Early detection and treatment of acute illness in medical patients with novel software: a prospective quality improvement initiative.

OBJECTIVE: An ageing population and rising healthcare costs place healthcare systems at risk of failure. Our goal was to develop a technology that would identify illness early, initiate action and therein improve patient care, outcomes and save healthcare resources. DESIGN: This was a prospective interventional quality improvement study. SETTING: A 40 bed medical floor in a 300 bed Canadian tertiary care regional referral hospital. PARTICIPANTS: General ward patients randomly assigned to control or treatment groups. There was no cross-over or loss to follow-up. INTERVENTION: We designed an algorithm and software programme capable of detecting the sentinel change in a deteriorating patient's clinical condition and once detected direct early investigation and care. Study duration was 1 year. MAIN OUTCOME MEASURES: Primary outcome was patient transfer from the general medical ward to the intensive care unit (ICU). The secondary outcome was the time needed to (1) order investigations (2) contact senior medical staff and (3) senior medical staff intervention. RESULTS: We identified a decrease in the transfer of patients from the medical ward to the ICU. Over the course of the study including 273 patients (110 in the control group and 163 in the treatment group), transfers dropped from 14 to 3 with a relative risk reduction of 85.54% (95% CI 84.96 to 86.1), a number needed to treat of 9.19 (95% CI 9.01 to 9.36) and a absolute risk reduction of 10.89% (95% CI 10.7 to 11.1). We also found a statistically significant reduction in the time required to order investigations (p=0.049), contact senior medical staff (p=0.040) and senior medical staff intervention (p=0.045). CONCLUSION: A novel algorithm and software in the hands of nursing staff identified acute illness with adequate sensitivity and specificity to dramatically reduce ICU transfers and time to clinical intervention on a medical ward.

Recommendations on ELISpot assay validation by the GCC.

Gene therapy, cell therapy and vaccine research have led to an increased need to perform cellular immunity testing in a regulated environment to ensure the safety and efficacy of these treatments. The most common method for the measurement of cellular immunity has been Enzyme-Linked Immunospot assays. However, there is a lack of regulatory guidance available discussing the recommendations for developing and validating these types of assays. Hence, the Global CRO Council has issued this white paper to provide a consensus on the different validation parameters required to support Enzyme-Linked Immunospot assays and a harmonized and consistent approach to Enzyme-Linked Immunospot validation among contract research organizations.

Recommendations for the content and management of Certificates of Analysis for reference standards from the GCC for bioanalysis.

The 13th Global CRO Council (GCC) closed forum for bioanalysis was held in New Orleans, LA, USA on 5 April 2019. This GCC meeting was organized to discuss the contents of the 2019 ICH M10 Bioanalytical Method Validation Draft Guideline published in February 2019 and consolidate the feedback of the GCC members. While ICH M10 will cover requirements for reference standards, one of the biggest challenges facing the CRO community is the lack of consistency and completeness of Certificates of Analysis for reference standards used in regulated bioanalysis. Similar challenges exist with critical reagents (e.g., capture and detection antibodies) used for assays supporting biologics. The recommendations provided in this publication are the minimum requirements for the content that GCC members believe should be included in Certificates of Analysis for reference standards obtained from commercial vendors, sponsors and compendial suppliers, for use in regulated bioanalytical studies. In addition, recommendations for internal standards, metabolites and critical reagents are discussed.

Project Step: A Randomized Controlled Trial Investigating the Effects of Frequent Feedback and Contingent Incentives on Physical Activity.

BACKGROUND: Financial incentives and feedback on behavior offer promise for promoting physical activity. However, evidence for the effect of each of these techniques is inadequate. The present study evaluated the effects of daily versus weekly feedback and incentives contingent on reaching a daily walking goal versus noncontingent incentives in a 2 × 2 trial. METHODS: Participants (N = 57) had a body mass index >25 kg/m2 and were insufficiently active. Participants received a daily walking goal that adapted weekly. RESULTS: Participants receiving daily feedback increased daily steps (P = .03) more than those receiving weekly feedback. Participants receiving contingent incentives did not significantly increase steps (P = .12) more than those receiving noncontingent incentives. A trend-level effect (P = .09) suggested that there may be an interaction such that the combination of daily feedback and contingent incentives is most effective. CONCLUSIONS: Results indicate that feedback is an important component of remotely delivered PA interventions and that evaluating each component of low-intensity interventions may help to improve efficacy. Moreover, results indicate that possible synergistic effects of feedback and rewards should be investigated further to help optimize interventions.

Self-harm presentation across healthcare settings by sex in young people: an e-cohort study using routinely collected linked healthcare data in Wales, UK.

BACKGROUND: This study used individual-level linked data across general practice, emergency departments (EDs), outpatients and hospital admissions to examine contacts across settings and time by sex for self-harm in individuals aged 10-24 years old in Wales, UK. METHODS: A whole population-based e-cohort study of routinely collected healthcare data was conducted. Rates of self-harm across settings over time by sex were examined. Individuals were categorised based on the service(s) to which they presented. RESULTS: A total of 937 697 individuals aged 10-24 years contributed 5 369 794 person years of data from 1 January 2003 to 30 September 2015. Self-harm incidence was highest in primary care but remained stable over time (incident rate ratio (IRR)=1.0; 95% CI 0.9 to 1.1). Incidence of ED attendance increased over time (IRR=1.3; 95% CI 1.2 to 1.5) as did hospital admissions (IRR=1.4; 95% CI 1.1 to 1.6). Incidence in the 15-19 years age group was the highest across all settings. The largest increases were seen in the youngest age group. There were increases in ED attendances for both sexes; however, females are more likely than males to be admitted following this. This was most evident in individuals 10-15 years old, where 76% of females were admitted compared with just 49% of males. The majority of associated outpatient appointments were under a mental health specialty. CONCLUSIONS: This is the first study to compare self-harm in people aged 10-24 years across primary care, EDs and hospital settings in the UK. The high rates of self-harm in primary care and for young men in EDs highlight these as important settings for intervention.

Evaluating the Feasibility, Acceptability, and Effects of Deposit Contracts With and Without Daily Feedback to Promote Physical Activity.

BACKGROUND: Despite interest in financial incentive programs, evidence regarding the feasibility, acceptability, and effectiveness of deposit contracts (ie, use of participants' own money as a financial reward) for increasing physical activity (PA) is limited. Furthermore, evidence regarding the use of feedback within incentive programs is limited. PURPOSE: To evaluate: (1) the feasibility and acceptability of deposit contracts for increasing objectively measured PA and (2) the effects of deposit contracts with or without ongoing feedback on PA. METHODS: Participants (n = 24) were exposed to 3 conditions (1) self-monitoring, (2) incentive, and (3) incentive with feedback in an ABACABAC design, with the order of incentive conditions counterbalanced across participants. RESULTS: Effect sizes suggest that individuals had a modest increase in PA during the incentive conditions compared with self-monitoring. Presentation order moderated results, such that individuals exposed to incentives with feedback first performed more poorly across both incentive conditions. In addition, individuals often cited the deposit contract as a reason for not enrolling, and those who did participate reported inadequate acceptability of the incentives and feedback. CONCLUSIONS: Results suggest that while deposit contracts may engender modest increases in PA, this type of incentive may not be feasible or acceptable for promoting PA.

12th GCC Closed Forum: critical reagents; oligonucleotides; CoA; method transfer; HRMS; flow cytometry; regulatory findings; stability and immunogenicity.

The 12th GCC Closed Forum was held in Philadelphia, PA, USA, on 9 April 2018. Representatives from international bioanalytical Contract Research Organizations were in attendance in order to discuss scientific and regulatory issues specific to bioanalysis. The issues discussed at the meeting included: critical reagents; oligonucleotides; certificates of analysis; method transfer; high resolution mass spectrometry; flow cytometry; recent regulatory findings and case studies involving stability and nonclinical immunogenicity. Conclusions and consensus from discussions of these topics are included in this article.

Recommendations for classification of commercial LBA kits for biomarkers in drug development from the GCC for bioanalysis.

Over the last decade, the use of biomarker data has become integral to drug development. Biomarkers are not only utilized for internal decision-making by sponsors; they are increasingly utilized to make critical decisions for drug safety and efficacy. As the regulatory agencies are routinely making decisions based on biomarker data, there has been significant scrutiny on the validation of biomarker methods. Contract research organizations regularly use commercially available immunoassay kits to validate biomarker methods. However, adaptation of such kits in a regulated environment presents significant challenges and was one of the key topics discussed during the 12th Global Contract Research Organization Council for Bioanalysis (GCC) meeting. This White Paper reports the GCC members' opinion on the challenges facing the industry and the GCC recommendations on the classification of commercial kits that can be a win-win for commercial kit vendors and end users.

Creating Value in Healthcare: The Need for Innovative Solutions.

The combined impact of an aging population's healthcare needs and the growing prevalence of chronic disease has, and will continue to have, a significant impact on healthcare capacity and economics. In the context of resource constraints there is a tendency to focus on doing more with less. However, the real opportunity may lie in building capacity by doing things differently. The authors propose a new paradigm for innovative hospital care and illustrate its potential by examining recent endeavours at a large, full-service hospital in Southern Ontario. Innovation is about finding new ways of doing things that lead to better outcomes. Many healthcare leaders characterize their organizations as innovative, asserting they are committed to identifying and implementing best practices in clinical care. Despite this pledge, the lag time in the clinical implementation of translational research can be up to 17 years (Morris et al. 2011). Clearly, there is an opportunity to achieve better outcomes by developing a more systematic approach to implementing this type of research. Creating a culture of innovation in which ideas thrive and there is a commitment to adopting proven best practices should be part of the solution.

Atomoxetine treatment of attention-deficit/hyperactivity disorder in young adults with assessment of functional outcomes: a randomized, double-blind, placebo-controlled clinical trial.

BACKGROUND: Attention-deficit/hyperactivity disorder (ADHD) is associated with significant impairment in multiple functional domains. This trial evaluated efficacy in ADHD symptoms and functional outcomes in young adults treated with atomoxetine. METHODS: Young adults (18-30 years old) with ADHD were randomized to 12 weeks of double-blind treatment with atomoxetine (n = 220) or placebo (n = 225). The primary efficacy measure of ADHD symptom change was Conners' Adult ADHD Rating Scale (CAARS): Investigator-Rated: Screening Version Total ADHD Symptoms score with adult prompts. Secondary outcomes scales included the Adult ADHD Quality of Life-29, Clinical Global Impression-ADHD-Severity, Patient Global Impression-Improvement, CAARS Self-Report, Behavior Rating Inventory of Executive Function-Adult Version Self-Report, and assessments of depression, anxiety, sleepiness, driving behaviors, social adaptation, and substance use. RESULTS: Atomoxetine was superior to placebo on CAARS: Investigator-Rated: Screening Version (atomoxetine [least-squares mean ± SE, -13.6 ± 0.8] vs placebo [-9.3 ± 0.8], 95% confidence interval [-6.35 to -2.37], P < 0.001), Clinical Global Impression-ADHD-Severity (atomoxetine [-1.1 ± 0.1] vs placebo [-0.7 ± 0.1], 95% confidence interval [-0.63 to -0.24], P < 0.001), and CAARS Self-Report (atomoxetine [-11.9 ± 0.8] vs placebo [-7.8 ± 0.7], 95% confidence interval [-5.94 to -2.15], P < 0.001) but not on Patient Global Impression-Improvement. In addition, atomoxetine was superior to placebo on Adult ADHD Quality of Life-29 and Behavior Rating Inventory of Executive Function-Adult Version Self-Report. Additional assessments failed to detect significant differences (P ≥ 0.05) between atomoxetine and placebo. The adverse event profile was similar to that observed in other atomoxetine studies. Nausea, decreased appetite, insomnia, dry mouth, irritability, dizziness, and dyspepsia were reported significantly more often with atomoxetine than with placebo. CONCLUSIONS: Atomoxetine reduced ADHD symptoms and improved quality of life and executive functioning deficits in young adults compared with placebo. Atomoxetine was also generally well tolerated.

Promoting smoking cessation.

Cigarette smoking causes significant morbidity and mortality in the United States. Physicians can use the five A's framework (ask, advise, assess, assist, arrange) to promote smoking cessation. All patients should be asked about tobacco use and assessed for motivation to quit at every clinical encounter. Physicians should strongly advise patients to quit smoking, and use motivational interviewing techniques for patients who are not yet willing to stop smoking. Clinical contacts with unmotivated patients should emphasize the rewards and relevance of quitting, as well as the risks of smoking and anticipated barriers to abstinence. These messages should be repeated at every opportunity. Appropriate patients should be offered pharmacologic assistance in quitting, such as nicotine replacement therapies, bupropion, and varenicline. Use of pharmacologic support during smoking cessation can double the rate of successful abstinence. Using more than one type of nicotine replacement therapy ("patch plus" method) and combining these therapies with bupropion provide additional benefit. However, special populations pose unique challenges in pharmacotherapy for smoking cessation. Nicotine replacement therapies increase the risk of birth defects and should not be used during pregnancy. They are usually safe in patients with cardiovascular conditions, except for those with unstable angina or within two weeks of a coronary event. Varenicline may increase the risk of coronary events. Nicotine replacement therapies are safe for use in adolescents; however, they are less effective than in adults. Physicians also should arrange to have repeated contact with smokers around their quit date to reinforce cessation messages.

The effects of fluticasone with or without salmeterol on systemic biomarkers of inflammation in chronic obstructive pulmonary disease.

RATIONALE: Small studies have suggested that inhaled corticosteroids can suppress systemic inflammation in chronic obstructive pulmonary disease (COPD). OBJECTIVES: To determine the effect of inhaled corticosteroids with or without long-acting beta(2)-adrenergic agonist on systemic biomarkers of inflammation. METHODS: We conducted a double-blind randomized placebo-controlled trial across 11 centers (n = 289 patients with FEV(1) of 47.8 +/- 16.2% of predicted) to compare the effects of inhaled fluticasone alone or in combination with salmeterol against placebo on circulating biomarkers of systemic inflammation over 4 weeks. The primary endpoint was C-reactive protein (CRP) level. Secondary molecules of interest were IL-6 and surfactant protein D (SP-D). MEASUREMENTS AND MAIN RESULTS: Neither fluticasone nor the combination of fluticasone/salmeterol had a significant effect on CRP or IL-6 levels. There was, however, a significant reduction in SP-D levels with fluticasone and fluticasone/salmeterol compared with placebo (P = 0.002). Health status also improved significantly in both the fluticasone and fluticasone/salmeterol groups compared with placebo, driven mostly by improvements in the symptom scores. Changes in the circulating SP-D levels were related to changes in health status scores. FEV(1) improved significantly only in the fluticasone/salmeterol group compared with placebo. CONCLUSIONS: ICS in conjunction with long-acting beta(2)-adrenergic agonist do not reduce CRP or IL-6 levels in serum of patients with COPD over 4 weeks. They do, however, significantly reduce serum SP-D levels. These data suggest that these drugs reduce lung-specific but not generalized biomarkers of systemic inflammation in COPD.

Can inhaled fluticasone alone or in combination with salmeterol reduce systemic inflammation in chronic obstructive pulmonary disease? Study protocol for a randomized controlled trial [NCT00120978].

BACKGROUND: Systemic inflammation is associated with various complications in chronic obstructive pulmonary disease including weight loss, cachexia, osteoporosis, cancer and cardiovascular diseases. Inhaled corticosteroids attenuate airway inflammation, reduce exacerbations, and improve mortality in chronic obstructive pulmonary disease. Whether inhaled corticosteroids by themselves or in combination with a long-acting beta2-adrenoceptor agonist repress systemic inflammation in chronic obstructive pulmonary disease is unknown. The Advair Biomarkers in COPD (ABC) study will determine whether the effects of inhaled corticosteroids alone or in combination with a long-acting beta2-adrenoceptor agonist reduce systemic inflammation and improve health status in patients with chronic obstructive pulmonary disease. METHODS/DESIGN: After a 4-week run-in phase during which patients with stable chronic obstructive pulmonary disease will receive inhaled fluticasone (500 micrograms twice daily), followed by a 4-week withdrawal phase during which all inhaled corticosteroids and long acting beta2-adrenoceptor agonists will be discontinued, patients will be randomized to receive fluticasone (500 micrograms twice daily), fluticasone/salmeterol combination (500/50 micrograms twice daily), or placebo for four weeks. The study will recruit 250 patients across 11 centers in western Canada. Patients must be 40 years of age or older with at least 10 pack-year smoking history and have chronic obstructive pulmonary disease defined as forced expiratory volume in one second to vital capacity ratio of 0.70 or less and forced expiratory volume in one second that is 80% of predicted or less. Patients will be excluded if they have any known chronic systemic infections, inflammatory conditions, history of previous solid organ transplantation, myocardial infarction, or cerebrovascular accident within the past 3 months prior to study enrollment. The primary end-point is serum C-reactive protein level. Secondary end-points include circulating inflammatory cytokines such as interleukin-6 and interleukin-8 as well as health-related quality of life and lung function. DISCUSSION: If inhaled corticosteroids by themselves or in combination with a long-acting beta2-adrenoceptor agonist could repress systemic inflammation, they might greatly improve clinical prognosis by reducing various complications in chronic obstructive pulmonary disease.

Emergencies in space.

Manned spaceflight is inherently risky and results in unique problems from a trauma and medical perspective. Emergency care under these special physiologic and environmental conditions calls for novel techniques for diagnosis and therapy.