Risk of myocardial infarction in patients taking cyclo- oxygenase-2 inhibitors or conventional non-steroidal anti-inflammatory drugs: population based nested case-control analysis purchase gabapentin 300 mg on line. Risk of hospitalization for myocardial infarction among users of rofecoxib gabapentin 300mg low cost, celecoxib purchase 600mg gabapentin mastercard, and other NSAIDs: a population-based case-control study. Patients exposed to rofecoxib and celecoxib have different odds of nonfatal myocardial infarction. The risk for myocardial infarction with cyclooxygenase-2 inhibitors: a population study of elderly adults. Effect of selective cyclooxygenase 2 inhibitors and naproxen on short-term risk of acute myocardial infarction in the elderly. Observational study of upper gastrointestinal hemorrhage in elderly patients given selective cyclo-oxygenase-2 inhibitors or conventional non-steroidal anti-inflammatory drugs. A systematic review of the observational studies of selective and nonselective inhibitors of cyclooxygenase 2. Non-steroidal anti-inflammatory drugs and risk of serious coronary heart disease: an observational cohort study. Shaya FT, Blume SW, Blanchette CM, Weir MR, Mullins CD. Selective cyclooxygenase-2 inhibition and cardiovascular effects. Relationship between selective cyclooxygenase-2 inhibitors and acute myocardial infarction in older adults. Risk of adverse gastrointestinal outcomes in patients taking cyclo-oxygenase-2 inhibitors or conventional non-steroidal anti-inflammatory drugs: population based nested case-control analysis.. Risk of upper gastrointestinal ulcer bleeding associated with selective COX-2 inhibitors, traditional non-aspirin NSAIDs, aspirin, and combinations. Nonsteroidal antiinflammatory drugs (NSAIDs) 47 of 72 Final Report Update 4 Drug Effectiveness Review Project 105. Celecoxib versus diclofenac and omeprazole in reducing the risk of recurrent ulcer bleeding in patients with arthritis. New England Journal of Medicine 2002;347(26):2104-2110. Celecoxib plus aspirin versus naproxen and lansoprazole plus aspirin: a randomized, double-blind, endoscopic trial. Celecoxib compared with lansoprazole and naproxen to prevent gastrointestinal ulcer complications. Combination of a cyclo-oxygenase-2 inhibitor and a proton-pump inhibitor for prevention of recurrent ulcer bleeding in patients at very high risk: a double-blind, randomised trial. Do proton-pump inhibitors confer additional gastrointestinal protection in patients given celecoxib? Chan F, Lanas A, Scheiman J, Berger M, Nguyen H, Goldstein J. Celecoxib versus omeprazole and diclofenac in patients with osteoarthritis and rheumatoid arthritis (CONDOR): a randomised trial. Risk of myocardial infarction associated with selective COX-2 inhibitors: meta-analysis of randomised controlled trials (Structured abstract). Advisory Committee Briefing Document:Celecoxib and Valdecoxib Cardiovascular Safety. Caldwell B, Aldington S, Weatherall M, Shirtcliffe P, Beasley R. Risk of cardiovascular events and celecoxib: a systematic review and meta-analysis. Do selective COX-2 inhibitors increase the risk of cerebrovascular events: a meta-analysis of randomized controlled trials (Structured abstract). Cardiovascular thrombotic events in arthritis trials of the cyclooxygenase-2 inhibitor celecoxib. Risk of cardiovascular events in patients receiving celecoxib: a meta-analysis of randomized clinical trials. Turajane T, Wongbunnak R, Patcharatrakul T, Ratansumawong K, Poigampetch Y, Songpatanasilp T. Gastrointestinal and cardiovascular risk of non-selective NSAIDs and COX-2 inhibitors in elderly patients with knee osteoarthritis. Velentgas P, West W, Cannuscio CC, Watson DJ, Walker AM. Cardiovascular risk of selective cyclooxygenase-2 inhibitors and other non-aspirin non-steroidal anti- inflammatory medications. Nonsteroidal antiinflammatory drugs (NSAIDs) 48 of 72 Final Report Update 4 Drug Effectiveness Review Project 119. Cardiorenal effects of celecoxib as compared with the nonsteroidal anti-inflammatory drugs diclofenac and ibuprofen. Meta-analysis of cyclooxygenase-2 inhibitors and their effects on blood pressure. Fracture risk associated with use of nonsteroidal anti-inflammatory drugs, acetylsalicylic acid, and acetaminophen and the effects of rheumatoid arthritis and osteoarthritis. Time dependent risk of gastrointestinal complications induced by non-steroidal anti-inflammatory drug use: a consensus statement using a meta- analytic approach. Nonsteroidal anti-inflammatory drugs and hepatic toxicity: a systematic review of randomized controlled trials in arthritis patients. Gastrointestinal safety profile of meloxicam: a meta-analysis and systematic review of randomized controlled trials. Risk of serious upper gastrointestinal and cardiovascular thromboembolic complications with meloxicam. Efficacy and tolerability of meloxicam in an observational, controlled cohort study in patients with rheumatic disease. Gastrointestinal-related complications in a long-term care population taking NSAIDs versus COX-2 inhibitor therapy. The risk of gastrointestinal bleed, myocardial infarction, and newly diagnosed hypertension in users of meloxicam, diclofenac, naproxen, and piroxicam. Gastrointestinal safety profile of nabumetone: a meta- analysis (Structured abstract). A population based historical cohort study of the mortality associated with nabumetone, Arthrotec, diclofenac, and naproxen. Association between aspirin and upper gastrointestinal complications: systematic review of epidemiologic studies. Risks of clinically significant upper gastrointestinal events with etodolac and naproxen: a historical cohort analysis. Variability in risk of gastrointestinal complications with individual non-steroidal anti-inflammatory drugs: results of a collaborative meta-analysis. Nonsteroidal antiinflammatory drugs (NSAIDs) 49 of 72 Final Report Update 4 Drug Effectiveness Review Project 134. Association between nonsteroidal anti- inflammatory drugs and upper gastrointestinal tract bleeding/perforation. An overview of epidemiologi studies published in the 1990s. Laporte J-R, Ibanez L, Vidal X, Vendrell L, Leone R. Upper gastrointestinal bleeding associated with the use of NSAIDs: newer versus older agents. Misoprostol reduces gastrointestinal complications in patients with rheumatoid arthritis receiving nonsteroidal anti-inflammatory drugs: A randomized, double-blind, placebo-controlled trial. Hooper L, Brown TJ, Elliott R, Payne K, Roberts C, Symmons D. The effectiveness of five strategies for the prevention of gastrointestinal toxicity induced by non-steroidal anti- inflammatory drugs: systematic review. Prevention of NSAID-induced gastroduodenal ulcers [Systematic Review]. Juni P, Nartey L, Reichenbach S, Sterchi R, Dieppe PA, Egger M.
This is very important as with large fibroids order 400 mg gabapentin overnight delivery, kidneys can be dilated generic gabapentin 300 mg without a prescription, which is an indica- tion for operation even if she doesn’t have a lot of Ultrasound symptoms gabapentin 600mg. During a hysterectomy, ureters can be If you have a vaginal and an abdominal ultrasound damaged or accidentally closed while suturing. Thus probe, always start with the vaginal probe to better you need to assess this prior and postoperatively to assess the cervical area, the endometrium and if exclude this happening (see below). Also you can already diagnose It is always good to document your findings fibroids from the ultrasound picture and this is most with a drawing and to write down the measure- often easier vaginally. Uterine fibroids have a clear ments of each fibroid (see Chapter 1). If the diag- border to the adjacent myometrium as the latter nosis of uterine fibroids was made by coincidence surrounds them like a capsule. They are mostly without the patient having any symptoms, you darker than the myometrium (Figure 2). Submu- should monitor the woman regularly by ultra- cosal fibroids are better diagnosed with the vaginal sound. By using the vaginal and abdominal operate on her to know what you found. In probe of the machine, assess the uterine size and, if Chapter 1 on gynecological examinations, you will you can, the number, size and location of the find an example of how to document ultrasound fibroids. This is important to decide about the type findings, which you can use by either photocopy- of operation (myomectomy or hysterectomy), ing it or drawing your own sketch. However some clinics in India have already developed ways There might be a routine investigation standards set- of doing outreach clinics with hysteroscopic equip- up in your laboratory for certain conditions or likely ment. HSC is very useful for assessing the amount operations. For patients with uterine fibroids make of distortion of the uterine cavity by intramural or sure they contain at the minimum the following: submucosal fibroids by introducing a scope with a • Hb to assess the amount of anemia which will camera into the uterus. At the same time you can help you to decide whether the patient needs an see if the internal os of the tubes is blocked and operation or not and whether you may need a how the endometrial lining looks. Be aware, however, that big fibroids can be necrotic without symptoms which Intravenous pyelography will raise the ESR and maybe even the WBC. If available in your facility, intravenous pyelography can help These investigations are only important for you to to evaluate this. Your anesthetist might want other additional investigations. DECISION-MAKING ON THERAPEUTIC Further investigations APPROACH Saline infusion hysterosonography We will now consider different possible treatment options with ‘pros and cons’. There are basically In cases where you are not sure if a fibroid is grow- three treatment options: ing submucosally you can perform saline ultra- sound (saline infusion hysterosonography, SIHS) as • Expectant management described in Chapter 1. The distention of the • Medical treatment uterine cavity will help you to see if the fibroid is • Surgical treatment. If more that will help you to offer the patient a good choice: than 50% of the fibroid is growing in the uterine wall it must be accessed abdominally. So you have • Does the patient still desire fertility? Hysterosalpingography • Does the patient desire to preserve the uterus? If you find intramural fibroids close to the right or (Single/multiple, size, number, site). With HSG as described in Chapter 18 on fast growing ‘fibroid’). Hysteroscopy • Is there a higher level health facility available Hysteroscopy (HSC) is a very useful investigation where they are experienced in hysterectomies or but as it needs high-tech equipment it is not gener- myomectomy? The patient and her family will have to decide if In this section you will learn about the different they are willing to take the expense for the desired treatment options available and how to decide treatment approach. In the decision-making section which approach to take. Under surgical treatment, below we will give you some hints on how to find major operation techniques will be explained as the best approach for each patient. With the broad range of symptoms and the fairly Pregnancy-related complications numerous treatment options available, it is clear that the approach to treatment should be indivi- During pregnancy the uterine tissue is softer and dualized and be fitted to the patient’s perceptions more prone to hemorrhage than outside pregnancy. Especially in Africa, women’s burden of You should not perform a myomectomy during disease is probably high but on the other hand pregnancy or during a cesarean section as severe many medical treatment options are not (yet) avail- hemorrhage is likely to occur and many fibroids re- able. Most complications of As there have been a lot of new developments in fibroids in pregnancy can be treated conservatively. In the past, many dedicated and skilled surgeons • Mechanical problems impacting the uterus in in low-resource settings tried to preserve the uterus the pouch of Douglas early in pregnancy or of young women by doing myomectomy as well leading to obstructed labor. Many women, however, could only • Post-partum hemorrhage. Abdominal hysterectomy A patient with a necrotic fibroid will usually present is likely to be the most frequently needed gyneco- with abdominal pain localized on the uterus. There logical operation in resource-limited settings, so it might be slight signs of peritonism but usually no is good to learn how to do it. WBC can be elevated and there Please don’t forget though that a hysterectomy is can be a slight fever. Through abdominal ultrasound a major debilitating operation and that a uterus is you will be able to locate the pain above a fibroid, not an appendix but a central organ for female iden- often with centrally reduced echogenicity. In one study, 64% of women therapy consists of bed rest and pain killers (prefer- offered medical treatment with a hormone-coated ably ibuprofen and diclofenac up to 32 weeks of levonorgestrel intrauterine device (LNG-IUD), pregnancy, then paracetamol). Important differen- who were scheduled for hysterectomy, had decided tial diagnoses are abruption of the placenta, acute against the operation after 6 months compared to appendicitis and torsion of an ovarian cyst or tumor 14% in the control group8. In another study done in and, although very rare torsion of a pedunculated the USA, 43% of patients asked after hysterectomy fibroid. Here ultrasound can differentiate between expressed regrets about having the operation9. Tor- ectomy yields satisfaction rates of over 90% as the sion of a pedunculated fibroid is actually the only definite cure for uterine fibroids because the source indication for laparotomy for pregnancy-related of their development is removed. Still you should try to avoid of fibroids after myomectomy is estimated to be myomectomy during laparotomy. You can see how important it is to fibroid and wait to see if it becomes reddish again. If the patient still deteriorates you will have hormonal treatment to treat symptoms or even to perform a myomectomy or refer the patient. Your patients on medical treat- medical hemostatic agents (see below) as your ment need to know that you are only treating patient is pregnant. Ligate the pedicle of the fibroid symptoms and that when the treatment is stopped, with two tight Vicryl-0 sutures and cut it. Sometimes, because of the fibroids, a pregnant The hormonal treatment available at present helps uterus can become impacted in the pelvis. Progestins patients with an impacted uterus will have urine show several effects in reducing menorrhagia: retention. An impacted retroflected uterus can be pushed out of the pouch of Douglas, vaginally, • They cause anovulation in the majority of cycles. If you • The endometrium becomes flat and inactive, need to do a cesarean section for obstructed labor, thus reducing the amount of tissue going off do not attempt to remove the fibroids. Studies Expectant management show a significant decrease of menorrhagia and an At present all experts agree that all women with increase in hemoglobin levels, especially with the asymptomatic fibroids should only be monitored LNG-IUD. Several studies showed for the latter a (level of evidence 5). However, nobody has ever decrease in size of fibroids and uterine volume. It is impor- a better outcome for most patients with fibroids. Normal IUDs won’t do the has and the harmlessness of this condition. LNG-IUDs are becoming increasingly avail- should know, however, that uterine fibroids need a able in resource-poor countries but you will regular follow-up by ultrasound to monitor growth probably have to look into private pharmacies to in order to remove them in due time when they find them. They are a bit expensive as well but they grow, before they are so big or numerous that only last for 5 years, decrease fibroid-associated dys- hysterectomy is an option. Intervals between ultra- menorrhea and are a good contraceptive as well.
Multivariate analysis: Measuring the impact of more than one variable at a time while analyzing a set of data purchase 600mg gabapentin. N-of-1 trial: A randomized trial in an individual to determine the optimum treatment for that individual generic gabapentin 800mg amex. Noninferiority trial: A trial designed to determine whether the effect of a new treatment is not worse than a standard treatment by more than a prespecified amount order gabapentin 300 mg fast delivery. Nonrandomized study: Any study estimating the effectiveness (harm or benefit) of an intervention that does not use randomization to allocate patients to comparison groups. There are many types of nonrandomized studies, including cohort studies, case-control studies, and before- after studies. Null hypothesis: The statistical hypothesis that one variable (for example, treatment to which a participant was allocated) has no association with another variable or set of variables. Number needed to harm: The number of people who would need to be treated over a specific period of time before one bad outcome of the treatment will occur. The number needed to harm (NNH) for a treatment can be known only if clinical trials of the treatment have been performed. Number needed to treat: An estimate of how many persons need to receive a treatment before one person would experience a beneficial outcome. Observational study: A type of nonrandomized study in which the investigators do not seek to intervene, instead simply observing the course of events. Odds ratio: The ratio of the odds of an event in one group to the odds of an event in another group. Off-label use: When a drug or device is prescribed outside its specific FDA-approved indication, to treat a condition or disease for which it is not specifically licensed. Outcome: The result of care and treatment and/ or rehabilitation. In other words, the change in health, functional ability, symptoms or situation of a person, which can be used to measure the Antihistamines Page 51 of 72 Final Report Update 2 Drug Effectiveness Review Project effectiveness of care/treatment/rehabilitation. Researchers should decide what outcomes to measure before a study begins; outcomes are then assessed at the end of the study. Outcome measure: Is the way in which an outcome is evaluated---the device (scale) used for measuring. One-tailed test (one-sided test): A hypothesis test in which the values that reject the null hypothesis are located entirely in one tail of the probability distribution. For example, testing whether one treatment is better than another (rather than testing whether one treatment is either better or worse than another). Open-label trial: A clinical trial in which the investigator and participant are aware which intervention is being used for which participant (that is, not blinded). Random allocation may or may not be used in open-label trials. Per protocol: The subset of participants from a randomized controlled trial who complied with the protocol sufficiently to ensure that their data would be likely to exhibit the effect of treatment. Per protocol analyses are sometimes misidentified in published trials as intention-to- treat analyses. Pharmacokinetics: the characteristic interactions of a drug and the body in terms of its absorption, distribution, metabolism, and excretion. Placebo: An inactive substance commonly called a "sugar pill. It does not contain anything that could harm a person. It is not necessarily true that a placebo has no effect on the person taking it. Placebo-controlled trial: A study in which the effect of a drug is compared with the effect of a placebo (an inactive substance designed to resemble the drug). In placebo-controlled clinical trials, participants receive either the drug being studied or a placebo. The results of the drug and placebo groups are then compared to see if the drug is more effective in treating the condition than the placebo is. A confidence interval is a measure of the uncertainty (due to the play of chance) associated with that estimate. Pooling: The practice of combing data from several studies to draw conclusions about treatment effects. Power: The probability that a trial will detect statistically significant differences among intervention effects. Studies with small sample sizes can frequently be underpowered to detect difference. Precision: The likelihood of random errors in the results of a study, meta-analysis, or measurement. The greater the precision, the less the random error. Confidence intervals around the estimate of effect are one way of expressing precision, with a narrower confidence interval meaning more precision. Prospective study: A study in which participants are identified according to current risk status or exposure and followed forward through time to observe outcome. Prevalence: How often or how frequently a disease or condition occurs in a group of people. Prevalence is calculated by dividing the number of people who have the disease or condition by the total number of people in the group. Antihistamines Page 52 of 72 Final Report Update 2 Drug Effectiveness Review Project Probability: The likelihood (or chance) that an event will occur. In a clinical research study, it is the number of times a condition or event occurs in a study group divided by the number of people being studied. Publication bias: A bias caused by only a subset of the relevant data being available. The publication of research can depend on the nature and direction of the study results. Studies in which an intervention is not found to be effective are sometimes not published. Because of this, systematic reviews that fail to include unpublished studies may overestimate the true effect of an intervention. In addition, a published report might present a biased set of results (for example, only outcomes or subgroups for which a statistically significant difference was found). P value: The probability (ranging from zero to one) that the results observed in a study could have occurred by chance if the null hypothesis was true. Q-statistic: A measure of statistical heterogeneity of the estimates of effect from studies. It is calculated as the weighted sum of the squared difference of each estimate from the mean estimate. Random-effects model: A statistical model in which both within-study sampling error (variance) and between-studies variation are included in the assessment of the uncertainty (confidence interval) of the results of a meta-analysis. When there is heterogeneity among the results of the included studies beyond chance, random-effects models will give wider confidence intervals than fixed-effect models. Randomization: The process by which study participants are allocated to treatment groups in a trial. Adequate (that is, unbiased) methods of randomization include computer generated schedules and random-numbers tables. Randomized controlled trial: A trial in which two or more interventions are compared through random allocation of participants. Regression analysis: A statistical modeling technique used to estimate or predict the influence of one or more independent variables on a dependent variable, for example, the effect of age, sex, or confounding disease on the effectiveness of an intervention. Relative risk: The ratio of risks in two groups; same as a risk ratio. Retrospective study: A study in which the outcomes have occurred prior to study entry. Risk: A way of expressing the chance that something will happen. It is a measure of the association between exposure to something and what happens (the outcome).
The subtypes are to some extent separated geographically and may not compete directly gabapentin 600mg on line. Even within regions discount gabapentin 800 mg free shipping, HIV-1 continues to spread to naive hosts cheap gabapentin 400 mg fast delivery, so escape from immune memory at a few key antibody epi- topes would not dominate the relative success of lineages. It would be interesting to see the shapes of HIV-1 phylogenies based on samples collected over several years from a single region. In the other shapes, the signal of diﬀerential success would usu- ally not be strong enough to associate particular substitutions with the survival of a lineage. However, the dominance of a single lineage as in ﬁgure 15. This corresponds to a star phylogeny when drawn as inﬁg. Some ex- tinctions occur in this case, but many diﬀerent lineages have survived to the present. Ineachtimeperiod, a single lineage gives rise to all survivors a few generations into the future. Powerful epidemics that start from just a few individuals also give rise to skewed phylogenetic trees, but the progenitors of those epidemics may simply have been lucky and may show no tendency to carry particular traits. INFLUENZA Inﬂuenza A phylogenies have just the sort of shape that could allow correlation between particular substitutions and ﬁtness. They as- signed each variable amino acid site to zero or more of four diﬀerent sets: 18 sites were positively selected with dN signiﬁcantly greater than dS,16siteswereassociated with the receptor binding site of the HA1 258 CHAPTER 15 Shd5: positively selected Har3: receptor binding Sant: fastest evolving NY15: antibody epitopes Shd5 Sant Har3? Shd5 Har3 NY15 Sant NY15 * 5 nucleotide substitutions Figure 15. The tree on the left shows evolutionary relationships between isolates from subtype H3 from 1983 to 1994. The horizontal axis measures the number of nucleotide sub- stitutions between isolates, which correlates closely with time. Thus, the lower isolates come from earlier seasons, with time increasing up and to the right. The bold line shows the single lineage that succeeded through time. The asterisk shows another lineage that succeeded for about ﬁve years after its divergence from the main line, but eventually died out. See the text for a description of the labeled isolates (ﬁlled circles) and how the left tree was used to predict evolution in theupperpartofthe right tree, which contains the data from 1983 to 1994 plus three additional years from 1994 to 1997. MEASURING SELECTION 259 surface, 20 sites evolved relatively faster than the other sites, and 41 sites were in or near the well-known antibody epitope domains A and B. Suppose amino acid changes in one of thefour sets consistently cor- related with the ultimate success of a lineage. Then, at any time, one could predict which of the currently circulating isolates would be most closely related to the progenitor of future lineages. In particular, those lineages with the most amino acids that had recently changed at the key sites would be most likely to succeed. In inﬂuenza, success probably occurs by escaping the host’s immunological antibody memory caused by recent epidemics. Variant sites near key antibody epitopes would be good candidates to produce antibody escape. In other words, those sites with amino acid replacements favored by selection in the past also provided the best in- formation about which amino acid changes would lead to success in the future. Instead, they used data from 1983 to 1997 to form eleven retrospective tests. A ret- rospective test analyzed data from 1983 to year x and predicted subse- quent evolution in the years following x,wherex varied between 1986 and 1997. The bold line along the left marks the single dominant “trunk” lineage. At the question mark, just before 1994, the data can no longer resolve the trunk lineage because several variants cocirculated at thattimeandthetrunkcanberesolved only after one knows which of those lineages succeeded. The ﬁlled circles show four isolates from 1994 that represented the four classiﬁcations for variable amino acids. Shd5 (A/Shangdong/5/94) represented the lineagewiththegreatest number of recent amino acid changes at sites that had been positively selected in the past, as inferred from the 1983–1997 data. The Har3 (A/Harbin/3/94) lineage had variant amino acids near the receptor binding site. The Sant (A/Santiago/7198/ 94) lineage had variant amino acids at those sites that had evolved rap- idly in the past. The NY15 (A/New York/15/94) lineage had variant sites in or near antibody epitopes A and B. Those data show which of the 1994 lineages succeeded and which died out. Suc- cessful prediction means choosing the isolate closest on the tree (most alike genetically) with the lineagethatcontinues along the trunk and gives rise to the future population. It turned out that Shd5 was closest to the successful trunk lineage among the candidates. In other words, the most changes in previously positively selected sites predicted which lineage succeeded in subsequent years. In nine of those elevenyears,thelineage that contained the most changes relative to its ancestor at the eighteen positively se- lected sites identiﬁed the section of the tree from which the future trunk emerged. The sites in the antibody epitopes only identiﬁed seven of eleven trunk lineages, and the other amino acid sets did worse. Thus, positive selection provided the best signal for which amino acid changes correlated most closely with ﬁtness. The epidemic strains con- tained amino acid replacements at a small number of sites that had previously been identiﬁed as crucial for escape from monoclonal anti- bodies. It would be interesting to compare these two methods in a single study of the same evolving parasite population. Substitutions at these positively selected sites correlated with the future success of MEASURING SELECTION 261 lineages during the years of sampling, 1983–1997. In the future, will these eighteen sites continue to be the primary target of selection? On the one hand, the eighteen sites may indeed be the most important for escape from protective antibodies. Ifso,futuresamples will continue to ﬁnd positive selection focused onthesesites. On the other hand, diﬀerent sites may dominate in the future, with little future selective change in the currently positively selected sites. A changing focus of selection may arise from evolving structural features of the viral surface that expose or hide diﬀerent sites or from a changed distribution in the immune memory proﬁles of hosts. If episodic selection frequently occurs, then the time scale over which one studies substitution patterns plays a critical role in inference. Sim- ply measuring aggregate rates of synonymous and nonsynonymous sub- stitutions may turn out to be a rather crude tool that misses a large proportion of the changes brought about by natural selection. As more data accumulate, it will become important to match statistical methods with explicit hypotheses about the biological processes of selection and the temporal scale over which selection varies. Kinds of selection detectable from standard analyses of population samples. Inﬂuenza has certain characters that make it a particularly good model for simple analysis of positive selection. Epidemic strains often have wide distribution; thus, there is relatively less spatial varia- tion in the exposure of hosts to diﬀerent strains than for many other parasites. The wide and relatively uniform distribution of epidemics creates relatively uniform selective pressure on the virus. In addition, infections do not persist within hosts, so most selective pressure on the surface hemagglutinin glycoproteinarisesbyescape from antibody rec- ognition during transmission between hosts. The uniformity of selective pressure means that aggregate samples can provide clear signals. By contrast, other parasites may face multiple selective pressures that vary over relatively small spatial and temporal scales. For example, Rou- zine and Coﬃn (1999) analyzed 213 pro sequences of HIV-1 from eleven infected individuals. This sampling scheme allowed them to analyze the diﬀerent patterns of selection within hosts and between hosts. This may be particularly important in HIV, which causes long, persistent in- fections within hosts.
X. Bandaro. Utah State University.
Richmond Rascals. 12 Richmond Hill. Richmond-Upon-Thames. TW10 6QX tel: 020 8948 2250