The number needed to treat: a clinically useful measure of treatment effect.

The relative benefit of an active treatment over a control is usually expressed as the relative risk, the relative risk reduction, or the odds ratio. These measures are used extensively in both clinical and epidemiological investigations. For clinical decision making, however, it is more meaningful to use the measure "number needed to treat." This measure is calculated on the inverse of the absolute risk reduction. It has the advantage that it conveys both statistical and clinical significance to the doctor. Furthermore, it can be used to extrapolate published findings to a patient at an arbitrary specified baseline risk when the relative risk reduction associated with treatment is constant for all levels of risk.     

Clonazepam use in pregnancy and the risk of malformations

BACKGROUND: Clonazepam (Klonopin) is a benzodiazepine that has been used widely to treat seizures and conditions such as panic attacks and anxiety disorder. However, the current findings about its use in pregnancy are derived from limited studies of small sample size. Because it is commonly prescribed during pregnancy, more information about its safety is needed. METHODS: The medical records of 28,565 infants were surveyed as part of a hospital-based malformation surveillance program to identify those who had been exposed prenatally to an anticonvulsant, including clonazepam. RESULTS: During a 32-month period, 166 anticonvulsant-exposed infants were identified; 52 had been exposed to clonazepam, 43 as monotherapy. A total of 33 (76.7%) of the monotherapy infants were exposed during the first trimester. One (3.0%) infant had dysmorphic features, growth retardation, and a heart malformation (tetralogy of Fallot). CONCLUSIONS: This study did not observe an increase in major malformations in births exposed to clonazepam monotherapy. However, this study is not large enough to have adequate power to determine whether or not the rate of major malformations is increased in clonazepam-exposed pregnancies. No increase has been identified in three other case series. Although the number of patients in this series was larger than previous reports, continued monitoring of pregnancies is needed to determine whether or not clonazepam is teratogenic.     

Quantifying Burial,the Transport of Matter from the Lake Biosphere to the Geosphere

Burial is one of the most fundamental processes in contexts of massbalance calculations for substances (such as nutrients, organics, metals and radionuclides) in lakes. Substances can leave a lake by two processes, outflow, i.e., the transport to a downstream system, and burial, i.e., the transport by sedimentation from the lake biosphere to the geosphere. This work gives for the first time, to there best of the author's knowledge, a review on the factors and processes regulating burial and presents a general model for burial. This approach accounts for bottom dynamic conditions (i.e., where areas of fine sediment erosion, transport and accumulation prevail), sedimentation, bioturbation, mineralisation, and the depth and age of the bioactive sediment layer. This approach has been critically tested with very good results for radiocesium, radiostrontium, many metals, calcium from liming and phosphorus, but it has not been presented before in a comprehensive way. This model for burial is meant to be used in massbalance models based on ordinary differential equations (i.e., box models) in contexts where burial is not a target y‐variable but a necessary model variable (an x‐variable). This means that there are also specific demands on this approach, e.g., it must be based on readily accessible driving variables so that it is not too difficult to use the model in practice within the context of an overall lake model. The factors influencing burial, e.g., the deposition of materials and the depth of the bioactive sediment layer, are also needed in calculations of sediment concentrations and to determine amounts of substances or pollutants in sediments. To carry out such calculations, one also needs information on sediment bulk density, water content and organic content. This paper also presents new empirical models for such calculations to be used in the new model for burial.     

Ecological integrity assessment as a metric of biodiversity: are we measuring what we say we are?

As the recognition of the importance of biological diversity in biological conservation grows, an ongoing challenge is to develop metrics that can be used for effective conservation and management. The ecological integrity assessment has been proposed as such a metric. It is held by some to measure species composition, diversity, and habitat quality, as well as ecosystem structure, composition, and function. The methodology relies on proxy variables that include data on landscape characteristics such as patch size, abiotic factors such as hydrology, and some features of vegetation structure and composition. We suggest that the measure is flawed on four levels. First, its putative representation of general ecological form and function, and its lack of specific detail about how it actually represents those attributes, leaves the metric without the focus needed to be useful for measuring ecological features on the ground and testing associated hypotheses and predictions. Second, the proxy variables used to represent biological diversity, such as habitat (vegetation) metrics and vascular plant species diversity, are not empirically correlated with diversity of a range of taxa or of other components of the biota. Third, like other ecological indices that integrate many distinct features, the ecological integrity index is subject to the loss of information in its condensation of multi-dimensional variability into a one-dimensional index, and it may be subject to systematic bias from the conversion of raw data into categorical scores. Fourth, the sampling protocols are at risk of sampling bias, observer bias, and measurement error, any of which can confound the estimation of conservation value. In terms of biological diversity, the methodology produces an unreliable estimate of the number of vascular plant species and their relative percentages of occurrence, and an absence of any protocols for taxa other than plants. For these reasons we believe that ecological integrity assessment is currently of limited value as a measure of site-specific biological diversity and its change over time. A considerable amount of investigation is needed in order to have confidence in the results of an ecological integrity assessment, especially if it is to be used for regulatory purposes. We suggest further refinements and discuss alternative measures of biological diversity that provide reliable metrics for assessing change. A thoughtful choice among measures can help to identify the most appropriate assessment for conservation decisions.     

Is metronidazole carcinogenic?

Metronidazole (MTZ, 1-[2-hydroxyethyl]-2-methyl-5-nitroimidazole), an antiparasitic and antibacterial compound, is one of the world’s most used drugs. MTZ is potentially carcinogenic to humans due to the following facts: it is a proven mutagen in bacterial systems, it is genotoxic to human cells and also, it is carcinogenic to animals. However, due to inadequate epidemiological evidence, it is not considered as a risk factor for cancer in humans. As it will be discussed here, the existing population studies are deficient since they have not included sufficient sample size, the follow-up time has not been long enough, and the individual sensitivity to the drug might have been acting as a confounding factor. Due to the increasing use of this drug, more and improved studies are needed to elucidate its mechanism of genotoxicity and its carcinogenic potential.     

Is metronidazole carcinogenic?

Metronidazole (MTZ, 1-[2-hydroxyethyl]-2-methyl-5-nitroimidazole), an antiparasitic and antibacterial compound, is one of the world's most used drugs. MTZ is potentially carcinogenic to humans due to the following facts: it is a proven mutagen in bacterial systems, it is genotoxic to human cells and also, it is carcinogenic to animals. However, due to inadequate epidemiological evidence, it is not considered as a risk factor for cancer in humans. As it will be discussed here, the existing population studies are deficient since they have not included sufficient sample size, the follow-up time has not been long enough, and the individual sensitivity to the drug might have been acting as a confounding factor. Due to the increasing use of this drug, more and improved studies are needed to elucidate its mechanism of genotoxicity and its carcinogenic potential.     

Variable ranges of interactions in polypeptide conformations with a method to complement molecular modeling.

Formulations of conformational weights for helix-coil transitions can be extended to substantially more complex situations than are usually pursued. General rules for matrix multiplication that depend parametrically on the interaction ranges and numbers of rotamers of residues are presented. The orders of the matrices of statistical weights can be increased with chain length, so that an individual matrix element can represent any specified single conformation, as needed. By the appropriate choice of interaction ranges and numbers of available conformers, approximations can be introduced in which: (1) an average of the conformations of any chain segment is obtained, (2) specific residue-residue interactions are excluded, or (3) the conformation of a part of the chain is restricted or fixed. The method is appropriate for treating specific interactions in peptides and could be used together with available experimental information to develop models of conformational transitions. As such, the methods represent a class of calculations aimed at more rigorous calculations built around known features of a molecule. The aim is to facilitate calculations that bridge the gap between nonquantitative molecular model building and more rigorous but less directed molecular mechanics calculations. The method can directly include any desired longer range of interactions, if the interaction range is not too long to make impossible the manipulation of the requisite matrices. An outline is presented of an application to treat salt bridges in the C peptide of ribonuclease A.     

Connective-tissue disease following breast augmentation: a preliminary test of the human adjuvant disease hypothesis

It has been proposed that scleroderma in particular or connective-tissue diseases in general may be caused by exposure to silicone-containing materials used for breast augmentation. We performed a historical cohort study to estimate the point prevalence of this potential complication sometimes referred to as "human adjuvant disease." Three-hundred and seventy-eight patients who underwent augmentation mammaplasty with silicone-containing envelope-type prostheses from 1970 through 1981 were surveyed. Regional musculoskeletal syndromes, fibrositis, or osteoarthritis occurred in a third (38 of 125) of our responders. No patient developed an inflammatory systemic rheumatic disease during the period of observation (mean 6.8 years for the 125 subjects). Using calculations based on risk for development of rheumatic disease, it does not appear likely that augmentation mammaplasty is a significant or major inducer of inflammatory connective-tissue diseases in general. However, the number of patients surveyed was small, and our results must be considered preliminary. We could not exclude a specific risk for the development of scleroderma.     

Efficient p-value evaluation for resampling-based tests

The resampling-based test, which often relies on permutation or bootstrap procedures, has been widely used for statistical hypothesis testing when the asymptotic distribution of the test statistic is unavailable or unreliable. It requires repeated calculations of the test statistic on a large number of simulated data sets for its significance level assessment, and thus it could become very computationally intensive. Here, we propose an efficient p-value evaluation procedure by adapting the stochastic approximation Markov chain Monte Carlo algorithm. The new procedure can be used easily for estimating the p-value for any resampling-based test. We show through numeric simulations that the proposed procedure can be 100-500 000 times as efficient (in term of computing time) as the standard resampling-based procedure when evaluating a test statistic with a small p-value (e.g. less than 10( - 6)). With its computational burden reduced by this proposed procedure, the versatile resampling-based test would become computationally feasible for a much wider range of applications. We demonstrate the application of the new method by applying it to a large-scale genetic association study of prostate cancer.     

Influence of method of reporting study results on decision of physicians to prescribe drugs to lower cholesterol concentration.

OBJECTIVE--To determine whether the reporting of study results by using reductions in relative or absolute risk and the number needed to treat affects the views of physicians about the effectiveness of drugs to lower lipid concentrations and decisions about treatment. DESIGN--Random allocation of two questionnaires presenting the results of three end points of the Helsinki heart study as results from separate trials by using reduction in either relative or absolute risk. In both questionnaires one end point was also presented by showing person years of treatment needed to prevent one myocardial infarction. The effectiveness of lipid lowering drugs was assessed for all end points on an 11 point scale. For each study result the likelihood to treat hypercholesterolaemia of 7.5 mmol/l in a healthy man had to be indicated on a seven point scale. SUBJECTS--Random sample of 802 internists and general practitioners representative of providers of primary care in Switzerland. RESULTS--The response rate was 69.6% (558). For the prevention of fatal and non-fatal myocardial infarction the mean ratings of effectiveness of lipid lowering drugs were 0.45 (95% confidence interval 0.21 to 0.69) and 1.39 (1.09 to 1.68) scale points lower when the reduction of absolute risk or number needed to treat were reported instead of the relative risk reduction (both P < 0.001). Physicians receiving trial results for identical end points in form of absolute reduction of risk or number needed to treat were less inclined to treat hypercholesterolaemia (both P < 0.001). CONCLUSIONS--Physicians'' views of the effectiveness of lipid lowering drugs and the decision to prescribe such drugs is affected by the predominant use of reduction of relative risk in trial reports and advertisements.     

Azathioprine, a genotoxic agent to be considered non-genotoxic in man

Azathioprine, an immunosuppressive drug, has been used for 25 years. Azathioprine is rapidly converted into a number of metabolites after absorption. Maximum blood levels in experimental animals (mice) were 11.3 micrograms/ml after a dosage of 33.3 mg/kg. Generally, levels of less than 1 microgram/ml are found. As azathioprine is ineffective in hypoxanthine guanine phosphoribosyltransferase (HPRT)-deficient patients, it will be clear that for immunosuppressive activity azathioprine must be metabolised. Regarding mutagenic activity, its mutagenicity for bacteria seems irrelevant for man because the nitroimidazole moiety can be reduced by bacteria but not or hardly at all by mammalian tissues. So 6-mercaptopurine (a metabolite of azathioprine) and its metabolites should be regarded as the active compounds. In vitro azathioprine can induce chromosome aberrations and other cytogenetic events at high, non-physiological doses. However, in view of the low blood levels it is unlikely that azathioprine can induce chromosome aberrations in kidney transplant patients. It is more probable that azathioprine inhibits the elimination of such aberrant cells through its immunosuppressive activity. It should be pointed out that in microbial mutagenicity systems also, azathioprine concentrations that are not reached in patients are needed to obtain an increased mutation rate.     

Issues in Exposure and Dose Assessment for Epidemiology and Risk Assessment

Epidemiologic studies have been effective in identifying human environmental and occupational hazards. However, most epidemiologic data has been difficult to use in quantitative risk assessments because of the vague specification of exposure and dose. Toxicologic animal studies have used applied doses (quantities administered, or exposures with fixed duration) and well characterized end points to determine effects. However, direct use of animal data in human risk assessment has been limited by uncertainties in the extrapolation. The applied dose paradigm of toxicology is not suited for cross species extrapolation, nor for use in epidemiology as a dose metric because of the complexity of human exposures. Physiologically based pharmacokinetic (PBPK) modeling can estimate the time course of tissue concentrations in humans, given an exposure-time profile, and it has been used for extrapolating findings from animals to humans. It is proposed that human PBPK modeling can be used in appropriately designed epidemiologic studies to estimate tissue concentrations. Secondly, tissue time courses can be used to form dose metrics based on the type and time course of adverse effects. These dose metrics will strengthen the determination of epidemiologic dose-response relationships by reducing misclassification. Findings from this approach can be readily integrated into quantitative risk assessment.     

Bipolar disorder: an update

Bipolar disorder (BPD) is one of the most severe forms of mental illness and is characterized by swinging moods. It affects both sexes equally in all age groups and its worldwide prevalence is approximately 3-5%. The clinical course of illness can vary from a mild depression to a severe form of mania. The condition has a high rate of recurrence and if untreated, it has an approximately 15% risk of death by suicide. It is the third leading cause of death among people aged 15-24 years and is a burden on society and families. The pathophysiology of the disorder is poorly understood. However, a variety of imaging studies suggests the involvement of structural abnormalities in the amygdala, basal ganglia and prefrontal cortex. There are two main biological models that have been proposed for depression. These are called the serotonin and norepinephrine hypotheses. Multiple lines of evidence support both of them. It is a life-long disease and runs in families but has a complex mode of inheritance. Family, twin and adoption studies suggest genetic factors but the candidate susceptibility genes, which when mutated can account for a substantial portion of BPD patients, have not yet been conclusively identified. There have been an increasing number of new generation antidepressant drugs developed to treat BPD. However, lithium salt is only the drug that is most efficient in long-term preventive treatment and it also has an anti-suicidal effect. The condition can be well managed by physicians and psychiatrists along with family and patient education. Identification of risk genes in the future may provide a better understanding of the nature of pathogenesis that may lead to a better therapeutic target.     

RESPECTING AUTONOMY WITHOUT DISCLOSING INFORMATION

There is widespread agreement that it would be both morally and legally wrong to treat a competent patient, or to carry out research with a competent participant, without the voluntary consent of that patient or research participant. Furthermore, in medical ethics it is generally taken that that consent must be informed. The most widely given reason for this has been that informed consent is needed to respect the patient's or research participant's autonomy. In this article I set out to challenge this claim by considering in detail each of the three most prominent ways in which ‘autonomy’ has been conceptualized in the medical ethics literature. I will argue that whilst these accounts support the claim that consent is needed if the treatment of competent patients, or research on competent individuals, is to respect their autonomy, they do not support the claim that informed consent is needed for this purpose.     

Novel treatments for complications after bariatric surgery

Bariatric surgery has been considered one of best treatments for obesity. As every surgical procedure—and any medical intervention, it is not exempt of complications, among which leaks, strictures, acute hemorrhages and fistulae highlight. Leaks are more common in the gastro-jejunal anastomosis (GJA) in the case of Roux-en-y Gastric Bypass (RYGB), while in Sleeve Gastrectomy (LSG) they locate in the stapler line. Stenosis can be seen in the gastro-jejunostomy in the RYGB and in the gastric tube in case of the LSG. For each of these complications, many innovative solutions have been developed, including new surgical devices. In spite of promising good results, evidence regarding utility and safeness of these technologies is still scarce. Self-expandable endoscopic stents have been used to treat leaks, with an overall success rate of 80–90 % and a migration rate of 15–35 %. The bear trap-like over-the-scope (Ovesco) clips have been used to treat GI hemorrhages, leaks and even fistulae, with a 70–80 % success rate, although more endoscopic sessions may be needed. Overstitch, an endosurgical suture devices, have been used to treat leaks, fistulae and perforations. Overall, technical success achievement approaches to 90 %, while clinical success ranges from 80 to 90 %, except for leaks closure, where a lower success rate has been observed. Despite of all of these advances, early diagnosis and treatment remains the main strategy to achieve success. In summary, novel therapies for complication management can be very useful, though further studies with larger series are still needed in order to confirm their efficacy and safeness.     

Simulation of gene pyramiding in Drosophila melanogaster

Gene pyramiding has been successfully practiced in plant breeding for developing new breeds or lines in which favorable genes from several different lines were integrated.But it has not been used in animal breeding,and some theoretical investigation and simulation analysis with respect to its strategies,feasibility and efficiency are needed before it can be implemented in animals.In this study,we used four different pure lines of Drosophila melanogaster,each of which is homozygous at a specific mutant gene ...     

Invasion dynamics of round goby (<Emphasis Type="Italic">Neogobius melanostomus</Emphasis>) in Hamilton Harbour,Lake Ontario

Most introduced non-native species fail to establish as a result of mortality or reproductive failure. An established population can increase the probability of survival and reproductive success of newly introduced individuals by reducing both Allee effects and demographic stochasticity. Previously, attention has been paid to the establishment phase of the invasion process and its probability modelled as a stochastic process, while the spread phase has received less attention. By analyzing data collected during the spread phase of an invasion of the round goby, Neogobius melanostomus, in Hamilton Harbour, Lake Ontario, we develop an analytical approach to backcalculate the time to establishment and to determine the time to habitat saturation. Our modelling shows that: (1) during the transition between arrival and establishment, propagule pressure in the form of new adults entering the area can be very low and still represent a significant probability of establishment; (2) much higher concentrations of juveniles would be needed to pose a significant risk of invasion; (3) the demographic contribution of propagule pressure during the spread phase is low and its total elimination will not halt population growth and spread; (4) a short elapsed time between arrival and establishment indicated that the transition between these two phases can be characterized as a deterministic process with high propagule pressure and low adult mortality rates; and, (5) very aggressive management actions would be needed to halt population growth after population establishment, suggesting that preventative measures are the most effective management options available to reduce risk of future invasions.     

The West of Scotland coronary prevention study: economic benefit analysis of primary prevention with pravastatin.

OBJECTIVE: To estimate the economic efficiency of using pravastatin to prevent the transition from health to cardiovascular disease in men with hypercholesterolaemia. DESIGN: Economic benefit analysis based on data from the West of Scotland coronary prevention study. Treatment specific hazards of developing cardiovascular disease according to various definitions were estimated. Scottish record linkage data provided disease specific survival. Cost estimates were based on extracontractual tariffs and event specific average lengths of stay calculated from the West of Scotland coronary prevention study. SUBJECTS: Men with hypercholesterolaemia similar to the subjects in the West of Scotland coronary prevention study. MAIN OUTCOME: Cost consequences, the number of transitions from health to cardiovascular disease prevented, the number needed to start treatment, and cost per life year gained. RESULTS: If 10,000 of these men started taking pravastatin, 318 of them would not make the transition from health to cardiovascular disease (number needed to treat, 31.4), at a net discounted cost of 20m Pounds over 5 years. These benefits imply an undiscounted gain of 2,460 years of life, and thus 8121 Pounds per life year gained, or 20,375 Pounds per life year gained if benefits are discounted. Restriction to the 40% of men at highest risk reduces the number needed to treat to 22.5 (5601 Pounds per life year gained (undiscounted) and 13,995 Pounds per life year gained (discounted)). CONCLUSIONS: In subjects without evidence of prior myocardial infarction but who have hypercholesterolaemia, the use of pravastatin yields substantial health benefits at a cost that is not prohibitive overall and can be quite efficient in selected high risk subgroups.     

Point and interval estimation of baseline risk and treatment effect based on logistic model for observational studies

In observational studies with dichotomous outcome of a population, researchers usually report treatment effect alone, although both baseline risk and treatment effect are needed to evaluate the significance of the treatment effect to the population. In this article, we study point and interval estimates including confidence region of baseline risk and treatment effect based on logistic model, where baseline risk is the risk of outcome of the population under control treatment while treatment effect is measured by the risk difference between outcomes of the population under active versus control treatments. Using approximate normal distribution of the maximum‐likelihood (ML) estimate of the model parameters, we obtain an approximate joint distribution of the ML estimate of the baseline risk and the treatment effect. Using the approximate joint distribution, we obtain point estimate and confidence region of the baseline risk and the treatment effect as well as point estimate and confidence interval of the treatment effect when the ML estimate of the baseline risk falls into specified range. These interval estimates reflect nonnormality of the joint distribution of the ML estimate of the baseline risk and the treatment effect. The method can be easily implemented by using any software that generates normal distribution. The method can also be used to obtain point and interval estimates of baseline risk and any other measure of treatment effect such as risk ratio and the number needed to treat. The method can also be extended from logistic model to other models such as log‐linear model.     

Protective effect of antibiotics against serious complications of common respiratory tract infections: retrospective cohort study with the UK General Practice Research Database

Objective To determine the extent to which antibiotics reduce the risk of serious complications after common respiratory tract infections.Design Retrospective cohort study.Setting UK primary care practices contributing to the general practice research database.Data source 3.36 million episodes of respiratory tract infection.Main outcome measures Risk of serious complications in treated and untreated patients in the month after diagnosis: mastoiditis after otitis media, quinsy after sore throat, and pneumonia after upper respiratory tract infection and chest infection. Number of patients needed to treat to prevent one complication.Results Serious complications were rare after upper respiratory tract infections, sore throat, and otitis media, and the number needed to treat was over 4000. The risk of pneumonia after chest infection was high, particularly in elderly people, and was substantially reduced by antibiotic use, with a number needed to treat of 39 for those aged ≥65 and 96-119 in younger age groups. Conclusion Antibiotics are not justified to reduce the risk of serious complications for upper respiratory tract infection, sore throat, or otitis media. Antibiotics substantially reduce the risk of pneumonia after chest infection, particularly in elderly people in whom the risk is highest.