The Coronary Drug Project. Role of the National Institutes of Health

A clinical trials staff within an Institute is essential for adequate participation in and monitoring of any large cooperative clinical trial supported by that Institute. At minimum such a staff should consist of a medical scientist with professional interests and experience in clinical trials methodology; a biometrician with direct experience and interest in the design, large-scale data collection, data analysis, and quality control needs of such trials; a contract specialist; and additional consultants in the technical areas related to the clinical disease or intervention study, such as pharmacology, laboratory operations, computer science, or other areas. The continuity of professional development and experience of such a staff is essential to expand the capabilities for participation and advancement of this rapidly developing science of the design, organization, and conduct of cooperative clinical trials.     

News in Brief

Intermediate end points are widely used in cardiovascular clinical trials mainly to forecast/foreshadow actual clinical cardiovascular outcomes. This approach is based on the historical atherosclerosis paradigm which states in part that the effects of traditional cardiovascular risk factors on clinical cardiovascular disease (CVD) events are solely mediated through subclinical cardiovascular disease/atherosclerosis. The utility of intermediate end point CVD clinical trials using either historical subclinical CVD markers such as quantitative angiography or current sophisticated markers such as coronary artery calcium, carotid intima–media thickness or brachial flow mediated dilation has been variable. Discoveries of other pathways pertinent to the pathogenesis of atherosclerosis calls for a new conceptual model or paradigm and helps explain the discordance in results from prior and ongoing intermediate end point–clinical CVD event trial pairs.     

What Might the Ideal Electronic Medical Record for Migraine Headache Look Like?

Electronic medical records (EMRs) have assumed a greater role in clinical practice and have the potential to improve clinical efficiency and documentation, reduce cost, and enhance clinical care. An EMR for migraine should allow customization to include fields important in migraine, such as migraine frequency and severity, weight, blood pressure, and outcome measures, such as the Migraine Disability Assessment. The physical examination should focus on common abnormalities, such as muscle spasm, allodynia, or papilledema, and allow free text to describe uncommon findings. Information from previous notes should be available for inclusion in the current visit, such as diagnoses and the plan from the previous visit. In the future, EMR will work with clinicians to recognize patterns of clinical features and medication responses within individual patients and across patients, assimilate that information with current best practices of evidence-based medicine, and suggest management considerations to improve outcomes.     

Medical research during the COVID-19 pandemic

The current pandemic of coronavirus disease 2019 (COVID-19) which was first detected in Wuhan, China in December 2019 is caused by the novel coronavirus named severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). The virus has quickly spread to a large number of countries leading to a great number of deaths. Unfortunately, till today there is no specific treatment or vaccination for SARS-CoV-2. Most of the suggested treatment medications are based on in vitro laboratory investigations, experimental animal models, or previous clinical experience in treating similar viruses such as SARS-CoV-1 or other retroviral infections. The running of any clinical trial during a pandemic is affected at multiple levels. Reasons for this include patient hesitancy or inability to continue investigative treatments due to self-isolation/quarantine, or limited access to public places (including hospitals). Additional barriers relate to health care professionals being committed to other critical tasks or quarantining themselves due to contact with COVID-19 positive patients. The best research approaches are those that adapt to such external unplanned obstacles. Ongoing clinical trials before COVID-19 pandemic have the potential for identifying important therapies in the long-term if they can be completed as planned. However, these clinical trials may require modifications due a pandemic such as this one to ensure the rights, safety, and wellbeing of participants as well as medical staff involved in the conduction of clinical trials. Clinical trials initiated during the pandemic must be time-efficient and flexible due to high contagiousness of severe acute respiratory syndrome coronavirus 2, the significant number of reported deaths, and time constraints needed to perform high quality clinical trials, enrolling adequate sample sizes. Collaboration between different countries as well as implementation of innovative clinical trial designs are essential to successfully complete such initiatives during the current pandemic. Studies looking at the long term sequalae of COVID-19 are also of importance as recent publications describe multi-organ involvement. Long term follow-up of COVID-19 survivors is thus also important to identify possible physical and mental health sequellae.     

Clinical trial simulation in drug development

The simulation of therapeutic models and clinical trial simulation have recently attracted attention as emerging techniques for developing new active molecules and the exploration of possible clinical trial results. Such approaches have benefited from fundamental progress in the development of 'in silico' models, as well as progress in nonlinear mixed-effect pharmacokinetic-pharmacodynamic models. Mixing the two approaches allows simulation of 'virtual' patients, who receive virtual treatments or placebo. These have various uses, such as proof of concept, decision analysis or experimental design optimisation. Also, the effect of departures from protocol on clinical trial results can easily be evaluated by the use of simulation. This technique is now implemented by the pharmaceutical industry for optimising phase II and III experimental designs when a good biomarker or a clinical outcome model is available, but the use of an in silico therapeutic model as a proof of concept is only just beginning. In order to see such methodologies used more widely in drug development, multidisciplinary efforts need to be initiated, new modelling and simulation tools developed, and sound modelling and simulation practice documents need to be adopted. A reduction in the number of failed clinical development projects, the number of negative phase II and III clinical trials, or in just their cost and duration, are among the expected benefits of modelling and simulation in clinical drug development.     

Depression, demoralisation or adjustment disorder? Understanding emotional distress in the severely medically ill

As emotional distress is often seen as an understandable reaction to a severe or life-threatening illness, clinicians are reluctant to make a diagnosis of depression and resort to alternative diagnoses such as adjustment disorder (AD) or demoralisation. This paper introduces these concepts and critically examines their clinical utility. It concludes that neither AD nor demoralisation can be clearly distinguished from depression on variables such as clinical symptoms, outcome or treatment response. Since AD and demoralisation are considered transient or understandable reactions, the risk of using these diagnoses as alternatives to depression in a clinical setting is that a simplistic approach of psychological therapies for the former and antidepressants for the latter will be adopted. Instead, a working diagnosis of a general distress syndrome complemented by a personalised formulation is advocated. This would lead to the generation of a problem list and a pragmatic management plan.     

Review article: A primer for clinical researchers in the emergency department: Part XI. Inertia before investigation: Pre‐test probability in emergency medicine

In this series, we address research topics in emergency medicine. Rational clinical decision making is based on knowledge of the disease prevalence, clinical assessment features and test characteristics such as sensitivity and specificity. The concept of pre‐test probability is important as it will allow the clinician and patient decide together if a ‘test threshold’ or ‘treatment threshold’ has been reached, or if further investigations are required to make such a decision. This research primer uses three case scenarios to explore these concepts.     

Functional MRI of the kidney

Functional MR imaging of the kidney has a great potential of development because the functional parameters, which can be approached noninvasively, are multiple: glomerular filtration, tubular concentration and transit, blood volume and perfusion, diffusion, and oxygenation. Until now, its limitations in clinical applications are due to the difficulties in obtaining reproducible and reliable information in this mobile organ and, sometimes, in understanding the physiologic substrate of the signal changes observed. These approaches require either endogeneous contrast agents, such as water protons (for perfusion and diffusion) or deoxyhemogobin (for oxgenation), or exogeneous contrast agents such as gadolinium chelates (for filtration and perfusion) or iron oxide particles (for perfusion). Clinical validation of these methods and evaluation of their clinical impact are now worthwhile before diffusing them in clinical practice.     

Foucault at the bedside: a critical analysis of empowering a healthy lifestyle

Since quite a few years, philosophy is heading towards the bedside of the patient: the practice of philosophy has stepped out of its ivory tower, it seems, to deal with empirical or practical questions. Apart from the advantages, we should keep in mind the importance of a critical analysis of medical or clinical practice as such. If ethics partakes the clinical stage, it runs the risk only to discuss the how question and to forget the more fundamental what or why questions: what are we doing exactly and why is it good for? Starting from the principle of the empowerment of the patient, we will demonstrate how the discourse on empowerment in health care seems to forget a profound reflection upon this principle as such. By rehearsing some basics from the governmentality theory of Michel Foucault and the actualization of it by Nicolas Rose, we will argue how philosophical investigation in medical‐ethical evolutions such as empowerment of the patient is still needed to understand what is really going on in today's clinical practice.     

小牛血去蛋白水解物治疗急性病毒性心肌炎的临床研究

目的 观察小牛血去蛋白水解物治疗心肌炎的临床疗效.方法 将134例患者分为对照组及治疗组,治疗组以小牛血去蛋白水解物及辅酶Q10等常规营养心肌治疗,对照组常规应用黄芪注射液及辅酶Q10等常规治疗.观察临床症状、心律失常、ST-T改变.结果 治疗组的临床症状、心律失常、ST-T改变、临床转归与对照组比较差异无统计学意义.结论 小牛血去蛋白水解物对病毒性心肌炎有治疗意义.     

The epidemiologic approach to the study of clinical nursing diagnoses

There is a nomenclature for classifying personal features of the host, that is, the patient. There is a nomenclature for classifying features of disease such as organs, tissues, and cells. There is also a nomenclature for classifying agents of treatment such as drugs. But there is no nomenclature in in either clinical medicine or clinical nursing for the classification of the features of interaction between the host and the disease, that is, the illness of the patient.     

Clinical significance of gene-diagnosis for defects in coagulation factors and inhibitors

cDNA sequences of all known coagulation factors and inhibitors of coagulation have been described and an enormous number of disease generating mutations in these factors has been found by genetic analysis of affected families. The vast majority of these defects have severe clinical consequences such as spontaneous bleeding or predisposition to venous thrombosis and pulmonary embolism. While all the genetic defects described so far cause disease, or at least represent a risk factor for diseases such as bleeding or thrombosis, only a minority of these conditions actually need DNA analysis to be detected and/or treated properly. The purpose of this review is therefore to describe clinical situations in which the knowledge of the underlying genetic defect is important for decision making in patients with inherited hemophilia or thrombophilia.     

Novel inhaled combined antibiotic formulations in the treatment of Pseudomonas aeruginosa airways infections in cystic fibrosis

In cystic fibrosis, chronic airways infection caused by Pseudomonas aeruginosa can be treated with inhaled antibiotics such as inhaled tobramycin, aztreonam or colistin. However, biofilm formation induced by this bacterium can reduce the effectiveness of such therapies and can contribute to antibiotic resistance. Inhaled antibiotic combination might represent an optimal antibiofilm strategy in this setting. This review discusses the rationale for combining the antibiotics as well as some emerging or existing combinations. Most of the combinations except for fosfomycin/tobramycin are at an early stage of development. The latter combination was found to be effective in Phase II clinical studies and is planned to be tested in Phase III trials. The clinical data on long-term efficacy are currently missing, but the existing evidence as well as the unmet therapeutic need can prompt the further evaluation of such compounds.     

Strategies for Managing Barriers to the Writing Process

Publication is essential to advancing nursing knowledge for clinical practice, but relatively few nurses publish the results of their research or other writings about clinical practice issues. This article identifies some common barriers to writing for publication-personal factors, such as inadequate knowledge and writing skills, lack of confidence, and low motivation for writing for publication; and situational factors, such as limited time, energy, and other resources constraints-and discusses strategies for managing such barriers.   Key words:     

microRNAs in liver disease: From diagnostics to therapeutics

There is a need to identify effective biomarkers for diagnosis, prognosis and prediction of treatment efficacy for many liver diseases such as hepatocellular cancer, and chronic viral hepatitis. The identification of disease-specific alterations in microRNA expression and the ability to detect microRNAs in the circulation provide the basis for identifying novel clinically effective treatments and biomarkers. Knowledge regarding miRNA in human liver disease may eventually lead to serum or tissue biomarkers with clinical utility. A selection of relevant studies is reviewed. There are major challenges that need to be addressed prior to clinical application such as the need for careful validation of diagnostic miRNA candidates in well described clinical cohorts, and technical issues such as quantitation and standardization of assays. The rapid progress in therapeutic interventions using miRNA based strategies for chronic hepatitis C and hepatocellular cancer provides optimism for novel approaches that will build on the existing and emerging knowledge regarding miRNA in liver diseases.     

肺泡蛋白沉积症12例临床分析

目的 提高临床医师对肺泡蛋白沉积症的认识,分别从临床表现、病理特点和诊断治疗等方面对该病加以探讨。方法 回顾12例肺泡蛋白沉积症病例资料,并结合文献进行其临床特点分析。结果 临床症状包括：活动性呼吸困难12例（100.00％）、咳嗽11例（91．67％）,咯痰9例（75．00％）、胸闷5例（41．67％）、咯血1例（8．33％）。体征包括：吸气性爆裂音或裂帛音5例（41．67％）、叩诊浊音4例（33．33％）、紫绀3例（25．00％）、杵状指2例（16．67％）。影像学表现包括：地图样表现ll例（91．67％）、肺水肿样表现8例（66．67％）、碎石路样表现6例（50％）、肺间质纤维化样表现5例（41.67％）、肺实变样表现3例（25％）。结论 肺泡蛋白沉积后的X线胸片表现缺乏特异性,CT／HRCT可出现相对典型的改变（地图样表现、碎石路样表现）。肺泡蛋白沉积症特征地表现为临床症状与体征分离,影像学与体征不符的现象。支气管肺泡灌洗是简便有效的诊疗方法。     

Immunoadsorption for collagen and rheumatic diseases

The field of therapeutics has seen remarkable progress in the recent years, which has made mainstream drug treatment possible for collagen and rheumatic diseases. However, treatment of intractable cases where drug effectiveness is poor is a challenge. Furthermore, organ damage, concurrent illnesses or allergic reactions make adequate drug therapy impossible. For such cases, therapeutic apheresis is very significant, and it is important how this should be valued related to drug therapies. Therapeutic apheresis for collagen and rheumatic diseases involves the removal of factors that cause and exacerbate the disease; the aim of immunoadsorption, in particular, is to improve the clinical condition of patients with autoimmune disease by selectively removing pathogenic immune complexes and autoantibodies from their plasma.Immunoadsorption, in particular, unlike plasma exchange and DFPP, utilizes a high-affinity column that selectively removes autoantibodies and immune complexes, leaving other plasma components intact. There is no need to replenish fresh frozen plasma or blood products such as albumin and gamma globulin preparations. Immunoadsorption is thus superior in terms of safety, as the risk of infection or allergic reaction relating to these preparations can be avoided. We anticipate future investigations of application of synchronized therapy using drugs and therapeutic apheresis, most notably immunoadsorption, in combination to treat intractable clinical conditions such as collagen and rheumatic diseases.In this paper, our discussion includes the indications for immunoadsorption such as collagen and rheumatic diseases, the relevant conditions and types, as well as the latest understanding related to methods and clinical efficacy.     

The development of thiazolidinedione drugs as anti-diabetic agents

Thiazolidinedione drugs which increase insulin sensitivity are attracting attention of diabetologists. The first drug, ciglitazone ameliorated hyperglycemia in animal models of obese type 2 diabetes such as KKAy mice, but the effect was too weak for clinical application. The first clinical drug troglitazone was approved and marketed in 1997, and the second drug pioglitazone in 1999. Troglitazone was designed to combine tocopherol, anti-peroxidant, and thiazolidinedione. Plasma glucose is lowered in type 2 diabetic patients by troglitazone or pioglitazone alone or in combination with sulfonylureas. The decrease in glycemia is accompanied with the decrease in plasma insulin, suggesting that the effect is mediated by the improvement of insulin sensitivity. Other new thiazolidinedione drugs such as rosiglitazone are in development. Rare but severe hepatic injury occasionally leading to death has been noticed after several months of clinical application of troglitazone. Monthly examination of liver enzymes reduced the number of severe hepatotoxicity. The ultimate evaluation of thiazolidinediones awaits more clinical experiences.     

Alcoholic liver disease

Liver injury may develop in some people who consume alcohol. The pathogenesis of liver damage in such subjects remains obscure. Major histopathologic features of alcohol-associated liver injury include steatosis, steatonecrosis, and cirrhosis. The clinical manifestations of alcoholic liver disease are nonspecific and range from asymptomatic hepatomegaly to stigmata of portal hypertension with advanced parenchymal failure. The severity of the clinical presentation and the degree of aminotransferase elevation correlate poorly with the liver histopathology, particularly in patients who continue to drink alcohol. Short-term mortality of such patients is best predicted by a composite of clinical and laboratory parameters that are influenced by alcohol consumption as well as by liver disease. Long-term prognosis is determined by residual damage to vital organs (that is, whether or not cirrhosis has developed) and whether or not the patient continues to drink. Current therapy of alcoholic liver disease includes abstinence and correction of nutritional deficiencies. Other therapies are experimental and are best utilized in the setting of controlled clinical trials.