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This is an open access article distributed under the Creative Commons Attribution License treatment bursitis buy generic tranexamic 500 mg online, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. This is due to the difference in length between the ventral and the dorsal side of the penis (corporocavernosal 1. Proximal hypospadias frequently have a penoscrotal transposition and/or bifid scrotum. With an incidence of 1:300, hypospadia is one of the most Further abnormalities in hypospadia concern the pre- common genital anomalies in male newborns [1]. Typically, there is a dorsal hump with excessive skin dia is defined as an anomaly (hypo- or dysplasia) involving on the dorsal and a scarcity of foreskin on the ventral aspect the ventral aspect of the penis [2]. Background Such ectopic urethral openings (meatus) can be located at the tip of the glans penis (hypospadia sine hypospa- the hypospadic penis is often anatomically similar to the dia), glanular, coronal, subcoronal, along the penile shaft, normal penis, at least as far as the dorsal aspect is concerned. The form and extent of However, the ventral aspect is pathological: the development malformation of the urethral opening varies as well and is of the prepuce incomplete, the formation of the urethral in some cases widely gaping and resembling the mouth of a plate into a urethra defective and the corpus spongio- fish. Histologically, the urethral plate consists Generally, severe forms of hypospadia are typically of well-vascularised tissue with large endothelial sinuses accompanied by an abnormal ventral curvature of the penis lined around an abortive urethral spongiosum. Fibrosis and 2 Advances in Urology (a) (b) Figure 1: Preparation of the dartos flap. These characteristics shortening the penis and optimal skin coverage that excludes make the urethral plate ideal for urethroplasty [5]. The development of the urethral plate is genetically the optimal age for correction of hypospadia is between influenced by cell differentiation, hormonal and enzymatic the 6th and the 24th month. Before the 7th topical application of dihydrotestosterone, it is possible to week of gestation, the structure of the genital is indifferent optimise the size of the penis at this early age of operation [2, 6]. In the majority of cases, the operation can be done elongation of the phallus, the formation of the penile in one step. A two-step approach is rarely necessary, for urethra, and the development of the prepuce [7]are example, in case of insufficiency of the urethral plate or influenced by the presence or absence of androgens and hypoplastic skin as often found in Re-Do Hypospadias [14]. More recent studies support Successful hypospadia surgery incorporates the following the theory of endodermal differentiation. According to this steps: straightening of the penis (orthoplasty), reconstruc- theory, the entire urethra stems from the urogenital sinus tion of the urethra (urethroplasty), the meatus (meato- [8]. The continual development of the urethral plate into plasty), the glans (glanuloplasty) and the skin of the penis the genital tubercle is followed by the ventral fusion of the as well as that of the scrotum whenever necessary. Thedevelopmentoftheprepucenotonly occurs simultaneous to the fusion of the urethral plate, this 2. In cases where the fusion of the urethral plate is altered, the prepuce on the ventral the fact that there are over 250 methods of surgical cor- aspect of the penis remains underdeveloped. The statement: There is nothing new in surgery gene defects are possible aetiological factors for hypospadia, not previously described [15] is especially true as far as that are only found in <5% of the patients [10, 11]. A possible explanation for this trend could be the increas- In the 19th century, Dieffenbach [16]triedtorecon- ing environmental pollution. In this context, it is known struct a neourethra through secondary epithelialisation by that human beings increasingly ingest substances with perforating the glans with a canula and therefore establishing estrogen, for example, as found in certain insecticides, a connection to the hypospadic urethra. Animal models demonstrated first used tubularised local flaps in the 19th century for that estrogens lead to an alteration or even complete hypospadia repair [17]. The meatal-based-flap-technique that is the basic idea behind aetiology of the majority of hypospadias though remains the Mathieu technique [18]. The idea of using a free flap for Surgical reconstruction is the only possible therapeutic urethroplasty is also not new. The primary objectives of the century, Nove-Josserand used skin grafts for the urethral reconstruction are to create a vertically slit orthotopic mea- reconstruction [19]. Ombredanne´ created Other important aspects for the reconstruction are to avoid the neourethra out of a round local submeatal flap and N. Horton and Devine introduced the so called Flip-Flap technique for the correction of distal hypospadias that is favoured by certain surgeons up to date [20]. At the same time, techniques that preferentially use vascularised island flaps were also further pursued. The best known of these is undoubtedly the urethroplasty using a transverse preputial island flap as popularised by Duckett in 1980 [21]. Although several trials were performed in the 20th century with free flaps, buccal mucosa is the only regularly used graft at the moment [22]. The mobilisation and elongation of the urethra is an interesting concept, which can in some cases be used to avoid urethroplasty. This idea too is not Figure 2: Incised and tubularised urethral plate with the ventrally new and was first described by Beck in 1889 [24]. Even though under different conditions, the same con- cepts are still applied up to date. The surgical results have been further improved by the use of modern sutures, loupe magnification, modern dressing material, better foley midline dorsal plication [2]. This technique is based on catheters, and better methods for the diagnostic and cor- studies on fetal phallus, which detected that there are no rection of penis curvature through artificial or medically nerves running in the neurovascular bundles in the midline induced erections. Urethroplasty during correction of more severe penile curvatures, a ventral the selection of the surgical technique for the reconstruction patch, in most cases out of preputial skin, can be used. In such cases, it is important to pay attention plate as well as that of the penile skin, the form of the glans, not to embed the penis in the scrotum or the mons pubis. This the major techniques of urethroplasty are described in is done with scrotal rotational flaps that are only mobilised detail under the subtitles proximal hypospadias and distal up to the subcutaneous layer in order not to compromise the hypospadias. The straightening of the penis as well as an optimal plas- tic reconstruction of the scrotum and penile skin demands 2. The penile curvature results from the dysplasia/hypoplasia on the ventral aspect of the penis. Distal hypospadias already be corrected by complete mobilisation of the penile skin. The majority of patients with this type of hypospadia If the curvature is still existent after such mobilisation, other can urinate with a straight urine stream and have not methods must be applied [25]. Nonetheless, most parents the presence of altered fibrotic tissue around the urethral wish for a normal penis for their child. This is, surgical reconstruction of distal hypospadias must meet therefore, a rather rare reason for penile curvatures. The psychosocial aspect it also easy to understand that a chordectomy alone rarely is another important factor to consider while making the leads to a straightening of the penis [2]. About 5% of the decision on performing the operative reconstruction in this patients have a so-called corporocavernosal disproportion, groupofpatients. In the recent With the use of the urethral plate for urethroplasty, the past, a number of authors seem to increasingly favour the complication rate has been clearly reduced. At the beginning, 4 Advances in Urology primary tubularisation, also known as the Thiersch-Duplay, grade of dysplasia. At the same time the penile curvature was performed in patients with wide urethral plates and deep increases, which makes it sometimes necessary to transect the fossa navicularis [28]. Its low complication rates, key to success, in this case, is the preservation of the urethral excellent cosmetic results and the simple surgical technique plate that builds the ventral portion of the neourethra. Most have made it very popular among hypospadia surgeons surgeons reconstruct the dorsal portion out of a pedicled [30]. The initial concerns and, subsequently, reports about inner preputial skin graft [2, 35, 36]. As the urethral plate, complications like proximal stenosis can long as there is no penile curvature, this technique is the be avoided. Furthermore, the fistula rate can be decreased method of choice for distal hypospadias [32]. This method down to 5–10% by using well-vascularised pedicled island is increasingly applied for the repair of penile hypospadias as grafts [36, 37]. Nonetheless, there are still complications mostly fistulas We generally prefer the use of the longitudinal preputial/ reported in [32]. In order to prevent fistulas, particularly penile island flap from the preputial and/or the dorsal penile healthy tissue from different areas is used to cover the skin.

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This is the same as finding the least squares regression of y on the r independent variables given by the columns of X medications online discount 500mg tranexamic otc. The minimum occurs when ′ ′ X Xb = X y, (the normal equations), or when ′ X (y − Xb) = 0. The latter says that the residuals (y − Xb) are orthogonal to X, or equiva- lently, to C(X). The observations are then decomposed into the sum of fitted values Y and residuals y − Y. If M is reparameterized to M = C(X⋆) where C(X) = C(X⋆), then Y remains the same, though the parameter estimates b may change. In particular, if we take Y0 to be zero, this tells us that we may decompose the (uncorrected) total sum of squares in y into a model sum of squares (Y −Y)′(Y −Y) and a residual sum of squares (y −Y)′(y −Y). If the vec- 0 0 tor 1 lies in M, then we may decompose the corrected total sum of squares in y into a model sum of squares around the overall mean (Y −y1)′(Y −y1) and a residual sum of squares (y − Y)′(y − Y). The degrees of freedom for a source or model is merely the dimension of the subspace. The sum of squares for a model (source) is the squared length of the part of y that A. If we have M1 = C(X1) and M2 = C(X2), then M1 ∩ M2 = M1 is equivalent to C(X1) ⊂ C(X2). Right angle Right triangle (y − Y2) ⊥ M2 (0, Y2, y) (y − Y1) ⊥ M1 (0, Y1, y) (Y2 − Y1) ⊥ M1 (0, Y1, Y2) Using these right triangles and the Pythagorean Theorem, we can make a variety of squared-length decompositions. We have r1 = 1, and r2 = g; thus the improvement in going from 570 Linear Models for Fixed Effects model 1 to model 2 is a g − 1 dimensional improvement. It arises when we want to compute the sum of squares for the improvement of model 2 (g group means) over model 1 (common mean). However, for matrix (d), the orthogonal complement of model 1 in model 2 is spanned by the last two columns of matrix (d). We can, of course, extend model comparison to a series of three (or more) nested models: M1 ⊂ M2 ⊂ M3. If V is the direct sum of U1 and U2, then v ∈ V may be written uniquely as v = u1 + u2, where u1 ∈ U1 and u2 ∈ U2. If V is the direct sum of U1 and U2 with v ∈ V written as v = u1 + u2 (u1 ∈ U1, u2 ∈ U2), then the projection of V onto U1 parallel to U2 is the linear map P : V → U1 given by P (v) = u1. If two subspaces are orthogonal (U1 ⊥ U2), we write their direct sum as U1⊕U2 to emphasize their orthogonality. If V = U1⊕U2, then the projection of V onto U1 is called an orthogonal projection. Suppose we have a space V = U1 ⊕ U2, with Pi being the orthogonal projection onto Ui. If M is a model and P is the orthogonal projection onto M, then the fitted values for fitting M to y are P y. Least-squares fitting of models to data is simply the use of the orthogonal projection onto the model subspace. When does the sum of squares for M12 equal the sum of squares for M1 plus the sum of squares for M2? By Pythagorean Theorem, 572 Linear Models for Fixed Effects the sum of squares for M12 is the sum of the sum of squares for M1 and ⊥ the sum of squares for M12 ∩ M1. This second model is M2 if and only if model 2 is orthogonal to model 1, so the sums of squares add up if and only if the two original models are orthogonal. Thus to get orthogonal subspaces, we must look at the orthogonal complement of the smaller subspace in the larger subspace. This is the improvement in going from the smaller subspace to the larger subspace. However, the model improvement going from constant mean to separate column means (M ∩ 1⊥) is orthogonal to the model improvement going from constant C mean to separate row means (M ∩ 1⊥). When we have two nonorthogonal models, we will get different sums of ⊥ ⊥ squares if we decompose M12 as M1 ⊕ M12 ∩ M1 or M2 ⊕ M12 ∩ M2. The first corresponds to fitting model 1, and then getting the improvement going to M12, and the second corresponds to fitting model 2, and then getting the improvement going to M12. These changing subspaces are why sequential sums of squares (Type I) depend on order. Thus the sum of squares for B will not equal the sum of squares for B after A unless B and A represent orthogonal subspaces. If y has the above distribution, then Cy (where C is a p by N matrix of constants) has a normal distribution with mean Cµ and variance matrix CΣ| C′. The fitted values Y have the distribution Y = P y ∼ N(P µ, σ2P P ′) = N(µ, σ2P) = N(Xβ, σ2P). The residuals have the distribution y − Y = (I − P)y ∼ N((I − P)µ, σ2(I − P)(I − P)′) = N(0, σ2(I − P)). These derivations give us the distributions of the fitted values and the residuals: they are both normal. To discover this, we use a little trick and look at two copies of y 574 Linear Models for Fixed Effects just stacked into a vector of length 2N, and we do separate projections on the two copies. Sums of squares are squared lengths, or quadratic forms, of normally distributed vectors. Let H (N by r) be an orthonormal basis for M; then H′ H is the r by r 1 1 1 ⊥ identity matrix. Let H2 (N by N − r) be an orthonormal basis for M ; then H′ H is the N − r by N − r identity matrix. This is, of course, σ2 times a chi-square distribution with N − r degrees of freedom. The noncentrality parameter µ′H H′ µ/σ2 also equals µ′µ/σ2, so the 1 1 expected model sum of squares is µ′µ + rσ2. We may test the null hypothe- sis H0 : µ = 0 against the alternative Ha : µ = 0 by taking the ratio of the model mean square to the error mean square; this ratio has an F-distribution under the null hypothesis and a noncentral F-distribution under the alterna- tive. The sum of squares for error is a multiple of chi-square with N − r2 degrees of freedom. The improvement sum of squares going from the smaller to the larger model is a multiple of a chi-square with r2 − r1 degrees of freedom if the null is true ((P2 − P1)µ = 0); otherwise it is a multiple of a noncentral chi-square. Note that estimability is defined in terms of a particular set of parameters, so estimability depends on the matrix X, not just the model space M. For h β′ to be estimable, we must have ′ ′ ′ ′ h β = E(t y) = t E(y) = t Xβ for all β, so that ′ h = X t. Thus h β′ is estimable if and only if h = X′t, or in other words, if h is a linear combination of the rows of X. Yes, it is unique because ′ ′ ′ h b = t Xb = t Y, so the estimable function only depends on the fitted value Y. Note that t′y has the same expectation as h′b, but we will see below that t′y can have a larger variance. If we directly attack h′b we get ′ ′ 2 ′ 2 ⋆′ ⋆ Var(h b) = Var(t Y) = σ t P t = σ t t. On the other hand, if we look at t′y, we find ′ 2 ′ 2 ⋆′ ⋆ ′ Var(t y) = σ t t = σ (t t + trtr). Consider a one-factor model with g treatments, parameterized by µ and αi, for i = 1, 2. An estimable h is of the form h = X′t, and with this X, X′t 1 2 g leads to 578 Linear Models for Fixed Effects X g hµ = nisi i=1 hα1 = n1s1 hα2 = n2s2. Two contrasts are orthogonal if their corresponding t vectors are orthog- onal: X n g g ⋆ ⋆ ⋆ ⋆ wiwi t ⊥ t ⇔ 0 = titi = nisisi =. All contrasts lie in M ∩ 1⊥, so we can have at most r − 1 mutually orthogonal contrasts in a collection. These contrasts form an orthogonal basis for M ∩ 1⊥, and of course there are many such bases. Alternatively, t y′ = h′b ∼ N(h′β, σ2t t′), so we may use t-style inference with the error mean square estimating σ2. The sum of squares for a contrast is the sum of squares for C(t), the model subspace spanned by the contrast. We can achieve this maximum by taking t = (Y − Y 1): (t′Y)2 ((Y − Y 1)′Y)2 ′ = t t (Y − Y 1)′(Y − Y 1) ((Y − Y 1)′(Y − Y 1))2 = (Y − Y 1)′(Y − Y 1) ′ = (Y − Y 1) (Y − Y 1). Under the null hypothesis of no treatment differences, this sum of squares is distributed as σ2 times a chi-square with g − 1 degrees of freedom.

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Male secondary sexual characteristics emerge after puberty: No monthly cycle (but evidence of seasonal fluctuations with lower levels of testosterone in spring) symptoms 9f diabetes purchase generic tranexamic pills, elongation of vocal cords (lower voice), broader shoulders and deeper chest cavity. Additional Male Characteristics: Generally taller and greater proportion of body weight composed of water. Proportionately larger heart and lungs, presumably to handle greater blood fluid volume. Exposure to greater levels of testosterone results in heavier body and facial hair, but also increased frequency and degree of baldness. Single X chromosome results in sex-linked conditions such as colorblindness and hemophilia. Male Circumcision Phallic Myths Sexual Arousal and Response How and Where is the Sexual Response Experienced? The answer to this question is one of the central reasons why this is a psychology course. To have a conscious experience of anything the associated sensations, no matter how stimulated, must reach the brain. In that sense human sexuality is very much like any of a number of other forms of sensation and perception. Sensory receptors located in the skin of the genitals become stimulated and messages are sent to the somatosensory cortex of the brain and to various pleasure centers in the limbic system. Other associated sensory inputs also come into play (various sights, sounds, smells, tastes, and tactile stimulation of other areas of the body) and are registered in other regions of the brain and cortex. This combination of activity is interpreted and perceived first as sensual in nature, and ultimately as sexual pleasure. The brain responds by sending signals to the various glands and other organs associated with sexual activity, directing further changes in blood flow and release of various secretions. This sexual response feedback cycle gains strength and spirals until orgasm (or some other event) completes the cycle and the resolution phase is initiated. Adrenal Glands - the adrenal glands of both sexes also produce lesser amounts of the various sex hormones. In the male only 5% of the total amount of androgens are produced by the adrenal glands, the rest being produced by the testes. Overall, an average male produces somewhere between 20 to 40 times as much testosterone as an average female. In both sexes, levels of testosterone are involved in the initiation of sexual motivation. Sensation and Sexual Arousal: Although all of the senses can influence and facilitate sexual arousal, tactile stimulation seems to play a primary role. Sexual Response Pattern: There are a number of differences between the female and male sexual response. Females do not necessarily reach orgasm during sexual intercourse or other sexual activity. Males almost always achieve orgasm during intercourse, and usually as a result of other sexual activities as well. This male refractory period is common to virtually all species for which there is data. And there is evidence that the ventral medial lemniscus, which lies along the neural pathway between the midbrain and the hypothalamus, may govern the male refractory period. Those problems may be transient or long-term, situation specific or global, physical or psychological, and may or may not be age related. There are treatments for virtually every sexual disorder, and failing that ways to adjust sexual activity to minimize the impact of the problem. This may stem from a greater interest or capacity for learning that extends to all aspects of life, including sexuality. Perhaps it is because educated people are more likely to try to understand and deal with problems. Those who are better informed have a higher awareness of the options available to them. The most common functional problem cited for women was lack of orgasm (24%), while for men it was premature orgasm (29%). Yes, there does seem to be a certain logical relationship here, but it has not been directly investigated. Other common problems for women include lack of subjective psychological and emotional feelings of arousal, overall lack of physical arousal, lack of vaginal lubrication, and pain during intercourse. However, inability to achieve orgasm affects roughly three times as many women as men. Problems hindering sexual functioning can be organic, cultural, individually based, or interpersonal in nature. Organic Factors Affecting Sexuality: Sexual difficulties often are linked to disturbances in vascular, endocrine, or neurological systems. Good communication between partners is essential for developing optional strategies. Obesity - Healthy diet, exercise, and normal weight are essential for optimal physical function, including sexual activity. One study found obese men were 90% more likely than average to develop erectile dysfunction. Men who regularly exercised a good deal were 30% less likely to develop erectile dysfunction (Bacon, et al. For men, bicycle seats can put pressure on the genitals and surrounding nerves affecting sensitivity and performance. For women excessive exercise resulting in below average weight can result in amenorrhea (disruption or absence of menstruation). It should also be noted that obesity is often linked to other conditions such as cardiovascular problems and adult onset diabetes, which also adversely affect sexual function. In addition, age can increase the likelihood, and exacerbate the effects, of any other conditions that may already be affecting sexual responses. Hypertension and Arteriosclerosis - Both adversely affect circulation and may result in male erectile dysfunction. These conditions may lead to strokes, which often decrease sexual interest, arousal, and activity particularly if there is a loss of mobility or coordination (Monga & Kerrigin, 1997). Diabetes is a leading cause of erectile problems in men due to nerve damage or circulatory problems (Hakim & Goldstein, 1996). Heavy or chronic alcohol abuse and poor blood sugar regulation increase the likelihood of these problems. Arthritis pain and associated fatigue, depression, or body image problems can reduce interest in sexual behavior (Nadler, 1997). Cancer and its treatment can disrupt many bodily functions, cause body image problems, and reduce sexual interest or response (Incrocci, 2006; Waldman & Eliasof, 1997). At least one half of multiple sclerosis patients have sexual problems (Stenager, et al. Those with cerebral palsy often have problems due to severe involuntary contractions of muscles that can interfere with the coordination of sexual activities. Spinal cord injury does not necessarily affect desire or psychological arousal, but it may impair erectile function and ability to experience orgasm (Alexander & Rosen, 2008). Medication and Drugs - Medications used to treat mental illness such as certain antidepressants, anti-psychotics, and minor tranquilizers (Valium and Xanax) have various effects on arousal and the sexual response. But the most common effect for both men and women is an inability to achieve orgasm. Six are now available, with fluoxetine (Prozac) and sertraline (Zoloft) being the most well known. By inhibiting the reuptake of serotonin, more of the neurotransmitter remains active. Recall that the role of serotonin in the sexual response pattern is to inhibit arousal, especially after orgasm. These drugs may work on that mechanism by increasing serotonin levels thereby inhibiting arousal or delaying orgasm. Anti-psychotics typically work by blocking the action of dopamine, which normally plays a key role in sexual arousal. Other medications such as anti-cancer medications, anti-hypertensives, gastro-intestinal medications, antihistamines, and methadone can all adversely affect sexual functioning. Recreational drugs, most notably alcohol, tobacco, marijuana, barbiturates, cocaine, and amphetamines can all affect sexual response. Generally, sedatives have greater effects on arousal, while stimulants have greater effects related to achieving orgasm.

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Chapter 5 Multiple Comparisons When we make several related tests or interval estimates at the same time symptoms 24 discount tranexamic 500mg with mastercard, we need to make multiple comparisons or do simultaneous inference. Each of the individual tests or confidence intervals has a Type I error rate Ei that can be controlled Multiple by the experimenter. If we consider the tests together as a family, then we can comparisons, also compute a combined Type I error rate for the family of tests or intervals. Multiple comparisons procedures deal with Type I error rates for families of tests. Suppose that regulations state that a mixture is safe if all of its constituents are safe (pretending we can ignore chemical interaction). Because we are testing at the 5% level, we expect 5% of the nulls to be rejected even when all the nulls are true. Thus, on average, 5 of the 100 chemicals will be declared to be carcinogenic, even when all are safe. Moreover, if the tests are independent, then one or more of the chemicals will be declared unsafe in 99. This vari- Determine error ety of combined Type I error rates is the source of much confusion in the use rate to control of multiple comparisons, as different error rates lead to different procedures. As data analyst, you need to decide which error rate is appropriate for your situation and then choose a method of analysis appropriate for that error rate. This choice of error rate is not so much a statistical decision as a scientific decision in the particular area under consideration. Data snooping Data snooping occurs when we first look over the data and then choose the null hypotheses performs many to be tested based on interesting features in the data. What we tend to implicit tests do is consider many potential features of the data and discard those with uninteresting or null behavior. When we data snoop and then perform a test, we tend to see the smallest p-value from the ill-defined family of tests that we considered when we were snooping; we have not really performed just one test. Simultaneous inference is deciding which error rate we wish to control, and then using a procedure that controls the desired error rate. We also have the combined, overall, or Individual and intersection null hypotheses H0 which is true if all of the H0i are true. The definitions of these error rates depend on numbers or fractions of falsely rejected null hypotheses H0i, which will never be known in practice. We set up the error rates here and later give procedures that can be shown mathematically to control the error rates. Controlling the per comparison error rate at E means that the expected frac- Comparisonwise tion of individual tests that reject H0i when H0 is true is E. This is just the error rate usual error rate for a t-test or F-test; it makes no correction for multiple com- parisons. The per experiment error rate or experimentwise error rate or familywise error rate is the probability of rejecting one or more of the H0i (and thus Experimentwise rejecting H0) in a series of tests when all of the H0i are true. Controlling error rate the experimentwise error rate at E means that the expected fraction of exper- iments in which we would reject one or more of the H0i when H0 is true is E. Controlling the experimentwise error rate at E necessarily controls the comparisonwise error rate at no more than E. The experimentwise error rate considers all individual null hypotheses that were rejected; if any one of them was correctly rejected, then there is no penalty for any false rejections that may have occurred. The false discovery fraction is 0 if there are no rejections; otherwise it is the number of false False discovery discoveries (Type I errors) divided by the total number of discoveries. The strong familywise error rate is the probability of making any false discoveries, that is, the probability that the false discovery fraction is greater than zero. Controlling the strong familywise error rate at E means that the Strong familywise probability of making any false rejections is E or less, regardless of how error rate many correct rejections are made. An error occurs when one of our confidence intervals fails to cover the true parameter value. If this true parameter value is also the null hypothesis value, Simultaneous then an error is a false rejection. The simultaneous confidence intervals cri- confidence terion states that all of our confidence intervals must cover their true param- intervals eters simultaneously with confidence 1 − E. Simultaneous 1 − E confidence intervals also control the strong familywise error rate at no more than E. Note that a single confidence interval in a collection of intervals with simultaneous coverage 1 − E will have coverage greater than 1 − E. As we go to more and more stringent Type I procedures are error rates, we become more confident in the rejections that we do make, but less powerful it also becomes more difficult to make rejections. Thus, when using the more stringent Type I error controls, we are more likely to fail to reject some null hypotheses that should be rejected than when using the less stringent rates. In simultaneous inference, controlling stronger error rates leads to less powerful tests. Any one image slice of the brain may contain 5000 voxels (individual locations to be studied), and one analysis method produces a t-test for each of the 5000 voxels. If we are studying a small, narrowly defined brain region and are uncon- cerned with other brain regions, then we would want to test individually the voxels in the brain regions of interest. The fact that there are 4999 other voxels is unimportant, so we would use a per comparison method. Suppose instead that we are interested in determining if there are any activations in the image. We recognize that by making many tests we are likely to find one that is significant, even when all nulls are true; we want to protect ourselves against that possibility, but otherwise need no stronger control. Suppose that we believe that there will be many activations, so that H0 is not true. This is acceptable because we are going to investigate several subjects; the truly activated re- jections should be rejections in most subjects, and the false rejections will be scattered. Finally, we might want to be able to estimate the amount of activation in every voxel, with simultaneous accuracy for all voxels. A multiple comparisons procedure is a method for controlling a Type I error rate other than the per comparison error rate. The literature on multiple comparisons is vast, and despite the length of this Chapter, we will only touch the highlights. I have seen quite a bit of nonsense regarding these methods, so I will try to set out rather carefully what the methods are doing. We begin with a discussion of Bonferroni-based methods for combining generic tests. Next we consider the Scheff´e proce- dure, which is useful for contrasts suggested by data (data snooping). Then we turn our attention to pairwise comparisons, for which there are dozens of methods. The Bonferroni procedure works for a fixed set of K null hypotheses to test or parameters to estimate. The Bonferroni procedure says to obtain simultaneous 1 − Ordinary E confidence intervals by constructing individual confidence intervals with Bonferroni coverage 1 − E/K, or reject H0i (and thus H0) if pi < E/K. The testing version controls the strong familywise error rate, and the confidence intervals are simultaneous. The tests and/or intervals need not be independent, of the same type, or re- lated in any way. The Holm procedure is a modification of Bonferroni that controls the strong familywise error rate, but does not produce simultaneous confidence Holm intervals (Holm 1979). Thus we start with the smallest p-value; if it is rejected we consider the next smallest, and so on. This is a little more complicated, but we gain some power since only the smallest p-value is compared to E/K. The table shows the characteristics grouped by type and p-values for testing the null hypothesis that there was no difference between the three cheeses in the various sensory characteristics. If we do choose an error rate other than the per comparison error rate, what is the appropriate family of tests? The answers de- pend on the goals of the study, the tolerance of the investigator to Type I error, how the results of the study will be used, whether the investigator views the three groups of characteristics as distinct, and so on. If we use the overall family, this is the tenth smallest p-value out of 21 p-values. If we use the flavor family, this is the fourth smallest p-value out of six p- values. Again, the choices of error rate and family of tests are not purely statistical, and controlling an error rate within a group of tests does not control that error rate for all tests.

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Please contact your Customer Service Representative if you have questions about fnding this option symptoms precede an illness purchase 500 mg tranexamic. The presence of residual disease Staging at a Glance Summary of anatomic stage/prognostic or positive margins may be more likely with more advanced grouping and major changes T or N category tumors. However, the absence or presence of from the 6th edition residual tumor and status of the margins may be recorded in Introduction Overview of factors affecting staging and outcome for the disease the medical record and cancer registry. Anatomic Primary tumor the absence or presence of residual tumor at the primary Considerations Regional lymph nodes tumor site after treatment is denoted by the symbol R. Each site chapter includes invasion, or lymph-vascular invasion (synonymous with a staging data form that may be used by providers and reg- lymphovascular ). If all time points are and the staging classification is defined in a separate chapter. The cancer staging form is a specific additional document Each chapter includes a discussion of information rel- in the patient records. It is not a substitute for documenta- evant to staging that cancer type, the data supporting the tion of history, physical examination, and staging evaluation, staging, and the specific rationale for changes in staging. Please contact your Customer Service Representative if you have questions about fnding this option. Job Name: - /381449t 2 Cancer Survival Analysis 2 Analysis of cancer survival data and related outcomes is neces- last known contact date), and this information is still valuable sary to assess cancer treatment programs and to monitor the in estimating survival rates. Similarly, it is usually not possible progress of regional and national cancer control programs. People may be lost to follow-up comes analyses requires an understanding of the correct appli- for many reasons: they may move, change names, or change cation of appropriate quantitative tools and the limitations physicians. Some of these individuals may have died and of the analyses imposed by the source of data, the degree to others could be still living. Thus, if a survival rate is to describe which the available data represent the population, and the qual- the outcomes for an entire group accurately, there must be ity and completeness of registry data. In this chapter the most some means to deal with the fact that different people in common survival analysis methodology is illustrated, basic the group are observed for different lengths of time and terminology is defined, and the essential elements of data col- that for others, their vital status is not known at the time of lection and reporting are described. In the language of survival analysis, subjects who are principles are applicable to both, the focus of this discussion observed until they reach the endpoint of interest (e. Discussion of statistical principles and methodology will Two basic survival procedures that enable one to deter- be limited. Persons interested in statistical underpinnings or mine overall group survival, taking into account both cen- research applications are referred to textbooks that explore sored and uncensored observations, are the life table method these topics at length. It is most useful when data are only avail- A survival rate is a statistical index that summarizes the prob- able in grouped categories as described in the next section. A survival curve is a summary display for each patient and is preferable when data are available in of the pattern of survival rates over time. For example, for a certain category of patient, one the specific method of computation, that is, life table might ask what proportion is likely to be alive at the end of a or Kaplan–Meier, used for a specific study should always be specified interval, such as 5 years. The greater the proportion clearly indicated in the report to avoid any confusion asso- surviving, the lower the risk for this category of patients. Rates com- Survival analysis, however, is somewhat more complicated puted by different methods are not directly comparable, and than it first might appear. If one were to measure the length of when the survival experiences of different patient groups are time between diagnosis and death or record the vital status when compared, the different rates must be computed by the same last observed for every patient in a selected patient group, one method. The In most real situations, not all members of the group are cases selected are a 1% random sample of the total num- observed for the same amount of time. Follow-up near the end of the study period are more likely to be alive of these patients continued through the end of 1999. Thus, at last contact and will have been followed for less time than for the earliest patients, there can be as many as 16 years of those diagnosed earlier. Even though it was not possible to follow-up, but for those diagnosed at the end of the study follow these persons as long as the others, their survival might period, there can be as little as 1 year of follow-up. Although we do are used both because they are realistic in terms of the actual not know the complete survival time for these individuals, we survival rates they yield and because they encompass a num- do know a minimum survival time (time from diagnosis to ber of cases that might be seen in a single large tumor registry Cancer Survival Analysis 15 In order to view this proof accurately, the Overprint Preview Option must be set to Always in Acrobat Professional or Adobe Reader. Please contact your Customer Service Representative if you have questions about fnding this option. They are intended only to illustrate the methodology and concepts of survival analy- sis. For each interval, the proportion surviving to the end of the interval is calculated on the basis of the number known to have experienced the endpoint event (e. Survival of 2,347 lung cancer patients from during the interval and the number estimated to have been at the Surveillance, Epidemiology, and End Results Program risk at the start of the interval. Thus, if the percent of the patients surviving the point at which half of the patients have experienced the the first interval is 90% and is the same for the second and endpoint event and half of the patients remain event-free. Two- In the case of breast cancer, the 10-year survival rate is thousand eight-hundred nineteen (2,819) patients diagnosed important because such a large proportion of patients live more between 1983 and 1998 were followed through 1999. The 10-year time frame for the life table calculation method for each year after diagnosis, lung cancer is less meaningful because such a large proportion the 1-year survival rate is 95. The 5-year cumulative survival of this patient group dies well before that much time passes. An important assumption of all actuarial survival the lung cancer data show a much different survival pat- methods is that censored cases do not differ from the entire tern (Figure 2. At 1 year following diagnosis, the survival collection of uncensored cases in any systematic manner that rate is only 41. For lung cancer patients the likely not to have died yet, tended to be detected with earlier- median survival time is 10. Median survival time is stage disease than the uncensored cases or if they were treated differently, the assumption about comparability of censored and uncensored cases would not be met, and the result for the group as a whole would be inaccurate. Thus, it is important, when patients are included in a life table analysis, that one be reasonably confident that differences in the amount of infor- mation available about survival are not related to differences that might affect survival. Survival of 2,819 breast cancer patients from the stepwise changes in the cumulative survival rate appear the Surveillance, Epidemiology, and End Results Program of to occur independently of the intervals on the Years Follow- the National Cancer Institute, 1983–1998. Please contact your Customer Service Representative if you have questions about fnding this option. For example, it would be misleading to compare the 2 overall survival depicted in Figure 2. The simplest approach to accounting for possible differences between groups is to provide survival results that are specific to the categories of patient, disease, or treatment that may affect results. Survival of 2,819 breast cancer patients from results should be subdivided is the stage of disease. Almost any variable can be used to subclassify survival rates, description of survival for a specific cancer should include but some are more meaningful than others. On the other hand, the race- cancer care the choice of treatment is often dependent on the specific and age-specific survival rates shown in Figures 2. Caucasians have the highest survival rates and African- confines of randomized clinical trials. Although the factors that affect survival may be unique to the survival rates depicted in the illustrations account for all each type of cancer, it has become conventional that a basic deaths, regardless of cause. Survival of 2,819 breast cancer patients from the Surveillance, Epidemiology, and End Results Program of the National Cancer Institute, 1983–1998. Survival of 2,819 breast cancer patients from life table method and stratified by historic stage of disease. Cancer Survival Analysis 17 In order to view this proof accurately, the Overprint Preview Option must be set to Always in Acrobat Professional or Adobe Reader. Please contact your Customer Service Representative if you have questions about fnding this option. Job Name: - /381449t interested in describing mortality attributable only to the information on cause of death is available, it is preferable to disease under investigation. This is particularly true when the calculated using the cause-adjusted survival rate, defined as series is small or when the patients are largely drawn from a the proportion of the initial patient group that escaped death particular socioeconomic segment of the population. This approach, however, is limited to factors into which patients may be the treatment of deaths from other causes as censored is con- broadly grouped. This approach does not lend itself to troversial, since statistical methods used in survival analysis studying the effects of measures that vary on an interval settings assume that censoring is independent of outcome. There are many examples of interval variables in can- this means that if the patient was followed longer, one could cer, such as age, number of positive nodes, cell counts, and eventually observe the outcome of interest.

Syndromes

• Floaters
• Tender or swollen lymph glands in the neck
• Wheat germ
• Fat malabsorption
• Take the drugs your surgeon told you to take with a small sip of water.
• Breathing in or swallowing small objects (young children)
• Quinine
• Stroke

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Speedy elimination of ureterolithiasis in lower part of ureters with the alpha 1-blocker-Tamsulosin permatex rust treatment buy generic tranexamic on-line. Relationship between prostate specific antigen density, microvessel density and prostatic volume in benign prostatic hyperplasia and advanced prostatic carcinoma. A comparison of fluid absorption during transurethral resection and transurethral vaporization for benign prostatic hyperplasia. Transurethral prostatic resection or laser therapy for men with acute urinary retention: the ClasP randomized trial. Anemia after kidney transplantation is not completely explained by reduced kidney function. Stromal and acinar components of the transition zone in normal and hyperplastic human prostate. Laser ablation of the prostate versus transurethral resection of the prostate in men with benign prostatic hyperplasia. The usefulness of prostate specific antigen density as a screening method for prostatic carcinoma. Change in urinary symptoms and quality of life in men with benign prostatic hyperplasia after transurethral resection of prostate. Reduction of length of hospital stay after transurethral resection of prostate by early catheter removal: a retrospective analysis. Long-term effects of angiotensin-converting enzyme inhibition and metabolic control in hypertensive type 2 diabetic patients. Rehabilitation outcomes following traumatic spinal cord injury in a tertiary spinal cord injury centre: a comparison with an international standard. Beneficial effect of intranasal desmopressin for men with benign prostatic hyperplasia and nocturia: preliminary results. Incidence and severity of vesicoureteral reflux in children related to age, gender, race and diagnosis. Safety and efficacy of transurethral resection of the prostate under sedoanalgesia. Evaluation of nuclear matrix protein-22 as a clinical diagnostic marker for bladder cancer. Correlation between serum prostate specific antigen and prostate volume in Taiwanese men with biopsy proven benign prostatic hyperplasia. Clinical study of benign prostatic disease, current concepts and future prospects: randomized controlled trials versus real life practice. Lower urinary tract symptoms suggestive of benign prostatic obstruction-Triumph: design and implementation. Pharmacological therapy of benign prostatic hyperplasia/lower urinary tract symptoms: an overview for the practising clinician. Randomized controlled trials for benign prostatic obstruction: problems and pitfalls. Differential diagnosis of prostate cancer and benign prostate hyperplasia using two- dimensional electrophoresis. Two-dimensional electrophoresis of prostate- specific antigen in sera of men with prostate cancer or benign prostate hyperplasia. Sleep apnea symptoms, nocturia, and diabetes in African-American community dwelling older adults. Comparison of once and twice daily dosage forms of Pygeum africanum extract in patients with benign prostatic hyperplasia: a randomized, double-blind study, with long- term open label extension. The role of the androgen receptor in the development of prostatic hyperplasia and prostate cancer. Successful voiding after trial without catheter is not synonymous with recovery of bladder function after colorectal surgery. Prenatal diagnosis of cystic bladder distension secondary to obstructive uropathy. Comparison of ofloxacin and norfloxacin concentration in prostatic tissues in patients undergoing transurethral resection of the prostate. The correlation between clinical outcome and residual prostatic weight ratio after transurethral resection of the prostate for benign prostatic hyperplasia. Hemolysis in transurethral resection of the prostate using distilled water as the irrigant. Lower urinary tract symptoms and uroflow in a community-based sample of Taiwanese men. Hepsin and maspin are inversely expressed in laser capture microdissectioned prostate cancer. Clinical investigation on the correlation between lower urinary tract infection and cystitis glandularis. Is surveillance necessary for inverted papilloma in the urinary bladder and urethra. Diagnosing symptomatic urinary tract infections in infants by catheter urine culture. Pediatric transperitoneal laparoscopic partial nephrectomy: comparison with an age-matched group undergoing open surgery. Endoscopic puncture of ureterocele as a minimally invasive and effective long-term procedure in children. The impact of polymorphism on prostate specific antigen gene on the risk, tumor volume and pathological stage of prostate cancer. Human kallikrein-2 gene polymorphism is associated with the occurrence of prostate cancer. Pilot study of transperineal injection of dehydrated ethanol in the treatment of prostatic obstruction. Results of holmium laser resection of the prostate for benign prostatic hyperplasia. Nephroureterectomy for transitional cell carcinoma - the value of pre-operative histology. Peripheral hypoechoic lesions of the prostate: evaluation with color and power Doppler ultrasound. Is the higher prevalence of benign prostatic hyperplasia related to lower urinary tract symptoms in Korean men due to a high transition zone index. Expression of senescence-associated beta-galactosidase in enlarged prostates from men with benign prostatic hyperplasia. Prostate carcinoma risk subsequent to diagnosis of benign prostatic hyperplasia: a population-based cohort study in Sweden. Superficial transitional cell carcinoma of the ureteral orifice: higher risk of developing subsequent upper urinary tract tumors. A comparison of sonourethrography and retrograde urethrography in evaluation of anterior urethral strictures. Expression of vascular endothelial growth factor in primary superficial bladder cancer. Initiation of nonselective alpha1-antagonist therapy and occurrence of hypotension-related adverse events among men with benign prostatic hyperplasia: a retrospective cohort study. Prostate tissue and leukocyte levels of n-3 polyunsaturated fatty acids in men with benign prostate hyperplasia or prostate cancer. Microsatellite alterations in urinary sediments from patients with cystitis and bladder cancer. Risk assessment of renal cortical scarring with urinary tract infection by clinical features and ultrasonography. Double-blind randomized comparison of single-dose ciprofloxacin versus intravenous cefazolin in patients undergoing outpatient endourologic surgery. Combination of ballistic lithotripsy and transurethral prostatectomy in bladder stones with benign prostatic hyperplasia: report of 120 cases. Toxicological effects of in utero and lactational exposure of rats to a mixture of environmental contaminants detected in Canadian Arctic human populations. Change in International Prostate Symptom Score after transurethral prostatectomy in Taiwanese men with benign prostate hyperplasia: use of these changes to predict the outcome. Botulinum toxin type A improves benign prostatic hyperplasia symptoms in patients with small prostates. Sustained beneficial effects of intraprostatic botulinum toxin type A on lower urinary tract symptoms and quality of life in men with benign prostatic hyperplasia. Intraprostatic injection of botulinum toxin type-A relieves bladder outlet obstruction in human and induces prostate apoptosis in dogs. Dual effects of ouabain on the regulation of proliferation and apoptosis in human prostatic smooth muscle cells.

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I implemented residual effects in the last example by including two single-degree-of-freedom terms called r1 and r2 medications ending in zine buy 500mg tranexamic free shipping. The regression coefficients for r1 and r2 are the residual effects of treatments 1 and 2; the residual effect of Implementing treatment 3 is found by the zero-sum constraint to be minus the sum of the residual effects first two residual effects. To implement residual effects for g treatments, we need g − 1 terms ri, for i running from 1 to g − 1. Their regression coefficients are the residual effects of the first g − 1 treatments, and the last residual effect is found by the zero-sum constraint. Begin the construction of term ri with a column 342 Complete Block Designs Residuals Versus the Fitted Values (response is lmilk) 2 1 0 -1 -2 -3 -4 6. Set to +1 those elements in ri corresponding to units that immediately follow treatment i, and set to –1 those elements in ri corresponding to units that immediately follow treatment g. In all these r terms, an observation has a –1 if it follows treatment g; in term ri, an observation has a +1 if it follows treatment i; all other entries in the r terms have zeroes. The r1 term would be (0, 1, 0, 0, 0, -1), and r2 term would be (0, 0, 1, 0, 1, -1). It is the temporal order in which subjects experience treatments that determines which treatments follow others, not the order in which the units are listed in some display. When resources permit an additional test period for each subject, consid- erable gain can be achieved by repeating the last treatment for each subject. Repeat last For example, if cow 13 received the treatments A, B, and C, then the treat- treatment ment in the fourth period should also be C. With this structure, every treat- ment follows every treatment (including itself) an equal number of times, and every residual effect occurs with every subject. These conditions permit more precise estimation of direct and residual treatment effects. The Latin Square design can be extended to control for three sources of extra- Graeco-Latin neous variability; this is the Graeco-Latin Square. For four or more sources Squares block of variability, we use Latin Hyper-Squares. Graeco-Latin Squares allow us to three ways test g treatments using g2 units blocked three different ways. Each entry in the table has one Treatments occur Latin letter and one Greek letter. Latin letters correspond to treatments, as in once in each a Latin Square, and Greek letters correspond to the third blocking factor. The blocking factor Latin letters occur once in each row and column (they form a Latin Square), and the Greek letters occur once in each row and column (they also form a Latin Square). Here is a four by four Graeco-Latin Square: A α B γ C δ D β B β A δ D γ C α C γ D α A β B δ D δ C β B α A γ Each treatment occurs once in each row block, once in each column block, and once in each Greek letter block. If two Latin Squares are superimposed and all g2 combinations of letters from the two squares once, the Latin Squares are called orthogonal. A Orthogonal Latin Graeco-Latin Square is the superposition of two orthogonal Latin Squares. For example, there are Graeco-Latin Squares for g of 3, 4, 5, 7, 8, 9, and 10, but not for g of 6. The usual model for a Graeco-Latin Square has terms for treatments and row, column, and Greek letter blocks and assumes that all these terms are Additive blocks additive. The balance built into these designs allows us to use our standard plus treatments methods for estimating effects and computing sums of squares, contrasts, and so on, just as for a Latin Square. For example, we may be able to block our units, but there may not be enough units in each block for each treatment. If units are very inexpensive, one possibility is to use only g units from each block. If there is some multiple of g units per block, say 2g or 3g, then we can randomly assign each treatment to two or three units in each block. This design, sometimes called a Generalized Randomized Complete Block, still has a simple structure and analysis. The standard model has treatments fixed, blocks random, and the treatment by blocks interaction as the denominator for treatments. A third possibility is that units are expensive, but the block sizes are not a nice multiple of the number of treatments. For example, with three treatments (A, B, and C) and three blocks of size 5, we could use (A, B, C, A, B) in block 1, (A, B, C, A, C) in block 2, and (A, B, C, B, C) in block 3. So each block has one full complement of the treatments, plus two more according to an incomplete block design. The final possibility that we mention is that we can have blocks with dif- ferent numbers of units; that is, some blocks have more units than others. Standard designs assume that all blocks have the same number of units, so we must do something special. The most promising approach is probably op- timal design via special design software. Optimal design allocates treatments to units in such a way as to optimize some criterion; for example, we may wish to minimize the average variance of the estimated treatment effects. The algorithms that do the optimization are complicated, but software exists that will do what is needed (though most statistical analy- sis packages do not). An experiment was conducted comparing four treatments: sodium chloride, calcium chloride, a proprietary organic compound, and sand. Traf- fic level was used as a blocking factor and a randomized complete block ex- periment was conducted. One observation is missing, because the spreader in that district was not operating properly. A B C D Block 1 32 27 36 Block 2 38 40 43 33 Block 3 40 63 14 27 Our interest is in the following comparisons: chemical versus physical (A,B,C versus D), inorganic versus organic (A,B versus C), and sodium ver- sus calcium (A versus B). A factorial experiment was conducted to determine which factors affect graininess. The factors were drying temperature (three levels), acidity (pH) of pulp (two levels), and sugar content (two levels). The exper- iment has two replications, with each replication using a different batch of pulp. D 44 B 26 C 67 A 77 B 51 D 62 A 71 C 49 C 39 A 45 D 71 B 74 C 63 A 74 D 67 B 47 B 52 D 49 A 81 C 88 A 74 C 75 B 60 D 58 A 73 C 58 B 76 D 100 D 82 B 79 C 74 A 68 Exercise 13. The six treatments are the factorial combinations of factor A at three levels and factor B at two levels. Give the sources and degrees of freedom for the Analysis of Variance of this design. A manufacturer compares four substrates: aluminum (A), nickel-plated aluminum (B), and two types of glass (C and D). It is felt that operator, machine, and day of production may have an effect on the drives, so these three effects were blocked. The design and responses (in microvolts ×10−2) are given in the following table (data from Nelson 1993, Greek letters indi- cate day): 13. Ruminant animals, such as sheep, may not be able to quickly utilize pro- Problem 13. Eventually the bacteria will die and the protein will be available for the ruminant, but we are interested in dietary changes that will help the protein get past the bacteria and to the intestine of the ruminant sooner. We can vary the cereal source (oats or hay) and the protein source (soy or fish meal) in the diets. There are twelve lambs available for the experiment, and we expect fairly large animal to animal differences. Each diet must be fed to a lamb for at least 1 week before the protein uptake measurement is made. The measurement technique is safe and benign, so we may use each lamb more than once. We do not expect any carryover (residual) effects from one diet to the next, but there may be effects due to the aging of the lambs.

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Graphics and visualization techniques are some of our best tools for un- Use models for f derstanding response surfaces symptoms intestinal blockage discount tranexamic 500 mg on-line. Unfortunately, response surfaces are difficult to visualize when there are three design variables, and become almost im- possible for more than three. On the other hand, experience has shown that simple models using low-order polynomial terms in the design variables are generally sufficient to describe sections of Polynomials are a response surface. In other words, we know that the polynomial models often adequate described below are almost surely incorrect, in the sense that the response models surface f is unlikely to be a true polynomial; but in a small region, polyno- mial models are usually a close enough approximation to the response surface that we can make useful inferences using polynomial models. A first-order model with q variables takes the form First-order model has linear terms yij = β0 + β1x1i + β2x2i + · · · + βqxqi + ǫij 512 Response Surface Designs X q = β0 + βkxki + ǫij k=1 ′ = β0 + xiβ + ǫij, where x = (x, x. These models are appropriate for describing portions of a response surface First-order that are separated from maxima, minima, ridge lines, and other strongly models describe curved regions. For example, the side slopes of a hill might be reason- flat, but tilted, ably approximated as inclined planes. These approximations are local, in surfaces the sense that you need different inclined planes to describe different parts of the mountain. First-order models can approximate f reasonably well as long as the region of approximation is not too big and f is not too curved in that region. A first-order model would be a reasonable approximation for the part of the surface in Figures 19. Bearing in mind that these models are only approximations to the true response, what can these models tell us about the surface? Suppose that we are at the design models show variables x, and we want to know in which direction to move to increase the direction of response the most. It turns out that steepest ascent we should take a step proportional to β, so that our new design variables are x + rβ, for some r > 0. If we want the direction of steepest descent, then we move to x − rβ, for some r > 0. Note that this direction of steepest ascent is only approximately correct, even in the region where we have fit the first-order model. As we move outside that region, the surface may change and a new direction may be needed. Contours or level curves are sets of design variables that have the same Contours are flat expected response. For a first-order surface, design points x and x + δ are P for first-order on the same contour if βkδk = 0. First-order model contours are straight models lines for q = 2, planes for q = 3, and so on. As described below, pure error and lack of fit are our tools for determining if the first-order model is an adequate Get parameters, approximation to the true mean structure of the data. And third, we need the pure error, and design to be efficient, both from a variance of estimation point of view and a LoF efficiently use of resources point of view. Data might not fit a model because of random error (the ǫij sort of error); this is pure error. Data also might not fit a model because the model is misspecified and does not Large lack of fit truly describe the mean structure; this is lack of fit. Our models are approx- implies model imations, so we need to know when the lack of fit becomes large relative to does not describe pure error. This is particularly true for first-order models, which we will then mean structure replace with second-order models. It is also true for second-order models, adequately though we are more likely to reduce our region of modeling rather than move to higher orders. We do not have lack of fit for factorial models when the full factorial model is fit. In that situation, we have fit a degree of freedom for every factor-level combination—in effect, a mean for each combination. We can get lack of fit when our models contain fewer degrees of freedom than the number of distinct design points used; in particular, first- and second-order models may not fit the data. Coding simply means that the design variables are rescaled so that 0 is in Coded variables the center of the design, and ±1 are reasonable steps up and down from the simply design center. For example, if cake baking time should be about 35 minutes, give or take a couple of minutes, we might rescale time by (x1 − 35)/2, so that 33 minutes is a –1, 35 minutes is a 0, and 37 minutes is a 1. The standard Two-series with first-order design is a 2q factorial with center points. The (coded) low and center points for high values for each variable are ±1; the center points are m observations first order taken with all variables at 0. First, the variation among the responses at the center point provides an estimate of pure error. Second, the contrast between the mean of the center points and the mean of the factorial Center points for points provides a test for lack of fit. When the data follow a first-order model, pure error and this contrast has expected value zero; when the data follow a second-order lack of fit model, this contrast has an expectation that depends on the pure quadratic terms. We begin with a first-order design in baking time and temperature, so we use a 22 factorial with three center points. Use the coded values –1, 0, 1 for 33, 35, and 37 minutes for time, and the coded values –1, 0, 1 for 340, 350, and 360 degrees for temper- ature. We will thus have three cakes baked at the package-recommended time and temperature (our center point), and four cakes with time and temperature spread around the center. Our response is an average palatability score, with higher values being desirable: x1 x2 y -1 -1 3. Some experimental situations can involve a sequence of designs and all these goals. In all cases, model fitting for response surfaces is done using multi- ple linear regression. The model variables (x1 through xq for the first-order Multiple model) are the independent or predictor variables of the regression. The regression to estimated regression coefficients are estimates of the model parameters βk. Let b be the vector of estimated coefficients for first-order terms (an estimate of β). Predictor variables are orthogonal to each other in many designs and models, but not in all cases, and certainly not when there is missing data; so it seems easiest just to treat all testing situations as if the model variables were nonorthogonal. To test the null hypothesis that the coefficients for a set of model terms are all zero, get the error sum of squares for the full model and the error sum of squares for the reduced model that does not contain the model terms being tested. The difference in these error sums of squares is the improve- Test terms of ment sum of squares for the model terms under test. The improvement mean interest adjusted square is the improvement sum of squares divided by its degrees of freedom for other terms in (the number of model terms in the multiple regression being tested). This model improvement mean square is divided by the error mean square from the full model to obtain an F-test of the null hypothesis. The F-test of βk = 0 (with one numerator degree of freedom) is equivalent to the t-test for βk that is printed by most regression software. In many response surface experiments, all variables are important, as there has been preliminary screening to find important variables prior to ex- Test to exclude ploring the surface. However, inclusion of noise variables into models can noise variables alter subsequent analysis. It is worth noting that variables can look inert in from model some parts of a response surface, and active in other parts. The direction of steepest ascent in a first-order model is proportional to the coefficients β. Inclusion of inert variables in the computation of this direction Direction of increases the error in the direction of the active variables. This effect is worst steepest ascent when the active variables have relatively small effects. Pure error is variation among responses that have the same explanatory Divide residual variables (and are in the same blocks, if there is blocking).

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One study assessed the impact of hydroxyurea on secondary stroke prevention by enrolling 67 35 children who needed to discontinue their chronic transfusion protocol medicine synonym effective 500mg tranexamic. The average dose of the drug was 27 mg/kg/day, and the children were treated for a mean of 42 months. In the Belgian Registry, during 426 patient-years of hydroxyurea treatment, the rate of central nervous system 37 events (stroke or transient ischemic attacks) was 1. One found no 64 difference in the 12 children in whom the number of pitted red blood cells was counted. A 56 cross-sectional study used Howell-Jolly bodies as the outcome: In the group of patients with spleens, patients on hydroxyurea therapy had a greater number of Howell-Jolly bodies than did those in the group not taking the drug. This relationship was true as well for the patients without spleens, suggesting that Howell-Jolly bodies are not simply a measure of splenic function. In a prospective study of 52 children, of whom 43 had had spleen function measured with scintigraphy both at baseline and on therapy, 6 patients (14 percent) completely recovered splenic function, and 2 (5 percent) had preserved splenic function after a median of 2. A retrospective 49 study reviewed the efficacy of hydroxyurea in reducing the progression of microalbuminuria : Of the 17 treated patients without microalbuminuria at baseline, 16 remained free from microalbuminuria; 4 of 9 patients with baseline microalbuminuria normalized their urinalysis during treatment. The study by Santos and coworkers was the only one to describe transfusion use in children, reporting that the transfusion rate decreased from 3. In the long-term followup study, which was observational after the initial period of randomization, the mortality rate was 40 percent lower (p=0. However, the long-term mortality, when analyzed according to the initial treatment assignment in the 2-year randomized trial, was similar for the hydroxyurea (3. The rates of stroke, sepsis, and renal and hepatic failure were also similar between the 43 two groups. Annualized total costs were $16,810 for the hydroxyurea group and $22,270 for the placebo group (p=0. The hydroxyurea and placebo groups were similar in terms of all the quality of life measures, but participants with the greatest increase in Hb F (upper half of the change in Hb F) had significantly better general health now (p<0. This improvement was accompanied by an increase in weight and decrease in the resting heart rate in the hydroxyurea group (3. In the six prospective, observational studies of adults that reported hematological outcomes, ∗ Hb F% increased significantly in all six studies (Table 2; Appendix C, Evidence Table 8). The smallest increase in Hb F% was seen in the study from Brazil, which reported outcomes by haplotype. This was a study of 22 patients; the greatest increase was among patients who had a homozygous Bantu haplotype (n=9 patients), from 4 80 percent to 9 percent (p=0. As in the pediatric studies, there was a small increase in hemoglobin in most studies. The retrospective study by Loukopoulos reported hematological 74 outcomes very comparable to those seen in the prospective studies. The frequency of crises experienced by the 32 patients who completed the study by Charache et al. In a study of Sicilians with Hb Sβ thalassemia and Hb Sβ thalassemia, the frequency of crises decreased from a mean of 7 (median of 9) per year to a mean of 1. In a non-randomized study comparing patients receiving hydroxyurea to those receiving cognitive behavioral therapy, those receiving the drug had fewer pain crises (1. In the study of Sicilians, the number of hospitalized days in a year declined from 22. For the group treated for fewer than 24 months, however, the investigators did not find a significant difference in hospitalization rates from baseline. In the study comparing hydroxyurea to cognitive behavioral therapy, the patients receiving the drug and those receiving behavioral therapy had similar hospitalization rates (1. Also, none of the patients had a stroke during the study, despite the fact that this was a sick population, with 9 of the 93 having a history of prior stroke and 19 having a history of acute chest syndrome. Many studies have explored predictors 73 of benefit from hydroxyurea (Table 3); one was designed specifically to address this question. Predictors of the fetal hemoglobin response to hydroxyurea were most frequently reported. A pediatric study also identified an 73 association with a higher baseline hemoglobin and greater response. Neither adult nor pediatric 40,46,73,75 studies found that Hb F% was predicted by age; ; the pediatric studies did not find that 73 75 gender, hematological toxicities, or haplotype predicted response. Men treated with the drug had greater absolute 41 increases in aerobic power (p<0. Two pediatric studies from Belgium did 44,58 not identify any predictors of clinical response; however, other observational studies did do so. Hospital admissions were significantly decreased in adults with at least 2 years of hydroxyurea treatment with no interruptions exceeding 2 weeks, when compared to those with a 52 shorter duration of therapy or interruptions. In children, an increasing dose of hydroxyurea was 62 associated with a decrease in cerebral blood flow velocity. As described above, studies were generally stratified by age (adult or pediatric); however, other subgroups were less thoroughly investigated. While the majority of patients studied were homozygous for Hb S, most of the studies had some patients with other genotypes. We identified eight studies that compared potential surrogate markers of disease severity or response in patients treated with or without 85-92 hydroxyurea. These studies were all cross-sectional or cohort studies with at least one ∗ comparison group (Appendix C, Evidence Tables 9-11). The studies enrolled patients from North America (5), Europe (2), or Central and Latin America (1). The description of the eligibility criteria was often quite limited, and the majority of studies were of moderate to poor quality. There was only limited information regarding patient characteristics and the starting dose, monitoring, and titration of hydroxyurea. Four studies included a report of hemoglobin and Hb F levels among groups and reported increases in total and fetal hemoglobin that were comparable to those of the other observational 86,87,90,92 studies in sickle cell disease after treatment with hydroxyurea. In three studies, treatment with hydroxyurea was associated with significantly increased levels of nitric oxide metabolites, 87,91 87 cyclic guanosine monophosphate, and nitric oxide synthase and with reduced levels of 86 arginase. Another study identified lower levels of endothelin-1, a potent vasoconstrictor, in children treated with hydroxyurea for more than 12 months, when compared to untreated 88 patients. These molecules may be biomarkers of abnormal vasoreactivity in sickle cell disease that may contribute to vaso-occlusive complications. Other potential biomarkers of vaso- occlusion were the significant decreases in rigidity and rates of elastic shear in patients with sickle cell disease who had been treated with hydroxyurea, when compared to those in untreated 85 sickle cell disease patients. However, these values were still significantly higher than those in controls without sickle cell disease. The higher percentage of oxyhemoglobin may reflect decreased adhesion and Table 4. The β-thalassemia genotype did not affect Hb F response; substantial increase in all groups. A final pediatric study demonstrated significant decreases in total bilirubin (most likely secondary to decreased hemolysis and release 90 of heme) after treatment with hydroxyurea. There was moderate evidence to support the claim that hydroxyurea reduces the frequency of pain crises, and a high grade of evidence to support the contention that treatment reduces the frequency and/or duration of hospitalization in children. There was only a low grade of evidence to support the claim that hydroxyurea reduces neurological events in children and insufficient evidence to allow any conclusions regarding transfusion frequency. There was also high-grade evidence that the drug reduces the frequency of pain crises and that it reduces the frequency and/or duration of hospitalization in adults. The evidence base was insufficient to allow us to comment on neurological events in adults (Table 5). Summary of the Evidence (continued) Outcomes Evidence Grade Basis for Grade Key Question 4-Barriers Negative provider attitudes are High More than one study, consistent finding barrier to use of pain medication Poor provider knowledge is a High More than one study, consistent finding barrier to use of pain medication Patient sex is not a barrier to use Moderate Few studies, but consistent of therapies Patient/family knowledge is a Low Few studies, and inconsistent barrier to use of therapies Number of hospital visits is a Low Few studies, and inconsistent barrier to use of therapies Patient age is a barrier to use of Low Few studies, and inconsistent therapies Key Question 4-Interventions Interventions do not improve Low Small studies, diverse outcome measures adherence to therapies for chronic disease management Interventions can overcome Moderate High quality studies, but few barriers to use of pain medications Interventions can overcome Moderate High quality studies, but few barriers to the receipt of routine, scheduled care. The 13-member expert panel discussed the data and finalized their opinions about the toxicity ofhydroxyurea, identified areas of knowledge gaps, and identified future research priorities. The panel concluded that hydroxyurea treatment of children aged 5 to15 years does not cause a growth delay. The panel felt that there were inadequate data regarding growth effects in infants and children younger than 5 years of age, as well as insufficient data to allow them to evaluate the effects of the drug on pubertal development. The expert panel also concluded that there were no data on the effects on subsequent generations following exposure of germ cells to hydroxyurea, including exposure during fetal life, infancy, childhood, and adolescence. The expert panel found sufficient data to conclude that there is developmental toxicity in rat and mice fetuses that are exposed to hydroxyurea in utero.

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This paper used both renal artery canine and auricular artery rabbit models over a period of three weeks symptoms flu order tranexamic online, with EmboGold microspheres (300–500 µm, Merit Medical Systems Inc. Authors and Year Test Material Time to Complete AcuteComplications Local and Systemic Embolization Device of Publication Study Model & Duration Information. Ease of Use Degradation of Test Recanalization (Vessel Foreign Body Effectiveness. None inflammatory reaction potentially effective 5 Beagles either 4-F or 5-F (sometimes intact but were recanalized at reported. Monitored immediate and weekly through catheter angiography Control material: EmboGold microspheres 300–500 µm J. The authors did not provide any commentary regarding the ease of use of either product, and no values for average volume delivered per injection were provided. This correlated, to a degree, with what was observed in their in vivo investigation; on angiography, embolized vessels were recanalized at three weeks. In line with this, the authors stated, the theoretical advantages of temporary embolization were not convincingly demonstrated in [their] model since temporary renal branch occlusions for the time periods investigated still led to tissue infarction [48]. It should be noted that a renal artery model is an end vessel model and may not be ideal for correlating infarction and degradation. The ideal degradation timeframe for embolic microspheres remains unclear and likely varies across different clinical indications. Due to the hypervascular nature of tumors/fibroids, these diseased tissues have been shown to preferentially attract blood flow and therefore microspheres, sparing neighboring healthy tissues. The risk of microsphere reflux was briefly mentioned in the methods of this paper as a potential complication to avoid; however, it was not discussed in detail, as unlike Kwak et al. The authors alluded to microsphere encapsulation in some tissue samples, but it appears this was not always the case. Preclinical Models Selecting an appropriate model for the preclinical evaluation of embolization products is critical for accurately assessing safety, efficacy, and performance prior to human use. As no animal model can truly represent the intended clinical conditions in their entirety, it is necessary to match the specific objectives under consideration to the best available model. Unfortunately, this proves to be a complicated process, as several variables are at play that can significantly alter outcomes and distort results – anatomy, vascular distribution, blood flow, and immune and coagulation responses are examples of such [51]. The following section is intended to outline the advantages and disadvantages of the models incorporated in the papers considered in this review. The kidney and uterus were the two main organs used to carry out the preclinical analyses reviewed in this paper. Embolization procedures are performed clinically in both of these organ structures (e. Both of these organs act as a filter, in which microspheres may be delivered, and entrapped, as the vascular diameters decrease from the renal/uterine artery down to end arterioles [53]. The uterus is perhaps less straightforward, in that the uterine artery often anastomoses with the contralateral uterine artery, ovarian artery, and/or vaginal artery [53]. In theory, these structures are suitable for evaluating the migration risk associated with degradation, as they allow the material to advance deeper into the vascular bed as it decreases in size, but remain entrapped within the organ. In the papers under review, the kidney and uterine models enabled, for the most part, effective evaluation of degradation, recanalization, and host response; however, commentary regarding migration was limited. Microsphere migration is perhaps the most difficult parameter to investigate, as vascular patterns and blood flow are so variable in different species, organs, and disease states [52]. None of the papers discussed in this review considered a diseased model, and thus the vascular distribution and blood flow dynamics limited the applicability of these results to clinical use for several reasons. Firstly, vascular tumors (including uterine fibroids) tend to show significant increases in blood flow relative to their non-diseased counterparts, and preferentially draw microspheres from the circulation to the tumor [54]. Secondly, the vasculature of tumors is generally more disorganized, potentiating migration of the material through poorly developed vessels beyond the tumor itself [54]. As degradable microspheres shrink and likely advance further downstream within the tumor vascular bed, the risk of this complication may be increased. The complicated nature of diseased tissue combined with the novelty of degradable microspheres questions the applicability of the healthy models used in the papers under review as preclinical evaluations prior to clinical use. Embolization is performed clinically for several different indications not covered by the models explored in this review, such as arteriovenous malformation and hepatocellular carcinoma [6]. It should be noted these indications have a unique set of inherent risks, perhaps the most concerning of which is bypass of the target tissue with shunting to vital organs. The vascular networks of these pathologies, and hypervascular tumors in general, is highly variable and poorly organized, potentially enabling passage of microspheres to the systemic circulation. Several groups report pulmonary emboli when particles <10 µm are utilized [57], and radioactive Y-90 microspheres are designed to limit pulmonary radiation below a given threshold, indicating migration beyond target tissue is an acceptable event associated with the use of these products. Although the kidney and uterine models discussed above are clinically relevant, they do not address this important issue and therefore the commentary made in relation to migration does not translate to all indications. More importantly, in reviewing this body of literature, it appears there is little consensus regarding the ideal characteristics of degradable microspheres. Specifically, ideal degradation timeframes, recanalization rates, and host responses (e. Furthermore, the degradability of these microspheres present new and complex risks that have not been previously considered, the most important of which may be migration. As degradable microspheres shrink in size, they may (i) potentially advance beyond the intended level of occlusion resulting in more profound ischemia and necrosis and/or, (ii) reflux into adjacent vessels, resulting in non-target embolization and/or (iii) through capillaries. In the future, degradable embolic materials may be engineered so as to permit repeat embolization procedures with radioactive embolic particles, drug-eluting particles, and bland embolic agents. Characterisation of physico-mechanical properties and degradation potential of calcium alginate beads for use in embolisation. A novel resorbable embolization microsphere for transient uterine artery occlusion: A comparative study with trisacryl-gelatin microspheres in the Sheep Model. In vitro degradation behaviour of non-porous ultra-fine poly(glycolic acid)/poly(l-lactic acid) fibres and porous ultra-fine poly(glycolic acid) fibres. Differential degradation rates in vivo and in vitro of biocompatible poly(lactic acid) and poly(glycolic acid) homo- and co-polymers for a polymeric drug-delivery microchip. A review of material degradation modelling for the analysis and design of bioabsorbable stents. Retrospective study of the impact of fellowship training on two quality and safety measures in uterine artery embolization. Temporary uterine artery occlusion for treatment of menorrhagia and uterine fibroids using an incisionless Doppler-guided transvaginal clamp: Case report. Targeting and recanalization after embolization with calibrated resorbable microspheres versus hand-cut gelatin sponge particles in a porcine kidney model. Bioresorbable Hydrogel Microspheres for Transcatheter Embolization: Preparation and in Vitro Evaluation. In vitro enzymatic degradation kinetics of polymeric blends of crosslinked starch and carboxymethyl cellulose. Synthesis and characterization of carboxymethylcellulose-methacrylate hydrogel cell scaffolds. Synthesis and in vitro characterizations of porous carboxymethyl cellulose-poly(ethylene oxide) hydrogel film. In vitro degradation of chitosan by bacterial enzymes from rat cecal and colonic contents. Quantitative determination of chitinolytic activity of lysozyme using half-deacetylated chitosan as a substrate. The controlling biodegradation of chitosan fibers by N-acetylation in vitro and in vivo. Calibrated bioresorbable microspheres: A preliminary study on the level of occlusion and arterial distribution in a rabbit kidney model. In vitro and in vivo evaluation of biodegradable embolic microspheres with tunable anticancer drug release. Calibrated bioresorbable microspheres as an embolic agent: An experimental study in a rabbit renal model. Chitin and chitosan based polyurethanes: A review of recent advances and prospective biomedical applications.