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PubMed1999

Using the Internet to calculate clinical action thresholds.

Understanding the risks and benefits of available treatments represents an essential element of clinical practice. Previous work has demonstrated that knowledge of net benefits and net risks can relate to our decisions on whether or not to administer a particular treatment or order a diagnostic test. A wider application of this model has been difficult because data on net benefits and net risks are not directly reported. We used more frequently reported data on treatment efficacy (E) and risks (Rrx) to obtain an equation for the treatment threshold probability above which treatment should be given and below which it should be withheld. The diagnostic test should only be performed if the probability of a disease is between the testing threshold and the treatment threshold. We first described a theoretical background for these calculations. We then used a JavaScript programming language to write a computer program which physicians can use to calculate these threshold probabilities effortlessly through the Internet. In most clinical situations we do not have to achieve maximum diagnostic certainty in order to act. However, we should never treat or order a diagnostic test if the risk of the treatment is greater than its efficacy. The minimally required E/R ratio of a particular treatment is equal to the reciprocal value of the mortality/morbidity of untreated disease. Similarly, the lowest number of patients needed to be treated (NNT) for therapy to be worth administering is equal to the reciprocal of the treatment risk. We show how evidence-based summary measures of therapeutic effects, such as the treatment efficacy, harms, and NNT, can successfully be integrated within a decision analytic model. This in turn will facilitate wider use of the quantitative benefit-risk analysis. Accessing the Internet for direct and immediate approach to the formulas described here should make this task even easier in everyday clinical decision making.

Adult↗
PubMed1989

Geriatric outpatient clinics: an audit of clinical action, transport and general practitioners' views.

An audit was performed of patients attending geriatric outpatient clinics for review during a calendar month. Patients were asked to complete a brief questionnaire and 93% of case notes were available for study. In 97 attendances, management was altered in 36, a new medical problem found in 16, and 49 patients were discharged. Forty-seven attendances followed recent discharge from hospital; 19 of these patients had no evident clinical benefit from attendance, although the majority were discharged. There may be scope for a liaison nurse to take over the follow-up of some patients to save their attending a clinic. A survey of local general practitioners suggested they would welcome this.

Aged↗
PubMed2005

Clinical actions of subarachnoid sevoflurane administration in vivo: a study in dogs.

BACKGROUND: Halogenated ethers produce clinical effects at spinal sites. Nevertheless, in vitro and in vivo studies have not determined whether the immobilizing effect in the spinal cord is due to inhibition of nociceptive or motor transmission or both. Our goal was to characterize the clinical effects of direct spinal sevoflurane administration. METHODS: Five adult beagle dogs completed the study. In a randomized and blinded manner each animal received placebo (saline 0.1 ml kg(-1)) and three concentrations of pure sevoflurane administered intrathecally (0.05, 0.075 and 0.1 ml kg(-1)) by means of a permanent spinal catheter. Sensory and motor block and state of consciousness were determined at baseline and at predetermined regular intervals until at least 2 h after total recovery. RESULTS: None of the dogs presented a decrease in consciousness with either 0.05 or 0.075 ml kg(-1) of sevoflurane. Administration of 0.1 ml kg(-1) produced light sedation (2 on a four-point sedation scale) in three of the five dogs. A comparison of the duration of the sensory and motor blocks among the three sevoflurane dosages shows a significant dose-dependent increase that is greater in all cases than that for the saline solution. CONCLUSIONS: Spinal administration of pure sevoflurane resulted in a dose-related and totally reversible motor and sensory regional block without any signs of clinical neurotoxicity or significant decrease in consciousness. Therefore the model allows us to comment on the analgesic effects at the spinal level in addition to the direct immobilizing effects of sevoflurane.

Anesthesia, Spinal↗
PubMed2002

Lactoferrin: mechanism of action, clinical significance and therapeutic relevance.

Lactoferrin is an iron binding protein involved in a large spectrum of biological actions including antimicrobial actions. Lactoferrin plays a central role in ferrokinetics: it binds free iron with great affinity limiting the amount of ions available for microorganism's metabolism. Its role in the host defence mechanisms consists in bacteriostatic and bactericidal effects; moreover it inhibits the proliferation of other microbes such as fungi and viruses. Lactoferrin is also involved in the modulation of immune system and recent studies indicate that lactoferrin directly modulates both production and function of neutrophils and monocytes.

Lactoferrin↗
PubMed2000

Polymorphism of gonadotropin action: clinical implications.

It has recently became apparent that the structural heterogeneity of gonadotropin molecules can contribute to variations of their action in different physiological and pathophysiological conditions. One reason for the structural variations of circulating gonadotropin molecules is the microheterogeneity caused by the variability of glycosylation of individual gonadotropin molecules. The carbohydrate moieties of gonadotropins are important for their intrinsic bioactivity, as reflected by measurement of their bioactivity to immunoreactivity (B/I) ratios. We have reassessed this phenomenon by improved in vitro bioassay and immunoassay methods, and it appears that the intrinsic bioactivity of gonadotropins, in particular of LH, is more constant than previously assumed. Many of the previously documented differences, some even considered diagnostic for certain clinical conditions, have turned out to be methodological artifacts. The first part of this review summarizes our recent findings on the B/I ratios of LH, with special reference to the male. The second part of this review describes a common polymorphism that was recently discovered in the gene of the LH beta-subunit. The variant LH beta allele contains two point mutations, which introduce to LH two amino acid changes and an extra glycosylation site. The LH variant is common world-wide, with carrier frequency varying from 0 to 52% in various ethnic groups. The LH variant differs functionally from wild-type LH, and it seems to predispose its carriers, both men and women, to mild aberrations of reproductive function. It is important for the clinician to be aware of this variant LH form, not detected by all immunoassays, because it may explain some aberrant results of LH measurements in patient samples.

Adolescent↗
PubMed1990

Neurochemical and pharmacokinetic correlates of the clinical action of benzodiazepine hypnotic drugs.

Benzodiazepine derivatives are presumed to exert their pharmacologic activity via interaction with specific molecular recognition sites, termed benzodiazepine receptors, within the brain. The various benzodiazepines used in clinical practice differ considerably in their intrinsic receptor affinity, but the qualitative character of the drug-receptor interaction is similar or identical among this class of drugs. All benzodiazepines are lipophilic (lipid-soluble) substances that relatively rapidly cross the blood-brain barrier and equilibrate with brain tissue. After equilibrium is attained, a constant brain:plasma ratio is maintained, such that plasma concentrations proportionately reflect concentrations of drug in brain. Brain concentrations are proportional to the extent of receptor occupancy, which in turn determines the acute behavioral effect. Clinical differences among benzodiazepines largely reflect differences in pharmacokinetic properties. The onset of action after single oral doses reflects the rate of absorption from the gastrointestinal tract, whereas the duration of action is determined by the rate and extent of drug distribution to peripheral tissues, as well as by the rate of elimination and clearance. During multiple dosage, long half-life drugs accumulate, with the concurrent possibility of daytime sedation. However, a benefit of long half-life drugs is that rebound insomnia on abrupt termination is unlikely. Short half-life drugs accumulate minimally and have a lower likelihood of producing daytime sedation. However, they may be more likely to produce rebound insomnia on abrupt discontinuation.

Anti-Anxiety Agents↗
PubMed1999

A proposal for the locus of metformin's clinical action: potentiation of the activation of pyruvate kinase by fructose-1,6-diphosphate.

Reduction of hepatic glucose output has been shown to be the chief basis for metformin's clinical benefit in diabetes, and the balance of the evidence suggests that this reflects inhibition of gluconeogenesis. Recent research with hepatocyte cell cultures demonstrates increased flux through pyruvate kinase in metformin-treated cells. An analysis of the conditions under which clinically relevant concentrations of metformin inhibit gluconeogenesis in hepatocyte cultures prompts the hypothesis that metformin potentiates the allosteric activation of pyruvate kinase by fructose-1,6-diphosphate. This model rationalizes several salient features of metformin's clinical activity: its ability to reduce hepatic triglyceride synthesis, its appetite-suppressant effect, and its failure to induce hypoglycemia.

Diabetes Mellitus↗
PubMed1995

Do blood cultures need continuous monitoring so that clinical action can be taken outside normal working hours?

Many automated blood culture reading systems monitor bacterial growth 24 hours a day but it is unclear if reacting to prompts indicating bacterial growth outside normal laboratory hours is of clinical benefit. An analysis of 50 blood cultures from 43 patients which had organisms seen on Gram films and had triggered positive out-of-hours showed that examination of the Gram film altered management of seven patients and the results of culture or sensitivity testing altered that of a further four. However, after review, it was felt the clinical outcome would not have been influenced by earlier intervention in any of these patients. We therefore consider that an out-of-hours service for dealing with positive blood cultures is not justified in our hospital. This conclusion may not apply universally, especially in hospitals where potential pathogens show less predictable antimicrobial sensitivity patterns.

Adult↗
PubMed1987

Anisoylated plasminogen streptokinase activator complex (APSAC). A review of its mechanism of action, clinical pharmacology and therapeutic use in acute myocardial infarction.

APSAC is a new thrombolytic agent with advantages over conventional therapy such as streptokinase. In particular, it is suitable for intravenous administration over 4 to 5 minutes, in contrast with the prolonged infusion required with intravenous streptokinase, thus facilitating treatment of acute myocardial infarction outside a coronary care unit. Additionally, its fibrinolytic action is theoretically selective for fibrin associated with thrombi, which should minimise systemic fibrinolysis. However, in practice, systemic fibrinolysis does occur to some extent in most patients, but clinically significant haemorrhagic complications are rare. At the recommended dose of 30U injected intravenously over a period of 4 to 5 minutes in patients with acute myocardial infarction of less than 6 hours' duration, reperfusion of occluded coronary arteries occurs in about 72% of patients (range 53 to 91% in individual studies). Subsequent reocclusion has been reported in 0 to 20% of patients in most studies, with an average reocclusion rate of around 10%. The reperfusion rate compares favourably with that reported for intracoronary streptokinase and has tended to be superior to that with intravenous streptokinase. Thus, APSAC is an important advance in thrombolytic therapy for patients with acute myocardial infarction. Of particular importance is its relative ease of administration, reducing the dependence on coronary care units with catheterisation facilities, and the associated costs and delays in implementing treatment. APSAC should result in effective thrombolytic therapy being rapidly introduced after acute myocardial infarction in a wider proportion of patients than was previously feasible.

Anistreplase↗
PubMedDate not supplied

Is making smoking status a vital sign sufficient to increase cessation support actions in clinical practice?

BACKGROUND: There is widespread belief that adding smoking status to the list of vital signs in medical practice will lead to an increased likelihood that physicians will offer more cessation support for smokers during office visits. This article evaluates the impact of introducing routine use of smoking status as a vital sign on clinician cessation support in a primary care setting. METHODS: A total of 429 adult health plan members who were smokers and recent quitters from 2 primary care clinics in Minneapolis, Minn, were administered a 28-item questionnaire by telephone. The instrument included questions about patient health status, smoking status, advice about smoking, clinic actions during the most recent visit, satisfaction with clinic actions, and intention to change smoking. Comparisons were made with a cohort of smoking patients before and after smoking status was used as a vital sign, using 2-tailed t tests for continuous variables and chi-square analysis for categorical variables. RESULTS: Patient self-report of receiving advice about smoking in the past year (about 66%) was unchanged after smoking status was implemented as a vital sign. Medical chart documentation of tobacco use increased from 38.0% to 78.4% of all encounters, whereas documentation of advice about smoking decreased from 33.5% to 18.8%. Except for identification of tobacco use before implementation of the guideline, none of the specific activities recommended in the guideline occurred at very high levels. CONCLUSION: Implementing smoking status as a vital sign appears to have increased the documentation of tobacco use but had little effect on specific implementation actions. Overall, the findings suggest that more consistent identification of tobacco use alone will not lead to guideline-recommended changes in cessation support actions by clinicians. Greater environmental changes will be needed if tobacco guideline goals are to be achieved.

Adult↗
PubMed2026

Clinically actionable stratification of uncommon MET fusions: a precision oncology framework.

BACKGROUND: MET fusions represent emerging therapeutic targets in solid tumors; however, functional interpretation of non-canonical variants remains poorly understood, posing a major challenge for precision oncology. METHODS: We conducted a multicenter, pan-cancer study analyzing 23,299 clinical samples using DNA-based next-generation sequencing (NGS) to profile MET fusions. Transcriptional validation was performed using RNA-based NGS on available samples. Preliminary clinical outcomes were assessed in four patients with advanced malignancies harboring uncommon MET fusions who received MET tyrosine kinase inhibitor therapy. RESULTS: We identified 116 MET fusions (incidence: 0.5%), with 55.2% (64/116) classified as uncommon fusions. These uncommon fusions were stratified into: Group A (5’-retained, n = 12), Group B (intergenic/exonic breakpoints, n = 19), Group C (rare partners, n = 23), and Group D (dual fusions, n = 10). RNA validation revealed an overall low transcriptional consistency of 43.8% (14/32) for uncommon fusions, versus 100% for canonical fusions (PTPRZ1::MET, CAPZA2::MET). Notably, most 5’-retained fusions were transcriptionally silent, while some intergenic fusions resolved into expressed canonical partners (e.g. PTPRZ1::MET). Therapeutically, all four MET inhibitor-treated patients achieved partial responses, including pediatric diffuse midline gliomas (DMG) (median OS: 11.2 months) and lung adenocarcinoma (median OS: 34 months), demonstrating preliminary clinical activity. CONCLUSIONS: uncommon MET fusions are heterogeneous at genomic and transcriptional levels. DNA-level findings often do not predict functional transcripts, underscoring the necessity of RNA-based confirmation for clinical interpretation. Despite low overall consistency, a subset retains therapeutic potential. We propose a refined diagnostic framework integrating DNA-based stratification and RNA validation to guide the management of MET-altered cancers in precision oncology workflows.

Humans↗