Six-month outcomes of a web-based intervention for users of amphetamine-type stimulants: Randomized controlled trial

Background: The use of amphetamine-type stimulants (ATS) places a large burden on health services.Objective: The aim was to evaluate the effectiveness of a self-guided Web-based intervention (“breakingtheice”) for ATS users over 6 months via a free-to-access site.Methods: We conducted a randomized trial comparing a waitlist control with a fully automated intervention containing 3 modules derived from cognitive behavioral therapy and motivation enhancement. The main outcome was self-reported ATS use in the past 3 months assessed at 3- and 6-month follow-ups using the Alcohol, Smoking, and Substance Involvement Screening Test (ASSIST). Secondary outcomes were help-seeking intentions (general help-seeking questionnaire), actual help seeking (actual help-seeking questionnaire), psychological distress (Kessler 10), polydrug use (ASSIST), quality of life (European Health Interview Survey), days out of role, and readiness to change. Follow-up data were evaluated using an intention-to-treat (ITT) analysis with a group by time interaction.Results: We randomized 160 people (intervention: n=81; control: n=79). At 6 months, 38 of 81 (47%) intervention and 41 of 79 (52%) control participants provided data. ATS scores significantly declined for both groups, but the interaction effect was not significant. There were significant ITT time by group interactions for actual help seeking (rate ratio [RR] 2.16; d=0.45) and help-seeking intentions (RR 1.17; d=0.32), with help seeking increasing for the intervention group and declining for the control group. There were also significant interactions for days completely (RR 0.50) and partially (RR 0.74) out of role favoring the intervention group. However, 37% (30/81) of the intervention group did not complete even 1 module.Conclusions: This self-guided Web-based intervention encouraged help seeking associated with ATS use and reduced days out of role, but it did not reduce ATS use. Thus, this program provides a means of engaging with some sections of a difficult-to-reach group to encourage treatment, but a substantial minority remained disengaged.Trial Registration: Australian and New Zealand Clinical Trials Registry: ACTRN12611000947909;https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=343307 (Archived by WebCite athttp://www.webcitation.org/6Y0PGGp8q).URL http://dx.doi.org/10.2196/jmir.3778</a

A Participatory Health Promotion Mobile App Addressing Alcohol Use Problems (The Daybreak Program): Protocol for a Randomized Controlled Trial

BACKGROUND: At-risk patterns of alcohol use are prevalent in many countries with significant costs to individuals, families, and society. Screening and brief interventions, including with Web delivery, are effective but with limited translation into practice to date. Previous observational studies of the Hello Sunday Morning approach have found that their unique Web-based participatory health communication method has resulted in a reduction of at-risk alcohol use between baseline and 3 months. The Hello Sunday Morning blog program asks participants to publicly set a personal goal to stop drinking or reduce their consumption for a set period of time, and to record their reflections and progress on blogs and social networks. Daybreak is Hello Sunday Morning's evidence-based behavior change program, which is designed to support people looking to change their relationship with alcohol. OBJECTIVE: This study aims to systematically evaluate different versions of Hello Sunday Morning's Daybreak program (with and without coaching support) in reducing at-risk alcohol use. METHODS: We will use a between groups randomized control design. New participants enrolling in the Daybreak program will be eligible to be randomized to receive either (1) the Daybreak program, including peer support plus behavioral experiments (these encourage and guide participants in developing new skills in the areas of mindfulness, connectedness, resilience, situational strategies, and health), or (2) the Daybreak program, including the same peer support plus behavioral experiments, but with online coaching support. We will recruit 467 people per group to detect an effect size of f=0.10. To be eligible, participants must be resident in Australia, aged =18 years, score =8 on the alcohol use disorders identification test (AUDIT), and not report prior treatment for cardiovascular disease. RESULTS: The primary outcome measure will be reduction in the AUDIT-Consumption (AUDIT-C) scores. Secondary outcomes include mental health (Kessler's K-10), days out of role (Kessler), alcohol consumed (measured with a 7-day drinking diary in standard 10 g drinks), and alcohol-related harms (CORE alcohol and drug survey). We will collect data at baseline and 1, 3, and 6 months and analyze them with random effects models, given the correlated data structure. CONCLUSIONS: A randomized trial is required to provide robust evidence of the impact of the online coaching component of the Daybreak program, including over an extended period

Impact of perioperative RSV or influenza infection on length of stay and risk of unplanned ICU admission in children: a case-control study

<p>Abstract</p> <p>Background</p> <p>Children with viral respiratory infections who undergo general anesthesia are at increased risk of respiratory complications. We investigated the impact of RSV and influenza infection on perioperative outcomes in children undergoing general anesthesia.</p> <p>Methods</p> <p>We performed a retrospective case-control study. All patients under the age of 18 years who underwent general anesthesia at our institution with confirmed RSV or influenza infection diagnosed within 24 hours following induction between October 2002 and September 2008 were identified. Controls were randomly selected and were matched by surgical procedure, age, and time of year in a ratio of three controls per case. The primary outcome was postoperative length of stay (LOS).</p> <p>Results</p> <p>Twenty-four patients with laboratory-confirmed RSV or influenza who underwent general anesthesia prior to diagnosis of viral infection were identified and matched to 72 controls. Thirteen cases had RSV and 11 had influenza. The median postoperative LOS was three days (intra-quartile range 1 to 8 days) for cases and two days (intra-quartile range 1 to 5 days) for controls. Patients with influenza had a longer postoperative LOS (p < 0.001) and patients with RSV or influenza were at increased risk of unplanned admission to the PICU (p = 0.04) than matched controls.</p> <p>Conclusions</p> <p>Our results suggest that children with evidence of influenza infection undergoing general anesthesia, even in the absence of symptoms previously thought to be associated with a high risk of complications, may have a longer postoperative hospital LOS when compared to matched controls. RSV and influenza infection was associated with an increased risk of unplanned PICU admission.</p

Primary care REFerral for EchocaRdiogram (REFER) in heart failure: a diagnostic accuracy study.

BACKGROUND: Symptoms of breathlessness, fatigue, and ankle swelling are common in general practice but deciding which patients are likely to have heart failure is challenging. AIM: To evaluate the performance of a clinical decision rule (CDR), with or without N-Terminal pro-B type natriuretic peptide (NT-proBNP) assay, for identifying heart failure. DESIGN AND SETTING: Prospective, observational, diagnostic validation study of patients aged >55 years, presenting with shortness of breath, lethargy, or ankle oedema, from 28 general practices in England. METHOD: The outcome was test performance of the CDR and natriuretic peptide test in determining a diagnosis of heart failure. The reference standard was an expert consensus panel of three cardiologists. RESULTS: Three hundred and four participants were recruited, with 104 (34.2%; 95% confidence interval [CI] = 28.9 to 39.8) having a confirmed diagnosis of heart failure. The CDR+NT-proBNP had a sensitivity of 90.4% (95% CI = 83.0 to 95.3) and specificity 45.5% (95% CI = 38.5 to 52.7). NT-proBNP level alone with a cut-off <400 pg/ml had sensitivity 76.9% (95% CI = 67.6 to 84.6) and specificity 91.5% (95% CI = 86.7 to 95.0). At the lower cut-off of NT-proBNP <125 pg/ml, sensitivity was 94.2% (95% CI = 87.9 to 97.9) and specificity 49.0% (95% CI = 41.9 to 56.1). CONCLUSION: At the low threshold of NT-proBNP <125 pg/ml, natriuretic peptide testing alone was better than a validated CDR+NT-proBNP in determining which patients presenting with symptoms went on to have a diagnosis of heart failure. The higher NT-proBNP threshold of 400 pg/ml may mean more than one in five patients with heart failure are not appropriately referred. Guideline natriuretic peptide thresholds may need to be revised

End-point definition and trial design to advance tuberculosis vaccine development

Tuberculosis (TB) remains a leading infectious cause of death worldwide and the coronavirus disease 2019 pandemic has negatively impacted the global TB burden of disease indicators. If the targets of TB mortality and incidence reduction set by the international community are to be met, new more effective adult and adolescent TB vaccines are urgently needed. There are several new vaccine candidates at different stages of clinical development. Given the limited funding for vaccine development, it is crucial that trial designs are as efficient as possible. Prevention of infection (POI) approaches offer an attractive opportunity to accelerate new candidate vaccines to advance into large and expensive prevention of disease (POD) efficacy trials. However, POI approaches are limited by imperfect current tools to measure Mycobacterium tuberculosis infection end-points. POD trials need to carefully consider the type and number of microbiological tests that define TB disease and, if efficacy against subclinical (asymptomatic) TB disease is to be tested, POD trials need to explore how best to define and measure this form of TB. Prevention of recurrence trials are an alternative approach to generate proof of concept for efficacy, but optimal timing of vaccination relative to treatment must still be explored. Novel and efficient approaches to efficacy trial design, in addition to an increasing number of candidates entering phase 2-3 trials, would accelerate the long-standing quest for a new TB vaccine

Traditional Roles in a Non‐Traditional Setting: Genetic Counseling in Precision Oncology

Next generation sequencing technology is increasingly utilized in oncology with the goal of targeting therapeutics to improve response and reduce side effects. Interpretation of tumor mutations requires sequencing of paired germline DNA, raising questions about incidental germline findings. We describe our experiences as part of a research team implementing a protocol for whole genome sequencing (WGS) of tumors and paired germline DNA known as the Michigan Oncology Sequencing project (MI‐ONCOSEQ) that includes options for receiving incidental germline findings. Genetic counselors (GCs) discuss options for return of results with patients during the informed consent process and document family histories. GCs also review germline findings and actively participate in the multi‐disciplinary Precision Medicine Tumor Board (PMTB), providing clinical context for interpretation of germline results and making recommendations about disclosure of germline findings. GCs have encountered ethical and counseling challenges with participants, described here. Although GCs have not been traditionally involved in molecular testing of tumors, our experiences with MI‐ONCOSEQ demonstrate that GCs have important applicable skills to contribute to multi‐disciplinary care teams implementing precision oncology. Broader use of WGS in oncology treatment decision making and American College of Medical Genetics and Genomics (ACMG) recommendations for active interrogation of germline tissue in tumor‐normal dyads suggests that GCs will have future opportunities in this area outside of research settings.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/147078/1/jgc40655.pd

Dissociable effects of 5-HT2C receptor antagonism and genetic inactivation on perseverance and learned non-reward in an egocentric spatial reversal task

Cognitive flexibility can be assessed in reversal learning tests, which are sensitive to modulation of 5-HT2C receptor (5-HT2CR) function. Successful performance in these tests depends on at least two dissociable cognitive mechanisms which may separately dissipate associations of previous positive and negative valence. The first is opposed by perseverance and the second by learned non-reward. The current experiments explored the effect of reducing function of the 5-HT2CR on the cognitive mechanisms underlying egocentric reversal learning in the mouse. Experiment 1 used the 5-HT2CR antagonist SB242084 (0.5 mg/kg) in a between-groups serial design and Experiment 2 used 5-HT2CR KO mice in a repeated measures design. Animals initially learned to discriminate between two egocentric turning directions, only one of which was food rewarded (denoted CS+, CS−), in a T- or Y-maze configuration. This was followed by three conditions; (1) Full reversal, where contingencies reversed; (2) Perseverance, where the previous CS+ became CS− and the previous CS− was replaced by a novel CS+; (3) Learned non-reward, where the previous CS− became CS+ and the previous CS+ was replaced by a novel CS-. SB242084 reduced perseverance, observed as a decrease in trials and incorrect responses to criterion, but increased learned non-reward, observed as an increase in trials to criterion. In contrast, 5-HT2CR KO mice showed increased perseverance. 5-HT2CR KO mice also showed retarded egocentric discrimination learning. Neither manipulation of 5-HT2CR function affected performance in the full reversal test. These results are unlikely to be accounted for by increased novelty attraction, as SB242084 failed to affect performance in an unrewarded novelty task. In conclusion, acute 5-HT2CR antagonism and constitutive loss of the 5-HT2CR have opposing effects on perseverance in egocentric reversal learning in mice. It is likely that this difference reflects the broader impact of 5HT2CR loss on the development and maintenance of cognitive function

The stb Operon Balances the Requirements for Vegetative Stability and Conjugative Transfer of Plasmid R388

The conjugative plasmid R388 and a number of other plasmids carry an operon, stbABC, adjacent to the origin of conjugative transfer. We investigated the role of the stbA, stbB, and stbC genes. Deletion of stbA affected both conjugation and stability. It led to a 50-fold increase in R388 transfer frequency, as well as to high plasmid loss. In contrast, deletion of stbB abolished conjugation but provoked no change in plasmid stability. Deletion of stbC showed no effect, neither in conjugation nor in stability. Deletion of the entire stb operon had no effect on conjugation, which remained as in the wild-type plasmid, but led to a plasmid loss phenotype similar to that of the R388ΔstbA mutant. We concluded that StbA is required for plasmid stability and that StbA and StbB control conjugation. We next observed the intracellular positioning of R388 DNA molecules and showed that they localize as discrete foci evenly distributed in live Escherichia coli cells. Plasmid instability of the R388ΔΔstbA mutant correlated with aberrant localization of the plasmid DNA molecules as clusters, either at one cell pole, at both poles, or at the cell center. In contrast, plasmid molecules in the R388ΔΔstbB mutant were mostly excluded from the cell poles. Thus, results indicate that defects in both plasmid maintenance and transfer are a consequence of variations in the intracellular positioning of plasmid DNA. We propose that StbA and StbB constitute an atypical plasmid stabilization system that reconciles two modes of plasmid R388 physiology: a maintenance mode (replication and segregation) and a propagation mode (conjugation). The consequences of this novel concept in plasmid physiology will be discussed

Oral Pirfenidone in patients with chronic fibrosis resulting from radiotherapy: a pilot study

<p>Abstract</p> <p>Background</p> <p>Fibrosis is a common side effect after treatment with ionizing radiation. Several methods to ameliorate debilitating fibrosis have been employed but without consistent results. The goal of this pilot study is to determine if Pirfenidone, a novel regulator of cytokine gene expression, has the potential to ameliorate established radiation-induced fibrosis.</p> <p>Methods</p> <p>Open label, prospective pilot study of 800 mg three times/day, orally administered Pirfenidone was administered to enrolled patients who were had completed radiation therapy and who had established radiation-induced fibrosis. Range of motion (ROM) was assessed using standard measures, and subjective measures of pain, fatigue, disability and global health were measured every three months.</p> <p>Results</p> <p>Seven patients were enrolled of whom 3 had ROM assessments of 1 site and 2 had ROM assessments of 2 sites. Of these assessments, 6 revealed increased ROM during drug intervention while 1 revealed a decreased ROM. There was an overall improvement in the mental composite score of the SF36 while physical composite score was decreased and the vitality score was unchanged. Two patients were removed from the study because of syncopal episodes.</p> <p>Conclusion</p> <p>Several patients experienced improved function of at least 25% and reported subjective improvement. Pirfenidone may benefit patients with radiation-induced fibrosis and is worthy of a larger well controlled trial.</p

Effects of Intracoronary Alteplase on Microvascular Function in Acute Myocardial Infarction

Background—Impaired microcirculatory reperfusion worsens prognosis following acute ST‐segment–elevation myocardial infarction. In the T‐TIME (A Trial of Low‐Dose Adjunctive Alteplase During Primary PCI) trial, microvascular obstruction on cardiovascular magnetic resonance imaging did not differ with adjunctive, low‐dose, intracoronary alteplase (10 or 20 mg) versus placebo during primary percutaneous coronary intervention. We evaluated the effects of intracoronary alteplase, during primary percutaneous coronary intervention, on the index of microcirculatory resistance, coronary flow reserve, and resistive reserve ratio. Methods and Results—A prespecified physiology substudy of the T‐TIME trial. From 2016 to 2017, patients with ST‐segment–elevation myocardial infarction ≤6 hours from symptom onset were randomized in a double‐blind study to receive alteplase 20 mg, alteplase 10 mg, or placebo infused into the culprit artery postreperfusion, but prestenting. Index of microcirculatory resistance, coronary flow reserve, and resistive reserve ratio were measured after percutaneous coronary intervention. Cardiovascular magnetic resonance was performed at 2 to 7 days and 3 months. Analyses in relation to ischemic time (<2, 2–4, and ≥4 hours) were prespecified. One hundred forty‐four patients (mean age, 59±11 years; 80% male) were prospectively enrolled, representing 33% of the overall population (n=440). Overall, index of microcirculatory resistance (median, 29.5; interquartile range, 17.0–55.0), coronary flow reserve(1.4 [1.1–2.0]), and resistive reserve ratio (1.7 [1.3–2.3]) at the end of percutaneous coronary intervention did not differ between treatment groups. Interactions were observed between ischemic time and alteplase for coronary flow reserve (P=0.013), resistive reserve ratio (P=0.026), and microvascular obstruction (P=0.022), but not index of microcirculatory resistance. Conclusions—In ST‐segment–elevation myocardial infarction with ischemic time ≤6 hours, there was overall no difference in microvascular function with alteplase versus placebo