Dietary fish oils containing eicosapentaenoic acid and the prevention of atherosclerosis and thrombosis.

Recent epidemiologic studies have shown that rates of cardiovascular disease are lower in populations such as the Greenland Eskimos than in those that do not eat seafood, even though the levels of dietary fat intake are often similar. Dietary fish oils are rich in eicosapentaenoic acid (EPA), a polyunsaturated fatty acid of the omega-3 series. EPA has been shown to prolong bleeding time and to decrease platelet aggregation and blood viscosity. EPA inhibits the production of prostaglandins from endogenous arachidonic acid, which is associated with the formation of thromboxane A2 and may also dampen cyclo-oxygenase and lipoxygenase metabolites involved in mediating endothelial cell proliferation. Dietary fish oils are now available in the form of EPA-enriched capsules. Short-term trials in humans have shown that EPA significantly reduces the levels of plasma triglycerides and may increase the levels of high-density lipoproteins; however, no consistent effect on serum cholesterol levels has been shown. The results of evaluations of EPA''s use in patients with renal disorders, mild hypertension, inflammatory disorders or hyperlipidemia have been promising. On the basis of the epidemiologic and biologic evidence dietary fish oils warrant further study in extensive clinical trials.     

Considerations for stakeholder engagement and COVID‐19 related clinical trials’ conduct in sub‐Saharan Africa

The aim of this study is to determine how stakeholder engagement can be adapted for the conduct of COVID‐19‐related clinical trials in sub‐Saharan Africa. Nine essential stakeholder engagement practices were reviewed: formative research; stakeholder engagement plan; communications and issues management plan; protocol development; informed consent process; standard of prevention for vaccine research and standard of care for treatment research; policies on trial‐related physical, psychological, financial, and/or social harms; trial accrual, follow‐up, exit trial closure and results dissemination; and post‐trial access to trial products or procedures. The norms, values, and practices of collectivist societies in Sub‐Saharan Africa and the low research literacy pose challenges to the conduct of clinical trials. Civil‐society organizations, members of community advisory boards and ethics committees, young persons, COVID‐19 survivors, researchers, government, and the private sector are assets for the implementation and translation of COVID‐19 related clinical trials. Adapting ethics guidelines to the socio‐cultural context of the region can facilitate achieving the aim of stakeholder engagement.     

Economic evaluation alongside pragmatic randomised trials: developing a standard operating procedure for clinical trials units

Background

There is wide recognition that pragmatic randomised trials are the best vehicle for economic evaluation. This is because trials provide the best chance of ensuring internal validity, not least through the rigorous prospective collection of patient-specific data. Furthermore the marginal cost of collecting economic data alongside clinical data is typically modest. UK Clinical Research Collaboration (UKCRC) does not require a standard operating procedure (SOP) for economic evaluation as a prerequisite for trial unit registration. We judge that such a SOP facilitates the integration of health economics into trials.

Methods

A collaboration between health economists and trialists at Bangor University led to the development of a SOP for economic evaluation alongside pragmatic trials, in addition to the twenty SOPs required by UKCRC for registration, which include randomisation, data management and statistical analysis.

Results

Our recent telephone survey suggests that no other UKCRC-registered trials unit currently has an economic SOP.

Conclusion

We argue that UKCRC should require, from all Trials Units undertaking economic evaluation and seeking registration or re-registration, a SOP for economic evaluation as one of their portfolio of supporting SOPs.     

Evidence-Based Medicine,Clinical Practice Guidelines,and Common Sense in the Management of Osteoporosis

ObjectiveTo evaluate the benefits and limitations of randomized controlled trials (RCTs), clinical practice guidelines (CPGs), and clinical judgment in the management of osteoporosis.MethodsA review was conducted of the English-language literature on the origins and applications of RCTs, CPGs, evidence-based medicine, and clinical judgment in the management of osteoporosis.ResultsEvidence-based medicine is use of the currently available best evidence in making clinical decisions for individual patients. CPGs are recommendations for making clinical decisions based on research evidence, sometimes with consideration of expert opinion, health care policy, and costs of care. The highest levels of medical evidence are usually thought to be RCTs and meta-analyses of high-quality RCTs. Although it is desirable and appropriate for clinicians to consider research evidence from RCTs and recommendations presented in CPGs in making clinical decisions, other factors—such as patient preference, comorbidities, affordability, and availability of care—are important for the actual implementation of evidence-based medicine.ConclusionDecisions about who to treat, which drug to use, how best to monitor, and how long to treat require clinical skills in addition to knowledge of medical research. The necessity of integrating common sense and clinical judgment is highlighted by the fact that many patients treated for osteoporosis in clinical practice would not qualify for participation in the pivotal clinical trials that demonstrated efficacy and safety of the drugs used to treat them. (Endocr Pract. 2009;15:573-579)     

Cross-Sectional Analysis of Data from the U.S. Clinical Trials Database Reveals Poor Translational Clinical Trial Effort for Traumatic Brain Injury,Compared with Stroke

Traumatic brain injury (TBI) is an important public health problem, comparable to stroke in incidence and prevalence. Few interventions have proven efficacy in TBI, and clinical trials are, therefore, necessary to advance management in TBI. We describe the current clinical trial landscape in traumatic brain injury and compare it with the trial efforts for stroke. For this, we analysed all stroke and TBI studies registered on the US Clinical Trials (www.clinicaltrials.gov) database over a 10-year period (01/01/2000 to 01/31/2013). This methodology has been previously used to analyse clinical trial efforts in other specialties. We describe the research profile in each area: total number of studies, total number of participants and change in number of research studies over time. We also analysed key study characteristics, such as enrolment number and scope of recruitment. We found a mismatch between relative public health burden and relative research effort in each disease. Despite TBI having comparable prevalence and higher incidence than stroke, it has around one fifth of the number of clinical trials and participant recruitment. Both stroke and TBI have experienced an increase in the number of studies over the examined time period, but the rate of growth for TBI is one third that for stroke. Small-scale (<1000 participants per trial) and single centre studies form the majority of clinical trials in both stroke and TBI, with TBI having significantly fewer studies with international recruitment. We discuss the consequences of these findings and how the situation might be improved. A sustained research effort, entailing increased international collaboration and rethinking the methodology of running clinical trials, is required in order to improve outcomes after traumatic brain injury.     

Gene therapy clinical trials worldwide to 2017: An update

To date, almost 2600 gene therapy clinical trials have been completed, are ongoing or have been approved worldwide. Our database brings together global information on gene therapy clinical activity from trial databases, official agency sources, published literature, conference presentations and posters kindly provided to us by individual investigators or trial sponsors. This review presents our analysis of clinical trials that, to the best of our knowledge, have been or are being performed worldwide. As of our November 2017 update, we have entries on 2597 trials undertaken in 38 countries. We have analysed the geographical distribution of trials, the disease indications (or other reasons) for trials, the proportions to which different vector types are used, and the genes that have been transferred. Details of the analyses presented, and our searchable database are available via The Journal of Gene Medicine Gene Therapy Clinical Trials Worldwide website at: http://www.wiley.co.uk/genmed/clinical . We also provide an overview of the progress being made in gene therapy clinical trials around the world, and discuss key trends since the previous review, namely the use of chimeric antigen receptor T cells for the treatment of cancer and advancements in genome editing technologies, which have the potential to transform the field moving forward.     

Biochemical (Prostate-Specific Antigen) Relapse: An Oncologist's Perspective

Consensus has not been reached on the exact definition of biochemical relapse after prostatectomy; individual institution definitions of relapse after prostatectomy range from consecutively rising prostate-specific antigen (PSA) values of > 0.2 to > 0.6 ng/mL. PSA measurements after radiation are even less predictable. PSA level is a sensitive marker of occult prostate-cancer relapse and provides early notification of recurrence, but a PSA relapse does not equal a clinical relapse or death from prostate cancer. Data are reviewed from retrospective, single-institution trials that have clarified features of PSA relapse after both prostatectomy and radiation, such as the PSA doubling time and the time to the first PSA elevation, which are associated with clinical progression. Various options for treatment of biochemical relapse are also reviewed; these include hormone therapy, combined chemohormonal therapy, alternative medicine and dietary tactics, new agents, and future strategies, such as vaccination. Currently, there is no standard treatment for biochemical failure with proven benefit in terms of quality of life, time to metastases, or survival. Current options include observation for patients with long PSA doubling times or comorbid medical issues and standard or nontraditional hormone therapy or a clinical trial for men who desire early therapy or who have rapid PSA doubling times (< 10-12 months). Trials combining the early use of chemotherapy with hormone therapy are promising. Patients should be encouraged to enroll in clinical trials to help establish standards of care.     

Bird carcass detection from integrated trials at multiple wind farms

It is often necessary to estimate the number of wind turbine collision fatalities to assess impacts to birds following construction of wind farms. Detection of bird carcasses at wind turbines in the field is affected by carcass persistence and searcher detection rate. Integrated detection trials, which integrate carcass persistence and searcher detection trials into the periodic fatality search, have been proposed as an effective method for estimating these parameters. The purpose of our study was to test whether and how environmental factors affect integrated detection trial outcomes at multiple wind farms. We conducted this study at 10 wind farms in various environments of Japan. Binary data on trial outcomes in open versus forested areas served as our response variable in a generalized additive mixed model informed by days into trial, carcass body mass, season, whether snow covered the ground, and precipitation. For both ground cover types, days into trial and body mass were included in all the top models, suggesting that these factors most influenced bird carcass detection probability in integrated trials. The best model in open areas included days into trial, body mass, snow, and precipitation, and the best model in forested areas included days into trial, body mass, snow, precipitation, and season. Values of area under the curve indicated high accuracy of the best model for both ground cover types. The survey design needs to be appropriate to the size of the target species and to the environment in which the impacts will occur, such as the site's seasonality, its ground cover, and whether snow will cover the ground. Frequency of post-construction fatality monitoring should also be set cautiously, especially at wind farms located on small-bird migration routes, at wind farms in open areas, in areas with snow-covered ground in winter, or in forested areas during spring and summer because detection probabilities decline fastest under such conditions.     

Nitrogen interactions with phosphorus and potassium for optimum crop yield,nitrogen use effectiveness,and environmental stewardship

The development of best management practices (BMPs) for optimum nitrogen (N) use by crops contributes to farm profitability, increased food and fiber production, and best stewardship of the environment and its resources. Such BMPs are both site- and crop-specific. Optimum N use by plants is influenced not only by climate and certain soil characteristics, but also by management practices such as tillage, time and method of N application, or positive interactions with nutrients and supporting cropping practices. Phosphorus (P) and potassium (K) are two of the nutrients essential for effective use of N by plants. Nitrogen interactions with P and/or K help to improve root system development, dry matter production, and other plant functions regulating crop yield and quality.     

Trans fatty acids: effects on cardiometabolic health and implications for policy

In both developed and developing countries, trans fatty acids (TFA) are largely consumed from partially hydrogenated vegetable oils. This article focuses on TFA as a modifiable dietary risk factor for cardiovascular disease, reviewing the evidence for lipid and non-lipid effects; the relations of trans fat intake with clinical endpoints; and current policy and legislative issues. In both observational cohort studies and randomized clinical trials, TFA adversely affect lipid profiles (including raising LDL and triglyceride levels, and reducing HDL levels), systemic inflammation, and endothelial function. More limited but growing evidence suggests that TFA also exacerbate visceral adiposity and insulin resistance. These potent effects of TFA on a multitude of cardiovascular risk factors are consistent with the strong associations seen in prospective cohort studies between TFA consumption and risk of myocardial infarction and coronary heart disease (CHD) death. The documented harmful effects of TFA along with the feasibility of substituting partially hydrogenated vegetable oils with healthy alternatives indicate little reason for continued presence of industrially produced TFA in food preparation and manufacturing or in home cooking fats/oils. A comprehensive strategy to eliminate the use of industrial TFA in both developed and developing countries, including education, food labeling, and policy and legislative initiatives, would likely prevent tens of thousands of CHD events worldwide each year.     

A pragmatic cluster randomized controlled trial of early intervention for chronic obstructive pulmonary disease by practice nurse-general practitioner teams: Study Protocol

ABSTRACT: BACKGROUND: Chronic Obstructive Pulmonary Disease (COPD) is a leading cause of disability, hospitalization, and premature mortality. General practice is well placed to diagnose and manage COPD, but there is a significant gap between evidence and current practice, with a low level of awareness and implementation of clinical practice guidelines. Under-diagnosis of COPD is a world-wide problem, limiting the benefit that could potentially be achieved through early intervention strategies such as smoking cessation, dietary advice, and exercise. General practice is moving towards more structured chronic disease management, and the increasing involvement of practice nurses in delivering chronic care. DESIGN: A pragmatic cluster randomised trial will test the hypothesis that intervention by a practice nurse-general practitioner (GP) team leads to improved health-related quality of life and greater adherence with clinical practice guidelines for patients with newly-diagnosed COPD, compared with usual care. Forty general practices in greater metropolitan Sydney Australia will be recruited to identify patients at risk of COPD and invite them to attend a case finding appointment. Practices will be randomised to deliver either practice nurse-GP partnership care, or usual care, to patients newly-diagnosed with COPD. The active intervention will involve the practice nurse and GP working in partnership with the patient in developing and implementing a care plan involving (as appropriate), smoking cessation, immunisation, pulmonary rehabilitation, medication review, assessment and correction of inhaler technique, nutritional advice, management of psycho-social issues, patient education, and management of co-morbidities. The primary outcome measure is health-related quality of life, assessed with the St George's Respiratory Questionnaire 12 months after diagnosis. Secondary outcome measures include validated disease-specific and general health related quality of life measures, smoking and immunisation status, medications, inhaler technique, and lung function. Outcomes will be assessed by project officers blinded to patients' randomization groups. DISCUSSION: This study will use proven case-finding methods to identify patients with undiagnosed COPD in general practice, where improved care has the potential for substantial benefit in health and healthcare utilization. The study provides the capacity to trial a new model of team-based assessment and management of newly diagnosed COPD in Australian primary care. Trial registration ACTRN12610000592044\     

Long-term dietary intervention trials: critical issues and challenges

ABSTRACT: BACKGROUND: There are many challenges involved in running randomised controlled dietary intervention trials that investigate health outcomes. The aim of this paper was to evaluate the recruitment process, retention of participants and challenges faced in our dairy intervention trial, and to provide strategies to combat the difficulties of running long-term dietary intervention trials. METHODS: A 12-month, randomised, two-way crossover study in overweight adults with habitually low dairy food consumption designed to assess the effects of a high dairy intake (HD; 4 serves of reduced fat dairy per day) compared to a low dairy intake (LD; 1 serve of reduced fat dairy per day) on measures of cardiometabolic and cognitive health was conducted. On completion of the HD phase, each participant was interviewed about their experience in the trial and responses were used to evaluate the key issues for study participants. RESULTS: Although the recruitment target was achieved, high rates of attrition (49.3%) and difficulties maintaining participant compliance (reported by 37.8% of participants) were major threats to the viability of the study. Factors that contributed to the high attrition included inability to comply with the dietary requirements of the study protocol (27.0%), health problems or medication changes (24.3%) and time commitment (10.8%). CONCLUSIONS: Attrition and adherence to study requirements present challenges to trials requiring longer-term dietary change. Including a run-in period to further assess the motivation, commitment and availability of participants, maintaining regular contact with participants during control phases, minimising time commitment, providing flexibility with dietary requirements, facilitating positive experiences, and stringent monitoring of diet are some key recommendations for future dietary intervention trials.     

Is dietary restriction beneficial for human health, such as for immune function?

PURPOSE OF REVIEW: The impact of dietary restriction on physiologic function in humans is now beginning to be examined. The clinical trials are fueled by decades of animal experiments showing that dietary restriction delays the aging process and decreases the incidence of many age-associated diseases. The critical issue addressed in this article is whether or not dietary restriction long term is feasible or beneficial in humans. RECENT FINDINGS: Short-term dietary restriction in humans does appear to have beneficial effects at lowering metabolism, especially when examining carbohydrates and weight loss. Dietary restriction long term does, however, have detrimental psychological effects in humans, making its feasibility questionable. Even short-term dietary restriction can negatively impact physical activity and potentially some aspects of immunity. The best avenue for humans to benefit from dietary restriction would be for pharmacological or bioactive food ingredient mimetics to be developed which would be more applicable for long-term use. SUMMARY: Dietary restriction per se is unlikely to emerge as a feasible long-term strategy to improve human health. Developing dietary restriction mimetics targeting energy metabolism may prove beneficial, not only in aging, but also in diabetes and obesity.     

Which practices co‐deliver food security,climate change mitigation and adaptation,and combat land degradation and desertification?

There is a clear need for transformative change in the land management and food production sectors to address the global land challenges of climate change mitigation, climate change adaptation, combatting land degradation and desertification, and delivering food security (referred to hereafter as “land challenges”). We assess the potential for 40 practices to address these land challenges and find that: Nine options deliver medium to large benefits for all four land challenges. A further two options have no global estimates for adaptation, but have medium to large benefits for all other land challenges. Five options have large mitigation potential (>3 Gt CO₂eq/year) without adverse impacts on the other land challenges. Five options have moderate mitigation potential, with no adverse impacts on the other land challenges. Sixteen practices have large adaptation potential (>25 million people benefit), without adverse side effects on other land challenges. Most practices can be applied without competing for available land. However, seven options could result in competition for land. A large number of practices do not require dedicated land, including several land management options, all value chain options, and all risk management options. Four options could greatly increase competition for land if applied at a large scale, though the impact is scale and context specific, highlighting the need for safeguards to ensure that expansion of land for mitigation does not impact natural systems and food security. A number of practices, such as increased food productivity, dietary change and reduced food loss and waste, can reduce demand for land conversion, thereby potentially freeing‐up land and creating opportunities for enhanced implementation of other practices, making them important components of portfolios of practices to address the combined land challenges.     

Comparing global warming potential,energy use and land use of organic,conventional and integrated winter wheat production

To ensure a sustainable food supply for the growing population, the challenge is to find agricultural systems that can meet production requirements within environmental constraints and demands. This study compares the impacts of winter wheat production on energy use, land use and 100 years Global Warming Potential (GWP₁₀₀) under different arable farming systems and farming practices. Life cycle assessment was used to simulate the impacts of organic, conventional and integrated farming (IF) systems along the production chain from input production up to the farm gate. The IF system models were designed to combine the best practices from organic and conventional systems to reduce negative environmental impacts without significant yield reductions. An integrated system that used food waste digestate as a fertiliser, and utilised pesticides and no‐tillage had the lowest energy use and GWP per functional unit of 1000 kg wheat output. When the impacts of some specific practices for reducing energy use and GWP were compared, the highest energy use reductions were achieved by replacing synthetic nitrogen fertilisers with anaerobically treated food waste or nitrogen fixing crops, increasing yields through crop breeding and using no‐tillage instead of ploughing. The highest GWP reductions were achieved by using nitrification inhibitors, replacing synthetic nitrogen fertilisers and increasing yields. The major contributors to the uncertainty range of energy use were associated with machinery fuel use and the assumed crop yields. For GWP results, the main source of uncertainty related to the N₂O emissions. In conclusion, farming systems that combine the best practices from organic and conventional systems have potential to reduce negative environmental impacts while maintaining yield levels.     

Auditing audits: use and development of the Oxfordshire Medical Audit Advisory Group rating system.

OBJECTIVES--To assess the value of the Oxfordshire Medical Audit Advisory Group rating system in monitoring and stimulating audit activity, and to implement a development of the system. DESIGN--Use of the rating system for assessment of practice audits on three annual visits in Oxfordshire; development and use of an "audit grid" as a refinement of the system; questionnaire to all medical audit advisory groups in England and Wales. SETTING--All 85 general practices in Oxfordshire; all 95 medical audit advisory groups in England and Wales. MAIN OUTCOME MEASURES--Level of practices'' audit activity as measured by rating scale and grid. Use of scale nationally together with perceptions of strengths and weaknesses as perceived by chairs of medical audit advisory groups. RESULTS--After one year Oxfordshire practices more than attained the target standards set in 1991, with 72% doing audit involving setting target standards or implementing change; by 1993 this had risen to 78%. Most audits were confined to chronic disease management, preventive care, and appointments. 38 of 92 medical audit advisory groups used the Oxfordshire group''s rating scale. Its main weaknesses were insensitivity in assessing the quality of audits and failure to measure team involvement. CONCLUSIONS--The rating system is effective educationally in helping practices improve and summatively for providing feedback to family health service authorities. The grid showed up weakness in the breadth of audit topics studied. IMPLICATIONS AND ACTION--Oxfordshire practices achieved targets set for 1991-2 but need to broaden the scope of their audits and the topics studied. The advisory group''s targets for 1994-5 are for 50% of practices to achieve an audit in each of the areas of clinical care, access, communication, and professional values and for 80% of audits to include setting targets or implementing change.     

No magic bullets: a systematic review of 102 trials of interventions to improve professional practice.

OBJECTIVE: To determine the effectiveness of different types of interventions in improving health professional performance and health outcomes. DATA SOURCES: MEDLINE, SCISEARCH, CINAHL and the Research and Development Resource Base in CME were searched for trials of educational interventions in the health care professions published between 1970 and 1993 inclusive. STUDY SELECTION: Studies were selected if they provided objective measurements of health professional performance or health outcomes and employed random or quasi-random allocation methods in their study designs to assign individual subjects or groups. Interventions included such activities as conferences, outreach visits, the use of local opinion leaders, audit and feedback, and reminder systems. DATA EXTRACTION: Details extracted from the studies included the study design; the unit of allocation (e.g., patient, provider, practice, hospital); the characteristics of the targeted health care professionals, educational interventions and patients (when appropriate); and the main outcome measure. DATA SYNTHESIS: The inclusion criteria were met by 102 trials. Areas of behaviour change included general patient management, preventive services, prescribing practices, treatment of specific conditions such as hypertension or diabetes, and diagnostic service or hospital utilization. Dissemination-only strategies, such as conferences or the mailing of unsolicited materials, demonstrated little or no changes in health professional behaviour or health outcome when used alone. More complex interventions, such as the use of outreach visits or local opinion leaders, ranged from ineffective to highly effective but were most often moderately effective (resulting in reductions of 20% to 50% in the incidence of inappropriate performance). CONCLUSION: There are no "magic bullets" for improving the quality of health care, but there are a wide range of interventions available that, if used appropriately, could lead to important improvements in professional practice and patient outcomes.