyl alkyl/aryl sulfide substituent are broad-spectrum metallo-β-lactamase inhibitors with re-sensitization activity.

Metallo-β-lactamases (MBLs) are important contributors of Gram-negative bacteria resistance to β-lactam antibiotics. MBLs are highly worrying because of their carbapenemase activity, their rapid spread in major human opportunistic pathogens while no clinically useful inhibitor is available yet. In this context, we are exploring the potential of compounds based on the 1,2,4-triazole-3-thione scaffold as an original ligand of the di-zinc active sites of MBLs, and diversely substituted at its positions 4 and 5.

Increased Energy Expenditure and Protection From Diet-Induced Obesity in Mice Lacking the cGMP-Specific Phosphodiesterase PDE9.

Cyclic nucleotides cAMP and cGMP are important second messengers for the regulation of adaptive thermogenesis. Their levels are controlled not only by their synthesis, but also their degradation. Since pharmacological inhibitors of cGMP-specific phosphodiesterase 9 (PDE9) can increase cGMP-dependent protein kinase signaling and uncoupling protein 1 expression in adipocytes, we sought to elucidate the role of PDE9 on energy balance and glucose homeostasis in vivo.

Fragment-based screening and hit-based substructure search: Rapid discovery of 8-hydroxyquinoline-7-carboxylic acid as a low-cytotoxic, nanomolar metallo β-lactamase inhibitor.

Metallo-β-lactamases (MBLs) are zinc-containing carbapenemases that inactivate a broad range of β-lactam antibiotics. There is a lack of β-lactamase inhibitors for restoring existing β-lactam antibiotics arsenals against common bacterial infections. Fragment-based screening of a non-specific metal chelator library demonstrates 8-hydroxyquinoline as a broad-spectrum nanomolar inhibitor against VIM-2 and NDM-1.

Elusive structural changes of New Delhi metallo-β-lactamase revealed by ultraviolet photodissociation mass spectrometry.

We use mass spectrometry (MS), under denaturing and non-denaturing solution conditions, along with ultraviolet photodissociation (UVPD) to characterize structural variations in New Delhi metallo-β-lactamase (NDM) upon perturbation by ligands or mutation. Mapping changes in the abundances and distributions of fragment ions enables sensitive detection of structural alterations throughout the protein. Binding of three covalent inhibitors was characterized: a pentafluorphenyl ester, an -aryloxycarbonyl hydroxamate, and ebselen.