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Schematic diagram to illustrate the concept of equivalence GENERAL ISSUES 21 The analysis and interpretation can be quite fixed sample size approach might have been straightforward but the design and management curtailed earlier had a sequential design been of equivalence trials is often much more complex trusted 20mg levitra soft ved erectile dysfunction treatment. The study procedures and medication all tend to bias accumulating patient data from this trial crossed results towards no difference order 20 mg levitra soft with amex how erectile dysfunction pills work. Since we are trying an early termination boundary which inferred an to offer evidence of equivalence, poor study advantage to α-interferon. In general, patient-by-patient as the information on the trial therefore, the quality of equivalence trials should endpoint is observed from them. Potentially, the would only be concerned with whether or not the number of preferences could continue indefinitely lower limit of the confidence interval is greater between the upper solid and broken lines or than the non-inferiority margin (− ). SEQUENTIAL TRIALS In contrast to the open sequential design, There has been an implicit assumption in the the closed design of Figure 2. Thus this design has a finite stage and before recruitment commences to the size and a conclusion will always be drawn. This fixed sample size approach Again the solid lines indicate stopping boundaries essentially implies that the data collected during for declaring a statistically significant difference the conduct of the trial will only be examined between treatments and if the broken line is for efficacy once the trial has closed to patient crossed, concluding that no significant difference accrual. However, the vast majority of Phase III was found between the treatments. Neverthe- to decrease the final trial size if the data are less, if one of the factors, say the chemotherapy indicating an advantage to one of the treatments option in the example we discussed previously, and this can be firmly established at an early stage is stopped by crossing a boundary during the or to extend the trial size in other circumstances. Again, the subsequent 22 TEXTBOOK OF CLINICAL TRIALS 20 A significantly better than B 10 0 No significant difference −10 B significantly better than A −20 0 10 20 30 40 50 Number of preferences Open sequential design. The solid lines indicate stopping boundaries for declaring a statistically significant difference between treatments A and B. If the broken boundary is crossed, then the study stops, concluding that no significant difference was found between the treatments. Potentially the number of preferences could continue indefinitely between the upper solid and broken lines or between the lower solid and broken lines; in such a case no conclusion would ever be reached. Open sequential design patients recruited may then be somewhat dif- terms the use of sequential designs is still some- ferent from those at the first stage of the trial. They do not however appear randomised consent design combines aspects of to give an actual clinical example of their use. They were motivated by the difficulties range from difficulties of financing a trial of expressed by clinicians in obtaining consent from uncertain size, making sure the data is fully up- women who they wished to recruit to trials to-date as the trial progresses, to the more tech- with breast cancer. However, Those who were randomised to the standard Whitehead,31 see also Jennison and Turnbull,32 treatment (conventional dressing in Figure 2. On GENERAL ISSUES 23 20 A significantly better than B 10 0 No significant difference −10 B significantly better than A −20 0 10 20 30 40 Number of preferences Closed sequential design. The solid lines indicate stopping boundaries for declaring a statistically significant difference between treatments A and B. For example, if out of ten patients expressing a preference for one or other treatment, nine preferred treatment B and only one preferred A, then the study would stop, concluding that B is significantly better than A. If the broken boundary is crossed, then the study stops and the conclusion is drawn that no significant difference was found between the treatments. Closed sequential design the other hand, those who are randomised to Eligible patients the experimental treatment (MEBO dressing in Figure 2. An alternative is that those randomised to the standard treatment may also Yes No Yes No be asked if they accept that treatment; again, Treat with Treat with Treat with Treat with they are actually given their treatment of choice. Compare The properties of these designs have been 34 Source: After Altman et al. In consent in conjunction with randomisation 24 TEXTBOOK OF CLINICAL TRIALS any event, they have rarely been used in prac- may be of assistance in interpreting the results tice although they continue to be advocated. Despite some technical difficulties, it is Nevertheless, in the large antenatal care trial fairly certain that Bayesian methods will become described by Donner et al. RANDOMISATION AND ALLOCATION BAYESIAN METHODS TO TREATMENT The essence of Bayesian methodology in the con- text of the design of clinical trials is to incorpo- We have indicated above that randomisation of rate relevant information into the design process. In fact it is in data monitoring (as trial data accumulate) and the key element. The object of randomisation is to with the final analysis and interpretation of the help ensure that the final comparison of treatment (now complete) trial data. In theory the informa- options is as unbiased as possible, that is, that any tion available and which is pertinent to the trial in difference or lack of difference observed between question can be summarised into a prior distribu- treatments in efficacy is not due to the method by tion.

It has been don percussion purchase levitra soft 20mg without a prescription erectile dysfunction venous leak, even when the mechanical stimu- suggested that group Ib afferents curtail the electri- lus is delivered carefully only to the appropriate callyevokedEPSPandthattheHreflexcanbealtered muscle: sensitive muscle and cutaneous receptors by altering transmission across the Ib inhibitory throughout the limb quality levitra soft 20 mg impotence 17 year old male, even those in antagonists, may interneurone, a situation not equally applicable be excited and the extent of this will be dependent to the tendon jerk (Burke, Gandevia & McKeon, only on effective transmission of the mechanical 1984). There is now direct experimental support stimulus (Burke, Gandevia & McKeon, 1983; Ribot- for this suggestion (Marchand-Pauvert et al. Hreflex Conclusions On the other hand, a 1-ms current pulse will excite axons only once, producing a more synchronised The tendon jerk and the H reflex are both dependent afferent volley, but one that involves group Ib as on the monosynaptic excitation from homonymous well as group Ia afferents. In addition, the stimu- Ia afferents, but they differ in so many other respects latednerveusuallyinnervatesmanymuscles:e. Underlying principle In the cat, Matthews & Rushworth (1957a,b) demon- Presynaptic inhibition of Ia terminals strated that it is possible to block efferents This is more effective on the afferent volley of the H using local anaesthetic applied directly to the reflex than on that eliciting the tendon jerk (Morita nerve because they are smaller than efferents. Rushworth (1960) then showed that injections of Methodology 119 dilute procaine into the motor point reduced both Acceptable techniques spasticity and rigidity, an effect attributed, not unreasonably, to efferent blockade (however, Microneurography see below). Microelectrode Situation in human subjects The first definitive reports of microneurography were publishedbyVallbo&Hagbarth(1968)oncuta- The situation in human subjects is quite differ- neous afferents and Hagbarth & Vallbo (1968)on ent from the controlled experimental circumstances muscle afferents. The basic technique has not rather than smaller axons, and this will also be changed greatly since then, and adequate descrip- so when the injection is into the motor point. The ents and efferents and, theoretically at least, reflex traditional microelectrode is a monopolar tungsten depression could result from loss of small afferent electrode with a shaft diameter of ∼200 m, insu- inputs rather than loss of fusimotor function. Loss lated to the tip, with an optimal impedance in situ of of the tendon jerk but preservation of near-normal ∼100–150 k for single unit recordings and perhaps strength does not constitute an adequate control for ∼50 k for multi-unit recordings. Some authorities the integrity of motor axons because consider- preferconcentricneedleelectrodeswithorwithouta able denervation is required before the triceps surae bevelled tip, but the electrode has a wider shaft and, muscles become weak to clinical testing. Finally, inpractice,thereisprobablylittleadvantageoverthe microneurographic studies have shown that, in gen- traditional electrode. It is likely that greater involvement of effer- into an appropriate nerve fascicle. In most labora- ents occurs during the recovery from a complete tories this is facilitated by delivering weak electrical local anaesthetic block than during its induction, stimuli through the electrode to produce radiating but this remains to be proven. Pressure blocks seem cutaneousparaesthesiae(whentryingtohomeinon to produce a more reliable sequence of axon block, a fascicle innervating skin) or a twitch contraction of large before small, possibly because their temporal the innervated muscle (when focussing on a fasci- development can be controlled, at least in part, by cle innervating muscle). When in situ,itwas supported without rigid fixation at one end by its connecting lead and at the other by the skin and subcutaneous tissue. Its position was adjusted within the nerve until the tip penetrated the desired nerve fascicle. Minor adjustments were made to bring the desired neural activity into focus. Note that the microelectrode has a shaft diameter of ∼200 m and that the largest axons have a diameter of ∼20 m. The target muscle was identified by the responses to intraneural electrical stimulation and the responses to passive and active movements of the digits. The ending increased its discharge during extension and passive abduction (not shown) at the fourth metacarpophalangeal joint, the responses to stretch and shortening being essentially static. This is preferable to external fix- to differentiate muscle spindle afferents from Golgi ation because movement by the subject cannot be tendonorganafferentsincludetheclassicalresponse avoided,andexternalfixationthenleadstoelectrode to a twitch contraction of the receptor-bearing mus- dislodgement. Even so, the stability of the recording cle (unloading with spindles: Figs. The twitch contractions can be pro- duced by stimuli delivered through the recording Identification microelectrode, transiently switching off the record- If arecording is obtained from a single axon it is ing to do so (McKeon & Burke, 1980;Burke, Aniss & necessary to identify the axon as an afferent and Gandevia, 1987)orbyusing external stimuli to thentocharacteriseitsresponsetovariousstimuliin the nerve trunk (e. This can be times ambiguous, possibly because of the above- time-consuming,andoftenrecordingsfrompartially mentioned fascial interconnections between nearby or completely identified afferents are lost before motor units and the spindle (see Burke, Aniss & Methodology 121 Fig. Note that an early discharge occurs before torque starts to rise (associated with the volley, cf. In both (c ) and (d ) the movement of the ankle joint is shown in the lower trace, but for simplicity, the goniometer record for the primary ending has been omitted. In (d) the imposed movements for the two endings were very similar, but not quite identical in amplitude, so that occasionally the discharge of the primary ending appears slightly out of phase. Both primary and secondary 122 Muscle spindles and fusimotor drive (b) (a) (c) (d) (e) f ) Fig. The effects of isometric voluntary contractions on background discharge rate of a secondary ending in extensor digitorum longus. Recording with a microelectrode in the common peroneal nerve (CPN) from an EDL muscle spindle secondary ending.

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Net depolarization and dis- tribution of recurrent inhibition within a motor nucleus buy 20mg levitra soft mastercard erectile dysfunction in 20s. Variableamplificationofsynapticinputtocatspinal shaw cell responses and monosynaptic reflexes from motoneuronesbydendriticpersistentinwardcurrent buy generic levitra soft 20mg icd 9 code erectile dysfunction 2011. Recurrent inhibition of Key mechanisms for setting the input–output gain across firing motoneurones in man. Progress in Brain Research, 143, 77– Clinical Neurophysiology, 69, 179–85. Distribution of effective soleus to quadriceps motor neurons during movement in synapticcurrentsunderlyingrecurrentinhibitionincattri- man. Recurrent inhibi- inhibition from soleus to quadriceps motor neurones in tion of cat phrenic motoneurons. Recur-¨ muscle spindle afferents and recurrent axon collaterals to rentinhibitionofsoleus -motoneuronsduringasustained motoneurones of wrist and digit muscles: a comparison in submaximal plantar flexion. Further evidence for Ren- hyperpolarization following a motoneurone spike. Nature shaw inhibition in man: a combined electrophysiological (London), 195, 910–11. Involvement of spinal recurrent inhibition in spas- of motoneurones in patients with upper motor neuron ticity. Journal of Enhancement of recurrent inhibition by intravenous Physiology (London), 355, 587–603. Progress in Neuro- Journal of Neurology, Neurosurgery and Psychiatry, 53, biology, 57, 325–55. Depression of inhibition of motoneurones prior to and during ramp and Renshawrecurrentinhibitionbyactivationofcorticospinal ballistic movements. Monosynaptic Ia excitation and recurrent References 195 inhibition from quadriceps to ankle flexors and extensors inhibition preceding and accompanying voluntary move- in man. Influence of discharge of motoneurones reflexexcitabilityoftibialisanteriorandsoleus. Presence of homonymous responses and their IPSPs evoked by tibial nerve stimula- recurrent inhibition in motoneurones supplying differ- tion in human soleus motor neurones. Renshaw inhibition to motoneurones innervating ents in the soleus motoneurone inhibition during a tibialis proximalanddistalmusclesofthehumanupperandlower anteriorvoluntarycontractioninman. In Muscle Afferents and Spinal Control of Movement, Research, 27, 509–22. Journal for Renshaw cell–motoneuron decoupling during tonic of Physiology (London), 493, 603–11. Paralysis of shaw cells evoked by volleys in ipsilateral cutaneous and descending control of Renshaw cells in patients with high threshold muscle afferents and their relationship to mental retardation. Evidence for recur- rent inhibition from gastrocnemius muscle to soleus rent inhibition by motoneurones in human subjects. RenshawcellmediatedinhibitionofRenshaw supraspinal influences on Renshaw inhibition during cells: Patterns of excitation and inhibition from impulses motor activity in man. Electroencephalography and Clinical of Renshaw cells by impulses in peripheral afferent nerve Neurophysiology, 40, 279–87. Tonicinhibitoryinfluenceofa Influenceofpostureandvoluntarymovementonrecurrent supraspinalmonoaminergicsystemonrecurrentinhibition inhibition in human subjects. Experimental Brain Research, 59, organization of recurrent inhibition: changes in recurrent 249–56. In NewDevelopments in Elec- Recurrent inhibition is increased in patients with spinal tromyography and Clinical Neurophysiology,vol. Progress in Neurobiology, 49, of Neurology, Neurosurgery and Psychiatry, 34, 699–711. The exten- sive convergence described on Ia interneurones In a decerebrate preparation Sherrington (1897) provided the first example of integration in the demonstrated that the contraction of a muscle spinal cord. Using allel from the brain to produce a co-ordinated monosynapticreflextesting,Lloyd(1946)considered contraction of agonists and relaxation of antag- the reciprocal inhibition of the mechanical antag- onists (Lundberg, 1970). Later intracellular sion in spinal pathways during movement (Tanaka, recordings established that one interneurone is 1974).

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