New Developments in Brief Interventions to Treat Problem Drinking in Nonspecialty Health Care Settings

The delivery of brief interventions (BIs) in health care settings to reduce problematic alcohol consumption is a key preventive strategy for public health. However, evidence of effectiveness beyond primary care is inconsistent. Patient populations and intervention components are heterogeneous. Also, evidence for successful implementation strategies is limited. In this article, recent literature is reviewed covering BI effectiveness for patient populations and subgroups, and design and implementation of BIs. Support is evident for short-term effectiveness in hospital settings, but long-term effects may be confounded by changes in control groups. Limited evidence suggests effectiveness with young patients not admitted as a consequence of alcohol, dependent patients, and binge drinkers. Influential BI components include high-quality change plans and provider characteristics. Health professionals endorse BI and feel confident in delivering it, but training and support initiatives continue to show no significant effects on uptake, prompting calls for systematic approaches to implementing BI in health care

Asymmetric triplex metallohelices with high and selective activity against cancer cells

Small cationic amphiphilic α-helical peptides are emerging as agents for the treatment of cancer and infection, but they are costly and display unfavourable pharmacokinetics. Helical coordination complexes may offer a three-dimensional scaffold for the synthesis of mimetic architectures. However, the high symmetry and modest functionality of current systems offer little scope to tailor the structure to interact with specific biomolecular targets, or to create libraries for phenotypic screens. Here, we report the highly stereoselective asymmetric self-assembly of very stable, functionalized metallohelices. Their anti-parallel head-to-head-to-tail ‘triplex’ strand arrangement creates an amphipathic functional topology akin to that of the active sub-units of, for example, host-defence peptides and ​p53. The metallohelices display high, structure-dependent toxicity to the human colon carcinoma cell-line HCT116 ​p53++, causing dramatic changes in the cell cycle without DNA damage. They have lower toxicity to human breast adenocarcinoma cells (MDA-MB-468) and, most remarkably, they show no significant toxicity to the bacteria methicillin-resistant Staphylococcus aureus and Escherichia coli. At a glanc

Effectiveness of interventions to promote healthy diet in primary care: systematic review and meta-analysis of randomised controlled trials

Background A diet rich in fruit, vegetables and dietary fibre and low in fat is associated with reduced risk of chronic disease. This review aimed to estimate the effectiveness of interventions to promote healthy diet for primary prevention among participants attending primary care.<p></p> Methods A systematic review of trials using individual or cluster randomisation of interventions delivered in primary care to promote dietary change over 12 months in healthy participants free from chronic disease or defined high risk states. Outcomes were change in fruit and vegetable intake, consumption of total fat and fibre and changes in serum cholesterol concentration.<p></p> Results Ten studies were included with 12,414 participants. The design and delivery of interventions were diverse with respect to grounding in behavioural theory and intervention intensity. A meta-analysis of three studies showed an increase in fruit consumption of 0.25 (0.01 to 0.49) servings per day, with an increase in vegetable consumption of 0.25 (0.06 to 0.44) serving per day. A further three studies that reported on fruit and vegetable consumption together showed a pooled increment of 0.50 (0.13 to 0.87) servings per day. The pooled effect on consumption of dietary fibre, from four studies, was estimated to be 1.97 (0.43 to 3.52) gm fibre per day. Data from five studies showed a mean decrease in total fat intake of 5.2% of total energy (1.5 to 8.8%). Data from three studies showed a mean decrease in serum cholesterol of 0.10 (-0.19 to 0.00) mmol/L.<p></p> Conclusion Presently-reported interventions to promote healthy diet for primary prevention in primary care, which illustrate a diverse range of intervention methods, may yield small beneficial changes in consumption of fruit, vegetables, fibre and fat over 12 months. The present results do not exclude the possibility that more effective intervention strategies might be developed.<p></p&gt

Differential expression of VEGF-Axxx isoforms is critical for development of pulmonary fibrosis

RATIONALE Fibrosis after lung injury is related to poor outcome, and idiopathic pulmonary fibrosis (IPF) can be regarded as an exemplar. Vascular endothelial growth factor (VEGF)-A has been implicated in this context, but there are conflicting reports as to whether it is a contributory or protective factor. Differential splicing of the VEGF-A gene produces multiple functional isoforms including VEGF-Aa and VEGF-Ab, a member of the inhibitory family. To date there is no clear information on the role of VEGF-A in IPF. OBJECTIVES To establish VEGF-A isoform expression and functional effects in IPF. METHODS We used tissue sections, plasma, and lung fibroblasts from patients with IPF and control subjects. In a bleomycin-induced lung fibrosis model we used wild-type MMTV mice and a triple transgenic mouse SPC-rtTATetoCreLoxP-VEGF-Ato conditionally induce VEGF-A isoform deletion specifically in the alveolar type II (ATII) cells of adult mice. MEASUREMENTS AND MAIN RESULTS IPF and normal lung fibroblasts differentially expressed and responded to VEGF-Aa and VEGF-Ab in terms of proliferation and matrix expression. Increased VEGF-Ab was detected in plasma of progressing patients with IPF. In a mouse model of pulmonary fibrosis, ATII-specific deficiency of VEGF-A or constitutive overexpression of VEGF-Ab inhibited the development of pulmonary fibrosis, as did treatment with intraperitoneal delivery of VEGF-Ab to wild-type mice. CONCLUSIONS These results indicate that changes in the bioavailability of VEGF-A sourced from ATII cells, namely the ratio of VEGF-Aa to VEGF-Ab, are critical in development of pulmonary fibrosis and may be a paradigm for the regulation of tissue repair

An airway epithelial IL-17A response signature identifies a steroid-unresponsive COPD patient subgroup

© 2019 American Society for Clinical Investigation. All rights reserved. BACKGROUND. Chronic obstructive pulmonary disease (COPD) is a heterogeneous smoking-related disease characterized by airway obstruction and inflammation. This inflammation may persist even after smoking cessation and responds variably to corticosteroids. Personalizing treatment to biologically similar "molecular phenotypes" may improve therapeutic efficacy in COPD. IL-17A is involved in neutrophilic inflammation and corticosteroid resistance, and thus may be particularly important in a COPD molecular phenotype. METHODS. We generated a gene expression signature of IL-17A response in bronchial airway epithelial brushings from smokers with and without COPD (n = 238), and validated it using data from 2 randomized trials of IL-17 blockade in psoriasis. This IL-17 signature was related to clinical and pathologic characteristics in 2 additional human studies of COPD: (a) SPIROMICS (n = 47), which included former and current smokers with COPD, and (b) GLUCOLD (n = 79), in which COPD participants were randomized to placebo or corticosteroids. RESULTS. The IL-17 signature was associated with an inflammatory profile characteristic of an IL-17 response, including increased airway neutrophils and macrophages. In SPIROMICS the signature was associated with increased airway obstruction and functional small airways disease on quantitative chest CT. In GLUCOLD the signature was associated with decreased response to corticosteroids, irrespective of airway eosinophilic or type 2 inflammation. CONCLUSION. These data suggest that a gene signature of IL-17 airway epithelial response distinguishes a biologically, radiographically, and clinically distinct COPD subgroup that may benefit from personalized therapy

Alcohol-related brief intervention in patients treated for opiate or cocaine dependence: a randomized controlled study

<p>Abstract</p> <p>Background</p> <p>Despite the importance of heavy drinking and alcohol dependence among patients with opiate and cocaine dependence, few studies have evaluated specific interventions within this group. The aim of the present study was to evaluate the impact of screening with the Alcohol Use Disorders Identification Test (AUDIT) and of brief intervention (BI) on alcohol use in a sample of patients treated for opioid or cocaine dependence in a specialized outpatient clinic.</p> <p>Methods</p> <p>Adult outpatients treated for opioid or cocaine dependence in Switzerland were screened for excessive alcohol drinking and dependence with the AUDIT. Patients with AUDIT scores that indicated excessive drinking or dependence were randomized into two groups--treatment as usual or treatment as usual together with BI--and assessed at 3 months and 9 months.</p> <p>Results</p> <p>Findings revealed a high rate (44%) of problematic alcohol use (excessive drinking and dependence) among patients with opiate and cocaine dependence. The number of drinks per week decreased significantly between T0 (inclusion) and T3 (month 3). A decrease in average AUDIT scores was observed between T0 and T3 and between T0 and T9 (month 9). No statistically significant difference between treatment groups was observed.</p> <p>Conclusions</p> <p>In a substance abuse specialized setting, screening for alcohol use with the AUDIT, followed by feedback on the score, and use of alcohol BI are both possibly useful strategies to induce changes in problematic alcohol use. Definitive conclusions cannot, however, be drawn from the study because of limitations such as lack of a naturalistic group. An important result of the study is the excellent internal consistency of AUDIT in a population treated for opiate or cocaine dependence.</p

Use of placebo interventions among Swiss primary care providers

Background: Placebo interventions can have meaningful effects for patients. However, little is known about the circumstances of their use in clinical practice. We aimed to investigate to what extent and in which way Swiss primary care providers use placebo interventions. Furthermore we explored their ideas about the ethical and legal issues involved. Methods: 599 questionnaires were sent to general practitioners (GPs) and paediatricians in private practice in the Canton of Zurich in Switzerland. To allow for subgroup analysis GPs in urban, suburban, and rural areas as well as paediatricians were selected in an even ratio. Results: 233 questionnaires were completed (response rate 47%). 28% of participants reported that they never used placebo interventions. More participants used impure placebos therapeutically than pure placebos (57% versus 17%, McNemar's chi2 = 78, p<0.001). There is not one clear main reason for placebo prescription. Placebo use was communicated to patients mostly as being "a drug or a therapy" (64%). The most frequently chosen ethical premise was that they "can be used as long as the physician and the patient work together in partnership" (60% for pure and 75% for impure placebos, McNemar's chi2 = 12, p<0.001). A considerable number of participants (11-38%) were indecisive about statements regarding the ethical and legal legitimacy of using placebos. Conclusions: The data obtained from Swiss primary care providers reflect a broad variety of views about placebo interventions as well as a widespread uncertainty regarding their legitimacy. Primary care providers seem to preferentially use impure as compared to pure placebos in their daily practice. An intense debate is required on appropriate standards regarding the clinical use of placebo interventions among medical professionals

Vascular Endothelial Growth Factor (VEGF) isoform expression and activity in human and murine lung injury

<p>Abstract</p> <p>Background</p> <p>The properties of vascular endothelial growth factor (VEGF) as a potent vascular permogen and mitogen have led to investigation of its potential role in lung injury. Alternate spliced VEGF transcript generates several isoforms with potentially differing functions. The purpose of this study was to determine VEGF isoform expression and source in normal and ARDS subjects and investigate the expression and regulation of VEGF isoforms by human alveolar type 2 (ATII) cells.</p> <p>Methods</p> <p>VEGF protein expression was assessed immunohistochemically in archival normal and ARDS human lung tissue. VEGF isoform mRNA expression was assessed in human and murine lung tissue. Purified ATII cells were cultured with proinflammatory cytokines prior to RNA extraction/cell supernatant sampling/proliferation assay.</p> <p>Measurements and Main Results</p> <p>VEGF was expressed on alveolar epithelium, vascular endothelium and alveolar macrophages in normal and ARDS human lung tissue. Increases in VEGF expression were detected in later ARDS in comparison to both normal subjects and early ARDS (p < 0.001). VEGF₁₂₁, VEGF₁₆₅and VEGF₁₈₉isoform mRNA expression increased in later ARDS (p < 0.05). The ratio of soluble to cell-associated isoforms was lower in early ARDS than normal subjects and later ARDS and also in murine lung injury. ATII cells constitutionally produced VEGF₁₆₅and VEGF₁₂₁protein which was increased by LPS (p < 0.05). VEGF₁₆₅upregulated ATII cell proliferation (p < 0.001) that was inhibited by soluble VEGF receptor 1 (<it>sflt</it>) (p < 0.05).</p> <p>Conclusion</p> <p>These data demonstrate that changes in VEGF isoform expression occur in ARDS which may be related to their production by and mitogenic effect on ATII cells; with potentially significant clinical consequences.</p

Alcohol email assessment and feedback study dismantling effectiveness for university students (AMADEUS-1): study protocol for a randomized controlled trial

BACKGROUND: Alcohol causes huge problems for population health and for society, which require interventions with individuals as well as populations to prevent and reduce harms. Brief interventions can be effective and increasingly take advantage of the internet to reach high-risk groups such as students. The research literature on the effectiveness of online interventions is developing rapidly and is confronted by methodological challenges common to other areas of e-health including attrition and assessment reactivity and in the design of control conditions. METHODS/DESIGN: The study aim is to evaluate the effectiveness of a brief online intervention, employing a randomized controlled trial (RCT) design that takes account of baseline assessment reactivity, and other possible effects of the research process. Outcomes will be evaluated after 3 months both among student populations as a whole including for a randomized no contact control group and among those who are risky drinkers randomized to brief assessment and feedback (routine practice) or to brief assessment only. A three-arm parallel groups trial will also allow exploration of the magnitude of the feedback and assessment component effects. The trial will be undertaken simultaneously in 2 universities randomizing approximately 15,300 students who will all be blinded to trial participation. All participants will be offered routine practice intervention at the end of the study. DISCUSSION: This trial informs the development of routine service delivery in Swedish universities and more broadly contributes a new approach to the study of the effectiveness of online interventions in student populations, with relevance to behaviors other than alcohol consumption. The use of blinding and deception in this study raise ethical issues that warrant further attention. TRIAL REGISTRATION: ISRCTN28328154

A Role for VEGFR2 Activation in Endothelial Responses Caused by Barrier Disruptive OxPAPC Concentrations

Introduction: Oxidation products of 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphatidylcholine (OxPAPC) differentially modulate endothelial cell (EC) barrier function in a dose-dependent fashion. Vascular endothelial growth factor receptor-2 (VEGFR2) is involved in the OxPAPC-induced EC inflammatory activation. This study examined a role of VEGFR2 in barrier dysfunction caused by high concentrations of OxPAPC and evaluated downstream signaling mechanisms resulting from the effect of OxPAPC in EC from pulmonary and systemic circulation