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By L. Moff. State University of New York College Maritime College at Fort Schuyler. 2018.

Although potentially more efficient order premarin 0.625mg otc, of infertility are important prognostic factors for GYNAECOLOGY AND INFERTILITY 351 fertility generic premarin 0.625mg line. Occasionally we allocate a group of subjects The unpredictability of the randomisation pro- together rather than individuals to treatments order premarin 0.625mg online. For cess can only be successful if followed by example order premarin 0.625mg fast delivery, in a health promotion study carried allocation concealment, i. This may involve display of publicity tion of a random allocation sequence without material in the waiting room, for example. Aware- this situation, we may need to keep groups of ness of the next treatment allocation could lead patients separate in order to avoid contamination. For special physiotherapist to advise patients in a example, in a trial of unexplained infertility, ward, it would be difficult for the nurse to visit women with a prolonged duration of infertility some patients and not others. Adequate want the subjects receiving training to pass on concealment would ensure that the decision to what they have learned to controls. This might be accept or reject a participant should be made and desirable in general, but not in a trial. A group of informed consent obtained without prior knowl- subjects allocated to a treatment together is called edge of the nature of the assignment. Clusters must be taken into account Trials that use inadequate or unclear allocation in the design as the use of clusters reduces the concealment have tended to yield 40% larger esti- power of the trial and so requires an increase in mates of effect compared to those which used sample size. Trials with poorly A practical problem relating to randomisation concealed allocation also generated greater het- concerns the emotive nature of some of the con- erogeneity in results, i. There may also be compelling social rea- Double blinding seeks to prevent ascertainment sons why women undergoing termination are less bias, protects the sequence after allocation and likely to opt for randomisation, comply with trial cannot always be implemented. Infertile with allocation concealment, lack of blinding couples may be required to fund their treatment may lead to exaggerated estimate effects of treat- themselves. A survey of trials in gynaecology found refuse to participate in a trial where the experi- that investigators could have used double blind- mental arm (such as assisted hatching) is substan- ing more often. It is recommended that authors provide 352 TEXTBOOK OF CLINICAL TRIALS adequate information about the methods used treatment irrespective of randomised assignment to ensure double blinding. Secondary anal- details such as the type of intervention (cap- yses are acceptable, as long as researchers label sules/tablets), and efforts made to duplicate the them as such, and as non-randomised compar- characteristics of the treatment (taste, appear- isons. The advantage of randomisation is entirely ance, route of administration). In addition it is lost when investigators exclude participants and important to be explicit about the methods used in effect present a non-randomised comparison as to control the allocation schedule, such as loca- the primary result, i. Although this may seem sensi- perceived success or failure of the double blind- ble in as much as the event of interest occurred ing efforts. It is important to attempt to minimise exclu- Exclusions can occur due to eventual discov- sions and be explicit about those cases where ery about ineligibility, deviations from protocol, exclusions occurred. Exclusions minimising the delay between randomisation and before randomisation do not affect the internal initiation of treatment. This can be particularly validity of the trial but can compromise general- relevant to infertility trials where couples could isability. For most pragmatic trials it is important fall pregnant before treatment can start or where to keep the eligibility criteria to a minimum. In the intervention is conditional on a set of clini- practice it is unusual to find significant qualitative cal criteria. For example, in couples randomised differences between women in trials and those to IVF or ICSI it may be more efficient to in the general population. Exclusions after trial delay randomisation until after oocyte recovery entry represent a further source of bias within so that women who have failed to respond to an RCT as any erosion over the course of the gonadotrophin stimulation are not included. For example in a trial comparing hysterec- the traditional method was to express outcomes tomy versus endometrial ablation many clinicians as pregnancy rates per cycle. This meant the would find it difficult to accept results of anal- duration of follow-up was brief.

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Increased peripheral vascular resistance Increased intravascular fluid volume Most of the available drugs are approved for use in hyper- Increased blood pressure tension discount premarin 0.625mg fast delivery. Nifedipine discount premarin 0.625 mg fast delivery, a short-acting calcium channel blocker discount 0.625mg premarin otc, has been used to treat hypertensive emergencies or urgencies buy generic premarin 0.625mg online, often by puncturing the capsule and squeezing the contents under the Figure 55–1 Angiotensin-converting (ACE) enzyme inhibitors in- tongue or having the client bite and swallow the capsule. Such hibit angiotensin-converting enzyme and thereby prevent formation of angiotensin II; angiotensin II receptor blockers (ARBs) prevent an- use is no longer recommended, because this practice is associ- giotensin II from connecting with its receptors and thereby prevent it ated with an increased risk of adverse cardiovascular events from acting on body tissues containing those receptors (eg, blood precipitated by rapid and severe decrease in blood pressure. As a group, the calcium channel blockers are well absorbed from the gastrointestinal tract following oral administration and are highly bound to protein. SNS stimulation produces widespread effects in the body, the effects relevant to this discussion are the increases in heart rate, force of myocardial contraction, cardiac output, Diuretics and blood pressure that occur. When the nerve impulse is in- hibited or blocked at any location along its pathway, the re- Antihypertensive effects of diuretics are usually attributed to sult is decreased blood pressure (see Chap. In fact, diuretics usually produce Alpha1-adrenergic receptor blocking agents (eg, prazosin) the same effects as severe dietary sodium restriction. In many dilate blood vessels and decrease peripheral vascular resis- cases of hypertension, diuretic therapy alone may lower blood tance. One adverse effect, called the first-dose phenomenon, cardiac output decrease. With long-term administration of a results in orthostatic hypotension with palpitations, dizziness, diuretic, cardiac output returns to normal, but there is a per- and perhaps syncope 1 to 3 hours after the first dose or an in- sistent decrease in peripheral vascular resistance. To prevent this effect, first doses and first in- been attributed to a persistent small reduction in extracellular creased doses are taken at bedtime. Another effect, associated water and plasma volume, decreased receptor sensitivity to with long-term use or higher doses, leads to sodium and fluid vasopressor substances such as angiotensin, direct arteriolar retention and a need for concurrent diuretic therapy. Cen- vasodilation, and arteriolar vasodilation secondary to elec- trally acting sympatholytics (eg, clonidine) stimulate pre- trolyte depletion in the vessel wall. When these drugs are taken, less to a diuretic alone, the diuretic may be continued and another norepinephrine is released and sympathetic outflow from the antihypertensive drug added, or monotherapy with a differ- vasomotor center is reduced. Stimulation of presynaptic ent type of antihypertensive drug may be tried. Reduced sympathetic activity commonly used in the management of hypertension. Loop CHAPTER 55 ANTIHYPERTENSIVE DRUGS 803 diuretics (eg, furosemide) or potassium-sparing diuretics • Oral contraceptives, corticosteroids, appetite sup- (eg, spironolactone) may be useful in some circumstances; pressants, nasal decongestants, non-steroidal anti- see Chapter 56 for discussion of diuretic drugs. Vasodilators (Direct Acting) • Check blood pressure accurately and repeatedly. As a rule, multiple measurements in which systolic pressure Vasodilator antihypertensive drugs directly relax smooth is above 140 mm Hg and/or diastolic pressure is above muscle in blood vessels, resulting in dilation and decreased peripheral vascular resistance. They also reduce afterload and 90 mm Hg, are necessary to establish a diagnosis of may be used in management of heart failure. These drugs have a limited effect surements cannot be overemphasized because there on hypertension when used alone because the vasodilating are many possibilities for errors. Some ways to im- action that lowers blood pressure also stimulates the SNS and prove accuracy and validity include using correct triggers reflexive compensatory mechanisms (vasoconstric- equipment (eg, proper cuff size), having the client tion, tachycardia, and increased cardiac output), which raise rested and in the same position each time blood pres- blood pressure. This effect can be prevented during long-term sure is measured (eg, sitting or supine with arm at therapy by also giving a drug that prevents excessive sym- heart level), and using the same arm for repeated mea- pathetic stimulation (eg, propranolol, an adrenergic blocker). These drugs also cause sodium and water retention, which • In most cases of early hypertension, elevated blood may be minimized by concomitant diuretic therapy. If symptoms do occur, they are usually nonspecific (eg, headache, weakness, fatigue, tachycardia, dizziness, palpitations, INDIVIDUAL DRUGS epistaxis). Antiadrenergic drugs are discussed in Chapter 19 and pectoris, myocardial infarction, or heart failure. Antihypertensive agents are pain, tachycardia, dyspnea, fatigue, and edema may shown in the Drugs at a Glance: Antihypertensive Drugs; occur. Brain damage may be indicated by transient antihypertensive-diuretic combination products are listed ischemic attacks or strokes of varying severity with in Drugs at a Glance: Oral Antihypertensive Combination symptoms ranging from syncope to hemiparesis. Ophthalmoscopic examination may reveal hem- orrhages, sclerosis of arterioles, and inflammation of Nursing Process the optic nerve (papilledema). Because arterioles can be visualized in the retina of the eye, damage to retinal Assessment vessels may indicate damage to arterioles in the heart, brain, and kidneys.

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During initialization of the chip purchase premarin 0.625mg without prescription, the initial state potentials are loaded to the state capacitors generic 0.625 mg premarin with amex. These analog values are refreshed regularly by o¤-chip cir- cuitry and can be changed by controlling software buy premarin 0.625mg cheap. Bias voltages to set the multi- pliers and variable resistors in the correct operational modes also are required purchase 0.625mg premarin otc. Depending on the complexity of the multiplier design, the resistance can vary from 300 W to 300 kW. If the state potential is larger than the threshold when an input pulse arrives, an output pulse is generated. Testing of fabricated chips shows a reproducibility of experimentally determined input-output behavior of hip- pocampal neurons with a mean-square error of less than 3%. Design of a High-Density Hippocampal Neuron Network Processor Although it is not yet known how many silicon neurons will be needed for an e¤ec- tive prosthesis, the number is likely to be in the hundreds or thousands. This de- mands a capability to scale up the type of fundamental design described here. To accomplish this goal, we have utilized concepts of neuron sharing and asynchronized processing to complete the design of a high-density neuroprocessor array consist- ing of 128 Â 128 second-order nonlinear processing elements on a single microchip (Tsai et al. Each single processor is composed of four data bu¤ers, four indium bump flip-chip bonding pads (see later discussion), and one shared-neuron model with second-order nonlinear properties (figure 12. The processing procedure is as follows: (1) The input data are held in an input memory as the data arrive. A Neural Prosthesis for Hippocampal Memory Function 261 of the input data is sent to the processor array, with each neuron processing four buf- fered data, one at a time. This design not only provides programmable kernel parameters, but also incor- porates indium bumps (four per processor) for flip-chip bonding to a second connec- tivity matrix chip. With the additional technology for flip-chip bonding, the combined multichip module (not yet fabricated) will function much like a multilayer cellular neural network (CNN) structure (Chua and Yang, 1988). VLSI Implementation of a Dynamic Synapse Neural Network The VLSI implementation of a limited-capacity dynamic synapse neural network has been designed and fabricated using Taiwan Semiconductor Manufacturing Company (TSMC) 0. The dy- namic synapse neural network chip includes six input neurons, two output neurons, one inhibitory neuron, eighteen dynamic synapses, and twenty-four input-output (I/O) pads. Each synapse consists of seven di¤erential processing blocks, two hys- teresis comparators, one and gate, two transmission gates, and biasing circuitry. As described in the previous section, the functional properties of each synapse are deter- mined by four dynamic processes, each having di¤erent time courses. Three of the processes are excitatory and one is inhibitory; two of the processes represent di¤erent second-order nonlinearities. The resistor-capacitor exponential decay circuit for the dynamic processes is im- plemented using poly (poly1/poly2) capacitance and N-type metal-oxide semicon- ductor (NMOS) active registers to save chip area. The voltage-controlled active NMOS channel resistance and current source are used to achieve the programmabil- ity of parameter values of the dynamic synaptic neural network by controlling biases. Each di¤erential equation-processing block is implemented with fully program- mable voltage-controlled active resistors, poly capacitors, and a current source. Each di¤erential processing circuit consists of two metal-oxide semiconductor field- e¤ect transistors (MOSFETs) for active resistors, one poly capacitor, three control MOSFETs, two transmission gates, and one inverter. A novel, e‰cient low-power analog summation circuit was developed without using operational amplifiers, which require significant silicon area and more power consumption. The capacity of this prototype dynamic synapse microchip is limited (because of the small number of output neurons), and not yet fully determined because the upper capacity depends in large part on the decoding scheme used to distinguish di¤erent 262 Theodore W. Berger and colleagues A Neural Prosthesis for Hippocampal Memory Function 263 temporal patterns, an issue that is still under investigation. Nonetheless, the success- ful implementation of this neural network model demonstrates that biologically real- istic nonlinear dynamics that perform a high-level pattern recognition function can be realized in hardware. We are currently working on an expanded design that will provide for 400 dynamic synapses and on-chip implementation of the dynamic learn- ing rule used to optimize feature extraction by the network.

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