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The mechanisms associated with these conditions are multiple and include gastrointestinal abnormalities, decreased appetite, effects of concomitant medication use, and role of inflammation. As protein and calorie intake decline, markers of nutrition health indicate worsening nutritional status. Low serum bicarbonate is an indicator of acidemia and associated with protein degrada tion. Assessment of body composition, especially with serial measurements can pro vide valuable information concerning long term adequacy of protein energy nutrition. The design of most studies measuring nutrition markers in chronic kidney disease is based on data derived from cross-sectional studies. In addition, there is a lack of uniform collective evaluation of the multiple markers of nutritional status in patients with chronic kidney disease. Individual decision making is recommended after discussion of risks and benefits. Studies show that the most effective nutrition interventions in pa tients with chronic kidney disease involve patient training in self management skills and frequent, ongoing feedback, and interventions with the nutrition team. Importantly, studies to define the optimal methods to evaluate nutritional status in chronic kidney disease patients are critical. Association 163 Irrespective of the cause, bone disease can lead to pain and an increased incidence of fractures. Abnormal calcium-phosphorus metabolism and hyperparathyroidism can also lead to calcification of blood vessels and potentially an increased risk of cardiovascu lar events. In osteomalacia there is an accumulation of unmineralized bone matrix, or increased osteoid volume, which may be caused by vitamin D deficiency or excess aluminum. Markers of Bone Disease and Abnormal Calcium-Phosphorus Metabolism in Chronic Kidney Disease Bone biopsy following double-tetracycline labeling is the gold standard for the diagnosis of bone disease in chronic kidney disease and is the only means of definitively differentiat ing them. Five bone lesions associated with chronic kidney disease have been classified based on bone formation rate, osteoid area, and fibrosis on bone biopsy of patients with kidney failure372,382 (Table 92). However, levels of many of these markers are affected by age, diet, liver function, and kidney function; thus, interpretation of levels is difficult. Strength of Evidence Bone disease and disorders of calcium and phosphorus metabolism develop during the course of chronic kidney disease (R). Calciphylaxis results in skin lesions that may become infected or gangrenous, leading to significant morbidity and mortality among patients on dialysis. The remaining studies (13/20) showed that serum calcium levels were lower with lower levels of kidney function. The studies showing conflicting results are of similar methodological quality and sample size. There were 21studies relating serum phosphorus levels to kidney function reviewed for this guideline. Fifteen studies showed the expected association of higher serum phosphorus levels with lower kidney function. The remaining 6 studies did not show an association of kidney function with serum phosphorus levels, although one did find a trend for increasing phosphorus levels when creatinine clearance was below 50 mL/min. There were 14 studies relating vitamin D3 (calcitriol) levels to kidney function reviewed for this guideline, with sample sizes ranging from 39 to over 200 subjects with kidney disease. Thirteen of the 14 studies evaluated 1,25 dihydroxyvitamin D levels, three of these also evaluated 24,25 dihydroxyvitamin D (2 studies) and/or 25 hydroxyvitamin D levels (3 studies), and one study evaluated only 25 hydroxyvitamin D levels. These data confirm that 1,25 dihydroxyvitamin D levels are lower in patients with decreased kidney function. The levels of kidney function ranged from nearly normal (creatinine clearance of 117 mL/min) to the initiation of dialysis. Among patients with kidney failure immediately prior to initiation of dialysis, 98% to 100% had abnormal bone histology, with the majority of the biopsies showing either 176 Part 6. The studies evaluating patients with varying levels of kidney function demonstrated: (1) a direct relationship between bone mineralization and kidney function415,421; (2) an inverse relationship be tween kidney function and bone osteoid/resorption415; or (3) a higher prevalence of abnormalities on bone biopsy (osteomalacia, resorption, osteoid) among patients with reduced kidney function. There were 4 studies of bone densitometry reviewed for this topic, which demon strated that bone mineralization is reduced with decreased kidney function. This is in part due to the lack of comparability of many of the studies given the diversity of the laboratory assays or tests for the particular abnormality. Similarly, the interpretation of bone biopsies and radiographic tests likely has a range of error, in this case related to inter-observer variability. This leads to the extrapolation of the results from other studies to such patients with variable levels of confidence for the various markers. The applications suggested above are based on review of the available literature pre sented herein and on opinion. Moreover, research on outcomes related to abnormal mineral metabolism or bone disease is lacking in both patients with mildly, as well as severely decreased kidney function. Research should also focus on the impact of interventions on levels of available mark ers and outcomes, specifically of interest would be comparing patients cared for by nephrologists with those not under the care of nephrologists, patients treated for some specified period of time for hyperparathyroidism compared to those not treated, and patients treated with corticosteroids compared to those never treated with such drugs. However, there are certain causes of chronic kidney disease that also affect the central and/or peripheral nervous system. With more advanced uremia delirium, visual hallucinations, disorientation, convul sions, and coma may develop. Neu ropathy is present in up to 65% of patients at the initiation of dialysis438,439; thus, it must begin to develop during an earlier phase of kidney disease. No articles were found that specifically related the presence of neuropathy to other outcomes among patients with chronic kidney disease. However, it is self-evident that impaired cognition and sleep, dysesthesias, and impaired autonomic function would at least lead to reduced quality of life and inability to function normally. If the neuropathy leads to skin ulcers, then certainly this would result in objective morbidity and potentially mortality. The studies had sample sizes ranging from 40 to 210 subjects, with 29 to 72 patients with decreased kidney function not yet on dialysis. Only one study was found that evaluated memory and cognition among pa tients with decreased kidney function prior to the availability of erythropoietin. Each of these test measures was significantly lower among patients with decreased kidney function, correlated with level of dysfunction, and was improved to varying degrees among patients on dialysis and to a greater degree among patients with a kidney trans plant. Only three studies were found that objectively evaluated autonomic function among patients with kidney disease. Each of these studies noted that autonomic function was impaired in more than 50% of patients with chronic kidney disease; however, only one of them found an association between level of kidney function and measures of autonomic nerve function. More articles than were reviewed were found with the literature search, but were not exhaustively reviewed as preliminary review suggested the lack of or inabil ity to extract the necessary information. This may have led to the omission of some articles that may have provided further information. More information on neuropathy among patients with chronic kidney disease with earlier stages of chronic kidney disease may provide other means to follow progression of chronic kidney disease. Association 185 kidney disease and a relationship to kidney function, treatments to delay its progression could be considered. In addition, the relationship between neuropathy and kidney function should be separately studied among patients with additional risks of neuropathy, such as diabetics and patients with amyloidosis. To improve functioning and well-being, patients must be referred sooner and complica tions and comorbid conditions must be managed appropriately. Armed with this knowledge, clinicians can more quickly identify stages of chronic kidney disease at which deficits are likely to 186 Part 6. Difficulties in measuring this poorly understood concept have led researchers in the articles reviewed to study several variables using different methods and instruments (Table 102). Use of different instruments has impeded comparing findings, interpreting results, and drawing conclusions. Strength of Evidence Indices of functioning and well-being are impaired in chronic kidney disease (R).

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In both cases, repeat ascertainment Kidney damage refers to a broad range of abnormalities of kidney function and kidney damage is recommended for observed during clinical assessment, which may be insensitive accurate diagnosis. The timing of the evaluation depends on and non-specic for the cause of disease but may precede clinical judgment, with earlier evaluation for the patients reduction in kidney function (Table 2). The causal mechanisms underlying these inferred from markers rather than direct examination of associations are not fully understood. Proteinuria is a general term for the presence by the kidney and an increased risk of drug-interactions are of increased amounts of protein in the urine. Reprinted from the Lancet, vol in general population cohorts: a collaborative meta-analysis, p. Often the diseases are genetic without underlying mality persists for greater than 3 months (note that this does pathologic abnormalities. Other diseases are acquired, due to not include simple cysts and clinical context is required drugs or toxins, and are usually with prominent tubular for action). Furthermore, as with any causal pathway between kidney disease and adverse outcomes diagnostic tests, ndings must be interpreted with considera is well-known. In addition, renal biopsy in patient specic factors these patients may reveal renal parenchymal lesions. K the criteria for duration 43 months does not apply to newborns or infants r3 months of age. It can be used to inform the need for specialist preterm) or infant being derived from urinary collections and referral, general medical management, and indications for creatinine clearance (CrCl) measurements, whereas the older investigation and therapeutic interventions. Such values may be found in a excretion in a well-described cohort of children with renal number of pediatric nephrology texts. Albuminuria is included as an additional expression of severity In primary kidney disease the process arises and is conned of disease not only because it is a marker of the severity of to the kidney whereas in systemic diseases the kidney injury but also because albuminuria itself strongly associates is only one victim of a specic process, for example with progression of kidney disease. Certain genetic diseases cross this bound identied the adverse prognostic implication of albuminuria ary by affecting different tissues. The purpose of this statement is to ensure clarity in There is wide geographic variation in the cause of kidney communication. This current classication such as kidney biopsy or invasive imaging studies are further acknowledges the importance of dividing Stage 3 based performed only when it is essential to conrm some on data supporting different outcomes and risk proles into diagnoses and the benets justify the risks and cost. As such, specic categorization of G1-5 as suggested in this Recommendation would seem not be of value, and might be misleading if applied to a child less than 2 years of age. The association of high levels of the risks of death, cardiovascular events, and hospitalization, 351: 1296-1305. Solid circles indicate statistical significance compared to the reference point (P o0. The categories with a rank number 1-8 are green, rank numbers 9-14 are yellow, the rank numbers 15-21 are orange and the rank numbers 22-28 are colored red. Albuminuria and proteinuria can be measured using excretion rates in timed urine collections, ratio of concentrations to creatinine concentration in spot urine samples, and using reagent strips in spot urine samples. At all ages, total urinary protein excretion 440 mg/m /hr 2 K should account for the possibility of tubular versus (43 grams/1. For other conditions, the risk adult guidelines with the understanding that modication to will be determined by risk factors specic for those the upper limit of expected values may be necessary in conditions. For out guidance in the local methods for requesting and interpreting comes that occur predominately in older adults. Use of risk scores dementia, fracture), the evidence is largely limited to cohorts which are being developed and rened is advised. Community or health-system based interventions and across the albuminuria categories. Levels of risk can be to reduce the incidence of kidney failure in populations identied and grouped into categories, but they may differ should be targeted and prioritized based on these 3 criteria. This the issue of puberty and its effect on rate of progression 77 translated to higher rates of kidney survival over 5 years in has recently been addressed by the ItalKids investigators. Life monitoring in children with respect to risk of progression table analysis in this study also suggested a cutoff value of include obesity, metabolic acidosis, anemia, calcium-phos 50 mg/kg/day of proteinuria as a strong predictor of time to a phate metabolism, chronic inammation, diabetes, hyperur 2 decline in CrCl410 ml/min/1. However, like all diagnostic tests, the study population in which they were developed. J Am Soc Nephrol 20: 2305-2313, 2009; permission conveyed through Copyright Clearance Center, Inc. In the opinion of the Work Group, these equation to estimate glomerular filtration rate. For all these reasons, the guideline from serum cystatin C rather than relying on the statement 1. When reporting serum cystatin C: the 2012 creatinine-cystatin C equation is more K We recommend reporting serum cysta accurate than equations using creatinine or cystatin C tin C concentration rounded to the separately (Figure 15), and more accurate than the th nearest 100 of a whole number when 2008 creatinine-cystatin C equation (Table 17). This recommendation is directed to laboratories with the intent to clarify the details of Based on their recent work comparing particle-enhanced such calibration and the use of specic equations so as to nephelometric to turbidometric immunoassays for cystatin C facilitate international standardization. We recognize that this ability does not currently constitute the denition of specialty kidney referral centers and that it may be problematic, but resources to ensure accurate measurement ought to be made available. This demonstrates the importance of Table 18 summarizes the strengths and limitations of using an assay calibrated and traceable to the international clearance methods and ltration markers for clearance standard reference material. Different countries and which may be possible with improved standardization of regions will have different availabilities for measurement of both assays and equations. Guidance is evolving regarding kidney morning urine sample is preferred) (2B): 13 function evaluation during drug development programs. Changes in laboratory assays or is relatively standardized and because it is the single most calculation methods should be reported to clinicians in order important protein lost in the urine in most chronic kidney to avoid confusion when serially following individuals. No No Moderately increased albuminuria Continue routine observation Figure 16 |Suggested protocol for the further investigation of an individual demonstrating a positive reagent strip test for albuminuria/proteinuria or quantitative albuminuria/proteinuria test. Patients with two or more positive (Z30mg/g or Z3mg/mmol) tests on early morning samples 1-2 weeks apart should be diagnosed as having persistent albuminuria. The concentration of protein or albumin in a urine sample will be affected by hydration. Creatinine excretion is considered Albumin should be measured using immunological assays to be fairly constant throughout the day and it has become capable of specically and precisely quantifying albumin at customary to correct for urinary concentration by expressing low concentrations and of producing quantitative results over either the protein or albumin concentrations as a ratio to the the clinically relevant range. Albumin concentration should be reported as a ratio to Why is albumin measurement being recommended instead urinary creatinine concentration (mg/mmol or mg/g). There A1-3 are a more clinically meaningful way to express information is also evidence that urinary albumin is a more sensitive test about categories within the continuum of albumin excretion. Total protein measurement is problematic in urine due to: Why are reagent strip devices for protein measurement large sample-to-sample variation in the amount and considered less accurate than laboratory measurement As discussed earlier, a positive reagent concentration; and high inorganic ion content. There is evidence that contribute to diverse estimates of proteinuria preva strips from different manufacturers perform differently at the 131,132 lence. When analyzing stored samples, they should be allowed to reach room temperatureand thoroughly mixed prior to analysis.

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Examples and Characteristics of Nociceptive Pain Superficial Somatic Pain Deep Somatic Pain Visceral Pain Nociceptor location Skin, subcutaneous tissue, Muscles, tendons, joints, Visceral organsa and mucous membranes fasciae, and bones Potential stimuli External mechanical, Overuse strain, mechanical Organ distension, muscle spasm, chemical, or thermal events injury, cramping, ischemia, traction, ischemia, inflammation Dermatologic disorders inflammation Localization Well localized Localized or diffuse and Well or poorly localized radiating Quality Sharp, pricking, or burning Usually dull or aching, Deep aching or sharp stabbing sensation cramping pain, which is often referred to cutaneous sites Associated symptoms Cutaneous tenderness, Tenderness, reflex muscle Malaise, nausea, vomiting, and signs hyperalgesia hyperesthesia, spasm, and sympathetic sweating, tenderness, reflex muscle allodynia hyperactivityb spasm Clinical examples Sunburn, chemical or Arthritis pain, tendonitis, Colic, appendicitis, pancreatitis, thermal burns, cuts and myofascial pain peptic ulcer disease, bladder contusions of the skin distension Sources: References 22-24 and 88-89. National Pharmaceutical Council 9 Section I: Background and Significance in origin. These include allodynia) or occurs when no identifiable stimu multidimensional classification systems, such as lus exists. It is associated with several types of pain, but it also may exist as a single entity. Trophic changes include thinning of the skin, abnormal hair or nail growth, and bone changes. Pain: Current Understanding of Assessment, Management, and Treatments 10 Section I: Background and Significance based on pain duration. It Even brief intervals of painful stimulation can also reviews elements of a mixed pain classifica induce suffering, neuronal remodeling, and tion system in which pain is categorized as acute chronic pain;10 associated behaviors. Therefore, increasing attention is being focused on the aggressive prevention and treat ment of acute pain to reduce complications, including progression to chronic pain states. Chronic Pain nitive, as well as sensory, features that occur in 22 Chronic pain was once defined as pain that response to tissue trauma. Acute pain is usually nociceptive, but may be Chronic pain is now recognized as pain that neuropathic. Common sources of acute pain extends beyond the period of healing, with lev include trauma, surgery, labor, medical proce els of identified pathology that often are low and dures, and acute disease states. Table 3 summa insufficient to explain the presence and/or rizes its key features. A host of protective reflexes and normal living, ceases to serve a protective Table 3. National Pharmaceutical Council 11 Section I: Background and Significance function, and instead degrades health and func els that only weakly correspond to identifiable tional capability. In some Environmental and affective factors also can cases, there is no discernable cause, and the pain exacerbate and perpetuate chronic pain, leading is considered the disease. Examples of Chronic First, its acute and chronic components and mul Noncancer Pain tiple etiologies make it difficult to classify based on duration or pathology alone. This find ing prompted recommendations including the scheduled administration of pain medications via other routes. These consequences affect hospitalized patients, 61% of the 217 patients patients, their families, and society as a whole interviewed reported pain ratings of 7 to 10 (on and can be broadly categorized as physiological, a scale from 0 for no pain and 10 for the worst psychosocial (quality of life), and financial. What Is the Size and Scope of adequacy of analgesia in an urban emergency Pain As A Health Care Problem Acute pain is the most common reason why Hispanic patients with long-bone fractures were patients seek medical attention. Chronic pain is also a problem of epidemic pro reported sufficient control of moderate pain. Results from a 2001 sur ing with their pain for more than 5 years and vey suggest that most individuals with severe experience pain almost 6 days a week. Low back pain, arthritis, and migraine headache alone account for pain in tens of mil Approximately two-thirds (67%) of the patients lions of Americans. What Are the Consequences and One study showed that pain levels in patients hospitalized for serious conditions. Physiological consequences treated pain early in life is associated with pain As discussed in Section I. Quality of life can have adverse effects if allowed to persist Inadequate control of pain interferes with the unchecked. Very young, very old, and frail patients 13 pain may experience anxiety, fear, anger, depres are at greatest risk for such complications. These indi Another key adverse effect of poorly con viduals report impairments on multiple measures trolled acute pain is progression to chronic 124-125 of physical, social, and psychological well-being, pain. Examples of Physiological Consequences of Unrelieved Pain Functional Domain Stress Responses to Pain Examples of Clinical Manifestations Endocrine/metabolic Altered release of multiple hormones. Pain: Current Understanding of Assessment, Management, and Treatments 14 Section I: Background and Significance ence health care. Barriers Within the Health Care toms can contribute to more serious conse System quences. Financial consequences standard pain assessment tool or to provide staff Pain costs Americans an estimated $100 bil with sufficient time and/or chart space for docu lion each year. Others fail organizations, and society bear this financial to provide clinicians with practical tools and burden. However, the greatest systems barrier to plications associated with inadequately con appropriate pain management is a lack of trolled acute pain can increase length of stay, re accountability for pain management practices. It is a leading cause of medically incidents) to ensure effective pain manage related work absenteeism and results in more ment. Patient care is more frag long-term or permanent unemployment or mented; thus, the risk of poor coordination of underemployment. Patient and Family Barriers patients with chronic pain do not seek medical Whereas poor clinician-patient communica attention. Legal and Societal Barriers Legal and societal issues also contribute to the undertreatment of pain. Common Misconceptions restrictive laws or regulations about the prescrib ing of controlled substances as well as confusion About Pain about the appropriate role of opioids in pain treatment. Although studies suggest a state of adaptation that often includes tol that the risk of iatrogenic addiction is quite low erance and is manifested by a drug class spe. Etiology, issues, and concerns may be essential in the treatment of acute pain Many medications produce tolerance and due to trauma or surgery and chronic pain, physical dependence, and some. Assessment is an essential, but challenging, com Successful pain management depends, in part, on cli ponent of any pain management plan. Pain is subjec nician adherence to such standards and guidelines tive, so no satisfactory objective measures of pain and commitment to some core principles of pain exist. Pain is also multidimensional, so the clinician assessment and management (Table 7). Goals and Elements of the Initial lation, clinician), so no single approach is appropriate Assessment for all patients or settings. Important goals of the initial assessment of pain this section reviews some core principles of pain include establishing rapport with the patient and pro assessment and management to help guide this 8 viding an overview of the assessment process. It then explores approaches that clinicians processes help to engage the patient, foster appropriate can use in the initial assessment of pain.

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When a person stands up, blood pools in the legs, pelvis, and abdomen due to gravity. If the blood volume were low, then because of gravitational blood pooling there would be less blood returning to the heart to pump to body organs including the brain, and the person could feel lightheaded or faint. In patients with chronic orthostatic intolerance, measurement of blood volume may be indicated, since if the blood volume were low, a drug such as fludrocortisone and a high salt diet might benefit the patient by increasing the blood volume. In the 131I-albumin blood volume test, an exact, known amount of 131I-albumin is injected. By definition, the concentration of a substance is the amount In the blood volume test, blood volume is calculated from the concentration and amount of a drug in the bloodstream. Since the amount of 131I injected is known, and the plasma concentration of 131I is measured in the laboratory, by algebra the plasma volume is the 131I concentration divided by the amount of injected 131I. From the plasma volume divided by the hematocrit (the percent of the - 360 - Principles of Autonomic Medicine v. Because the concentration of 131I-albumin in the blood may change slightly over time (such as by leakage out of the blood vessels), blood is sampled at several time points, and the concentration that is estimated to be present in the blood immediately after injection is used for the calculation of blood volume. This is because the main chemical messengers of these systems, norepinephrine and epinephrine (adrenaline), can be measured in the plasma, whereas the main chemical messenger of the parasympathetic nervous system, acetylcholine, undergoes rapid enzymatic breakdown and cannot be measured in the plasma. I use the term, catechols, to refer to chemicals that have the catechol structure in them. At least some of plasma dopamine is derived from vesicles in sympathetic noradrenergic nerves, presumably because of exocytotic release from the vesicles before the dopamine has had a chance to be converted to norepinephrine. Therefore, in order to produce norepinephrine, dopamine in the cytoplasm must be taken up into the vesicles. The relationship between the rate of sympathetic nerve traffic - 364 - Principles of Autonomic Medicine v. Determinants of plasma norepinephrine levels Here is a brief description of some of the complexities involved: First, only a small percent of the norepinephrine released from sympathetic nerves actually makes its way into the bloodstream. Second, the plasma norepinephrine level is determined not only by the rate of entry of norepinephrine into the plasma but also by the rate of removal of norepinephrine from the plasma. This means that a person might have a high plasma norepinephrine level because of a problem with the ability to remove norepinephrine from the plasma, such as in kidney failure. In using plasma norepinephrine levels to indicate activity of the sympathetic noradrenergic system, several complicating factors must be taken into account. Third, norepinephrine is produced in sympathetic nerve terminals by the action of three enzymes, in concert with other required chemicals such as vitamin C, vitamin B6, and oxygen. Fourth, the plasma norepinephrine level usually is measured in a blood sample drawn from a vein in the arm. Because the skin and skeletal muscle in the forearm and hand contain - 367 - Principles of Autonomic Medicine v. Fifth, the plasma norepinephrine level depends importantly on the posture of the person at the time of blood sampling (the level normally approximately doubles within 5 minutes of standing up from lying down), the time of day (highest in the morning), whether the person has been fasting, the temperature of the room, dietary factors such as salt intake, and any of a large number of commonly used over-the-counter and prescription drugs or herbal remedies. A large number of common and difficult to control life experiences influence activity of the sympathetic adrenergic system. These include drugs, alterations in blood glucose levels (such as after a meal), body temperature, posture, and especially emotional distress. This can especially be a problem in people who drink a lot of coffee, even if it is decaffeinated, because of chemicals in the plasma that can mimic adrenaline in the assay procedure. Because of these issues, it is important that blood sampling and chemical assays for plasma adrenaline levels be carried out by experienced and expert personnel. A high plasma 3-methoxytyramine level is a sensitive test for metastatic pheochromocytoma or paraganglioma. Indeed, plasma 3-methoxytyramine is the most accurate biomarker for discriminating pheo patients with vs. The immune system raises an antibody or produces immune cells that target a protein that is expressed in the autonomic nervous system. Probably the most well characterized form of auto-immune attack is autoimmune autonomic neuropathy from a circulating antibody to the neuronal nicotinic receptor. Since ganglionic neurotransmission depends on this receptor, autoimmune autonomic neuropathy can manifest with decreased function of any component of the autonomic nervous system. A variety of infectious diseases can result in autonomic neuropathies, such as mononucleosis, herpes simplex, and Coxsackie B. This syndrome is most commonly associated with symptoms and signs of parasympathetic nervous system failure. In general, there is no specific test to identify the specific offending antibody. Some associated with autonomic neuropathies are antinuclear antibody and Rheumatoid factor. It should be noted that the presence of an antibody, such as to the neuronal nicotinic receptor, does not mean that the antibody is pathogenic and causes or contributes to dysautonomia. The nerves then dive into the muscle and form mesh-like networks that surround the heart muscle cells. Because neuroimaging tests have a limit of resolution of a few millimeters, the imaging does not show individual nerves but gives a general picture, and since the nerves are found throughout the heart muscle the picture looks very much like a scan of the heart muscle. The radioactive drugs used for imaging the sympathetic nerves in the heart are given by injection into a vein, and they are delivered to the heart muscle by way of the coronary arteries. One must be able to distinguish decreased radioactivity in the scan due to loss of sympathetic nerves from decreased radioactivity due to blockage of a coronary artery, because either nerve loss or coronary blockage would lead to the same lack of radioactivity in the heart muscle. Centers that carry out sympathetic neuroimaging therefore may do two scans in the same testing session, one scan to see where the blood is going and the other to see where the sympathetic nerves are. Cardiac sympathetic neuroimaging is available in few centers in the United States but is done routinely at many centers in Europe and Japan. In common forms of dysautonomia such as postural tachycardia syndrome the problem is not a loss of the sympathetic nerves but a change in activity or function of those nerves. You could determine if there were something radioactive inside by using a detector, such as a Geiger counter. If the object were small, most of the slices - 384 - Principles of Autonomic Medicine v. Eventually, at the level of the object, you would see an image of the object in the slice. Other tomographic scans in nuclear medicine use a somewhat different source of radioactivity, but the idea is about the same. Fluorodopamine is structurally similar to two of the biochemicals of the sympathetic nervous system, norepinephrine and adrenaline. Just as some radioactive chemicals get taken up by bone, producing a bone scan, or get taken up by the brain, producing a brain scan, fluorodopamine gets taken up by sympathetic nerves, and the result is a scan of the sympathetic nervous system.

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Renal function was favourable for tacrolimus treated patients, but did not reach statistical significance in most analyses. Recommendations Strength rating Use calcineurin inhibitors for rejection prophylaxis as they represent current best practice Strong pending publication of long-term results using newer agents. Strong Monitor blood-levels of both cyclosporine and tacrolimus to allow appropriate dose Strong adjustment of calcineurin inhibitors. This is the rate-limiting step for the synthesis of guanosine monophosphate in the de novo purine pathway. There is also a higher incidence of polyoma nephropathy, especially when mycophenolate is combined with tacrolimus [223]. Mycophenolic acid is not formally approved for use with tacrolimus, though this is the most frequently used drug combination in many countries worldwide and recommended by guidelines [204]. Despite its frequent use with tacrolimus, there is insufficient evidence to support the optimal dosage for this combination [203, 218, 220]. Most transplant centres use the same starting dose as in cyclosporine-treated patients, however dose reductions are frequent, especially because of gastrointestinal side effects. Recommendation Strength rating Administer mycophenolate as part of the initial immunosuppressive regimen. When added to dual therapy with cyclosporine and steroids, a meta-analysis found no significant benefit for azathioprine with respect to major outcome parameters [229]. Recommendation Strength rating Azathioprine may be used in a low-risk population as an immunosuppressive drug, Weak especially for those intolerant to mycophenolate formulations. Most practitioners still consider steroids (either prednisolone or methylprednisolone) to be a fundamental adjunct to primary immunosuppression, even though successful steroid withdrawal has been achieved in the vast majority of patients in many prospective, randomised trials [203, 205, 206, 226]. These trials suggest the risk of steroid withdrawal depends on the use of concomitant immuno-suppressive medication, immunological risk, ethnicity, and time after transplantation. Although the risk of rejection diminishes over time, potential benefits may be less prominent after a prolonged steroid treatment period [203-206, 226]. Recommendations Strength rating Initial steroid therapy should be part of immunosuppression in the peri-operative and early Strong post-transplant period. Consider steroid withdrawal in standard immunological risk patients on combination therapy Weak with calcineurin inhibitors and mycophenolic acid after the early post-transplant period. They inhibit multiple intracellular pathways and block cytokine signals for T-cell proliferation. Similar effects are seen on B-cells, endothelial cells, fibroblasts, and tumour cells. Other potential side effects include hyperlipidaemia, oedema, development of lymphoceles, wound-healing problems, pneumonitis, proteinuria, and impaired fertility. Sirolimus has a half-life of about 60 hours, is given once a day and is licensed for prophylaxis in kidney recipients only. Everolimus has a half-life of about 24 hours, is licensed for kidney, liver and heart recipients and is given twice a day. Everolimus is licenced for use with cyclosporine and can be given simultaneously with cyclosporine, while sirolimus should be given four hours after cyclosporine. Sirolimus is also licensed in combination therapy with steroids for cyclosporine withdrawal from combination therapy with cyclosporine. Therapeutic monitoring of trough levels is recommended because of the narrow therapeutic window and the risk of drug-to-drug interactions [203, 215, 230-233]. Proteinuria and poor renal function at conversion are associated with inferior outcomes [203, 205, 215, 230 232]. Strong Monitor blood-levels of both sirolimus and everolimus to allow for appropriate dose Strong adjustment. Several large controlled trials support the efficacy and safety of quadruple therapy with tacrolimus, mycophenolate and steroids. Interleukin-2 receptor antibodies may allow early steroid withdrawal [226], although higher rejection rates were described. Therefore, this regimen is proposed as first line immunosuppression in patients with low to normal immunological risk [204]. Recommendation Strength rating Use interleukin-2 receptor antibodies for induction in patients with normal immunological Weak risk in order to reduce incidence of acute rejection. In addition these potent biological agents are used for the treatment of severe, steroid resistant rejection episodes [241]. Use of T-cell depleting antibodies in immunological low-risk patients has not been associated with improved long-term outcomes but with an increased risk of severe opportunistic infections and malignancy, particularly post-transplant lymphoproliferative disease [203, 204, 206, 238, 241, 242]. Graft rejection rates are initially lower with induction treatment, however, some studies suggest an increased rejection rate after cessation of lymphocyte depletion [241]. Recommendation Strength rating T-cell depleting antibodies may be used for induction therapy in immunologically high-risk Weak patients. Long-term data from three randomised studies of de novo kidney transplant recipients demonstrated better renal function versus cyclosporine-based immunosuppression, although rates and grades of acute rejection were higher for belatacept in the first year post-transplant [203, 206, 215, 243-246]. The long-term safety profile of belatacept treated patients was similar to cyclosporine controls, less belatacept treated patients discontinued due to adverse events. Recommendation Strength rating Belatacept may be used for immunosuppressive therapy in immunologically low-risk Weak patients, who have a positive Epstein-Barr virus serology. There is great variation in the timing and severity of rejection episodes and how they respond to treatment. Therefore, all rejections should be verified by renal biopsy and biopsies should be classified according to the most recent Banff criteria [251], which are the basis for prognosis and treatment [202, 246]. The reported risk of major complications (including substantial bleeding, macroscopic haematuria with ureteric obstruction, peritonitis or graft loss) is approximately 1%. Most important contraindications are anti-coagulant therapy including anti-platelet agents and uncontrolled hypertension. Take regular blood samples in addition to regular monitoring of urine output and ultrasound Strong examinations in order to detect graft dysfunction during hospitalisation. Immediately rule out other potential causes of graft dysfunction in cases of suspected acute Strong rejection. Perform a renal biopsy, graded according to the most recent Banff criteria, in patients with Strong suspected acute rejection episodes. Reassess the immunosuppressive therapy of all patients with rejection, including patient Strong adherence to the medication, which is of particular importance in late rejections. It results from circulating, complement-fixing IgG antibodies, specifically reactive against incompatible donor antigen, which engages with and destroys the vascular endothelium within minutes or hours after vascularisation. Imaging and histology reveals generalised infarction of the graft, which has to be treated by graft nephrectomy. Parenteral methylprednisolone (500 mg to 1 g) should be given intravenously as one pulse per day for three days. Anuria or a steep rise in the serum creatinine may indicate steroid-refractory rejection and the need for another three day course of pulsed methylprednisolone therapy [204, 248]. In addition, baseline immunosuppression should be optimised to ensure adequate drug exposure [204, 248]. In severe rejection, a conversion from cyclosporine to tacrolimus and/or from azathioprine to mycophenolate is recommended [204, 248]. If biological agents are used, other immunological suppression should be adapted and daily T-cell monitoring should be considered to minimise the dose of the biological agent [241]. Before immunosuppression is intensified, especially before the use of T-cell depleting agents, the prognosis of the graft should be critically assessed against the risks of the aggravated immunosuppression. Recommendations Strength rating Use steroid bolus therapy as first-line treatment for T-cell mediated rejection in addition to Strong ensuring adequate baseline immunosuppression. In severe or steroid-resistant rejection, use intensified immunosuppression, high-dose Strong steroid treatment, and eventually T-cell depleting agents. In order to target the antibody producing plasma cell, several centres have advocated the use of bortezomib, a proteasome inhibitor approved for the treatment of multiple myeloma [260]. In addition, to drug therapy most centres also try to remove antibodies using plasmapheresis or immune-adsorption columns. Retrospective and prospective case series clearly suggest efficacy [204, 248, 254-258], although details of the procedures vary widely.

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Within the foregoing guidelines, reconstruction of genitalia and mastectomy are insured benefits. However, since the hormonal treatments associated with sex-reassignment themselves give rise to breast enlargement, augmentation mammoplasty or breast reconstruction in a male to female conversion is not an insured benefit, in keeping with the previously outlined policy regarding breast surgery in females. Sex-Assignment Surgery Sex-assignment surgery for persons with congenitally ambiguous genitalia is an insured service. Prior authorization from the Ministry of Health and Long-Term Care is not required. These services are limited to a maximum of one per patient every 24-month period regardless of whether the first claim for either service or a major eye examination is or has been submitted for a service rendered by an optometrist or physician. For physicians other than ophthalmologists, claims submitted for any other service by the same physician the same day as either of these services are not eligible for payment. The fee codes are specific to the applicable form and are not to be claimed for completion of any other government document. K061 Taking of blood samples in a hospital setting at the request of a police officer. For a complete text version of Section 18 of Regulation 114/94 under the Medicine Act, please refer to. Please Refer to the Primary Health Care Fact Sheets for complete billing information. Physicians participating in Patient Enrolment Models who are eligible for Preventive Care Bonus Payment are not eligible to bill this 5. Reported illnesses have ranged from mild to severe, including illness resulting in death. Older people, those with compromised immune systems, and people with certain underlying health conditions like heart disease, lung disease and diabetes, for example, seem to be at greater risk of serious illness. Otherwise, discuss alternative provision of services, such as telehealth or in home care. You may need to ask for help from friends, family, neighbors, community health workers, etc. Please consult your medical provider for any other symptom that is severe or concerning. In addition, relevant stakeholders with evaluate the health, public safety, and economic differing viewpoints have weighed in on the impact of legalizing marijuana. To ensure legalized marijuana in surrounding states was a comprehensive assessment, data from a variety of identified as an important issue to consider in the sources were acquired. A 2017 Marist Poll showed that 52 percent some jurisdictions that have legalized marijuana of Americans 18 years of age or older have tried and some that are likely to legalize soon. In addition, experts of certain racial and ethnic groups that has a in State agencies were consulted, including the negative impact on families and communities. Peer-reviewed literature, news reports, and anecdotal evidence demonstrate that In addition to health impacts, the prohibition of marijuana is beneficial for the treatment of pain, marijuana has had significant impacts on criminal epilepsy, nausea, and other health conditions. However, possession of marijuana in public with medical programs across the country has led view remains a misdemeanor. In 2012, the States with medical marijuana programs have been Governor introduced legislation to ensure that found to have lower rates of opioid overdose possession of a small amount of marijuana, whether deaths than other states. Since the include provisions to address the collateral program was established, continued improvements consequences of prior criminal convictions for have been made to better serve patients. To marijuana possession or use, such as barriers to improve patient access, nurse practitioners and housing and education. These 4 associated with marijuana have been identified, Findings although research for some of those risks is divided. For example, research has demonstrated an association between maternal marijuana smoking and lower birth weight of newborns. For individuals who are susceptible to Regulating marijuana reduces risks and psychosis, regular use lowers age of onset of 8 improves quality control and consumer psychosis. Risks can be monitored and the organization Doctors for Cannabis Regulation reduced in a regulated marijuana environment with states that regulation benefits public health by the establishment of regulations that enhance State enabling government oversight of the production, control. Regulating marijuana enables public health testing, labeling, distribution, and sale of officials to minimize the potential risks of marijuana 9 marijuana. Potency can vary widely based on the use through outreach, education, quantity limits at strain of marijuana, the way the plant is grown, the point of sale, quality control, and consumer part of the plant that is used, how it is stored, and protection. In an unregulated market where there is principles can and should be incorporated into a no standardization or quality control, there are regulated marijuana program to help ensure many opportunities for unsafe contaminants to be consumer and industry safety. Legalizing introduced, such as fungi spores, mold, bacteria, marijuana could remove research restrictions in heavy metals, pesticides, and growth enhancers. States legalization, there was a significant increase in the with medical marijuana programs have been found number of children under age 12 admitted to to have lower rates of opioid overdose deaths than emergency rooms due to unintentional marijuana other states,18 perhaps lower by as much as 25 ingestion (over half the cases involved medical percent. Testing and labeling products will State saw a short-term reversal of the upward trend ensure quality and protect public health. Medical marijuana has added another option for pain relief Marijuana has intrinsic health benefits and which may reduce initial prescribing of opioids and risks. The medicinal benefits of Besides the dramatic increase in the number of marijuana have been acknowledged. Marijuana is an effective treatment for pain, greatly Amotivational syndrome is anecdotally reported to reduces the chance of dependence, and eliminates be associated with chronic marijuana use. This is the risk of fatal overdose compared to most opioid not supported in the literature. Regulating marijuana will provide an opportunity to furnish Adolescents who use marijuana regularly have an information regarding the various methods of increased risk of developing psychosis. Additionally, for individuals who are susceptible to psychosis, regular use of marijuana lowers the age Most women who use marijuana stop or reduce of onset of psychotic disorders. Others noted there is substantial Marijuana can have effects on mental evidence of the effects of marijuana use on health. Regular marijuana use in youth is will need to conduct surveillance on youth associated with lower academic achievement,32 but marijuana use and any possible impacts on the causation is unclear. Research has identified a It is likely that some people who have never used variety of mechanisms by which youth obtain marijuana before due to fear of legal repercussions tobacco, one of which is social sources. Drawing parallels this does not mean that those individuals will from tobacco research, regulating marijuana would become regular or even semi-regular marijuana 45 enable the State to establish controls over users. In number of people who use marijuana can be addition, the creation of a regulated marijuana partially attributed to under-reporting prior to program would establish a legal distinction between underage and adult marijuana use. Decreasing social stigma surrounding Subject matter experts noted that marijuana will marijuana and no longer having to fear legal be more difficult for youth to obtain in a regulated repercussions can lead to accurate reporting on use marijuana environment. They Subject matter experts noted that there is no asserted that the illicit economy operates now conclusive evidence about whether legalizing with no rules or regulations, youth know how to marijuana increases use. It was pointed out that obtain marijuana, and the notion that regulation as with alcohol, use varies. They noted that such Law enforcement raised a concern about a report increases are, at least in part, the result of from the Rocky Mountain High Intensity Drug tourism. As more of the country legalizes, these Colorado and found that youth past-month increases will fade. However, other studies have shown little or no the majority of credible evidence suggests change in adolescent marijuana use following legalization of marijuana has no or minimal legalization. Marijuana is the most commonly used illicit rates, both lifetime use and current use, among 8 high school students in Colorado did not change use. Legalization will allow for a more honest and significantly following legalization.

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Ventricular conduction disturbances are occasionally observed which may result in cardiomyopathy (Daccarett et al. Epidemiological studies indicate no permanent increased risk of cardiovascular disease. Contributing risk factors are male gender, tobacco use and obesity that often exist among cannabis users (Mittleman et al. Chronic use of cannabis may inhibit the secretion of reproductive hormones and induce impotence in men and menstrual irregularities in women (Hollister, 1986b). Chronic marijuana use may decrease the male prostate and testes, reduce sperm count and block ovulation, these changes are reversible, and do not imply infertility (Abel, 1981). The illicit use of cannabis pose certain obstacles and challenges to the dental professional. Marijuana has been shown to decrease intraocular eye pressure, involuntary movement and perceived pain, and to stimulate appetite (Hollister, 1986a, Hollister, 1992a). The strongest evidence of possible health benefits for marijuana use appears to be focused on increasing appetite, and decreasing nausea and vomiting (as a result of cancer therapy), and possibly improving pain tolerance (Hollister, 1992b). In the Netherlands, amphetamine is the predominant amphetamine and it is usually administered by either the oral or the intranasal route. Routes of administration effects and risks Route Effect Risks Intravenous High and rapid peak Needle sharing. Snorting Weaker onset and Damages epithelium and nasal septum, slower reduction in potentially causing nasal ulcers, runny intensity than i. Time is required for absorption to and quantity of the occur before effect is experienced (see drug formulation oral use above). It is evident from Tables 3 and 4 that both route of administration and dose determine the extent of the effects, with a potential for more harmful effects at high doses. Note that the data of Tables 3 and 4 originate from Australia, where methamphetamine is the predominant amphetamine. Clinically, the effects of amphetamine are very similar to those of cocaine, but the amphetamine effects are more prolonged (half-life of 10 to 15 h). Stroke has been reported in patients with amphetamine intoxication; it results from hypertension and is usually haemorrhagic (Agaba et al. There have also been reports of cerebral vasculitis and haemorrhage with chronic abuse of amphetamine (Buxton and McConachie, 2000, Matick et al. Systemic necrotizing vasculitis, resembling peri arteritis nodosa, has been associated with chronic amphetamine abuse (Welling et al. The population attributable risk suggests that amphetamine abuse is responsible for 0. Other acute clinical symptoms include reduction in fatigue, hunger, and an increase in energy, sexual drive, and self-confidence. Methamphetamine use is associated with ischemic stroke, intracerebral and subarachnoid haemorrhage, especially among young patients (Ho et al. Both ischemic and haemorrhagic stroke has been reported with methamphetamine abuse, and in some cases the stroke was delayed by 10 to 12 hours after last use (Perez et al. Cardiovascular symptoms, including irregular heart beats, have developed in more than half of the methamphetamine abusers (Beebe and Walley, 1995). Methamphetamine use related cardiomyopathy may be reversible, but this depends on cessation of drug use (Islam et al. Pulmonary oedema is reported in over 70% of methamphetamine-related deaths (Karch et al. Methamphetamine overdose related symptoms seen in emergency rooms are chest pain, hypertension, shortness of breath, acute coronary syndrome and tachycardia (Richards et al. Acute coronary syndrome occurs in 25% of methamphetamine abusers admitted for chest pain (Turnipseed et al. Damage to small blood vessels in the brain can result in stroke, paralysis, and brain damage (Newton et al. Oral health problems most often seen among methamphetamine abusers include rampant caries, tooth fracture, and periodontal disease. In addition to caries and gingivitis, methamphetamine abusers often present with tooth wear and temporomandibular joint syndrome related to bruxism, which may be a reaction to anxiety and restlessness, especially during early abstinence (Curtis, 2006, Hamamoto and Rhodus, 2009). Methamphetamine abusers may show self-inflicted wounds supposed to result from activation of dopaminergic pathways (Israel and Lee, 2002). The top four medical conditions associated with methamphetamine-related emergency room visits were mental health (18. Medical somatic complications of opiate use Respiratory Cardiovascular Other Cough suppression Hypotension Pruritis (irritation of the 1 skin) Hypoventilation Bradycardia Progressive nephrotic 2 syndrome Respiratory arrest Conduction abnormalities. Chronic abuse of heroin has been associated with progressive nephrotic syndrome resulting in renal failure (Dubrow et al. Respiratory depression may occur following the high doses, but life-threatening respiratory depression is much less likely with partial agonist buprenorphine as compared to heroin and morphine. Hepatic necrosis and hepatitis with jaundice have been reported, especially after intravenous injection of crushed tablets (Boothby and Doering, 2007, Karch, 2006, Vadivelu and Hines, 2007). Studies revealed that a single dose of buprenorphine up to 70 times the recommended analgesic dose did not induce life-threatening effects, indicating a broad therapeutic index. The effects of methadone last longer than heroin and methadone easily accumulates with repeated dosing. Although it is less sedative, repeated administration of methadone would cause severe sedation in non tolerant users. Side effects of opioids Frequency Symptoms Common Nausea, vomiting, constipation, drowsiness, mental confusion Moderate sweating, pruritus, dry mouth, hallucinations, dysphoria, urinary retention, headache Rarely thrombocytopenia, rash, urticaria, vertigo, palpitations, orthostatic hypotension Table 7. Side effects of opioids System Effects Cardiovascular Hypotension, bradycardia, peripheral vasodilation, tachycardia, sinus bradycardia. The membrane stabilizing properties of methadone may cause cardiac arrhythmias or cardiovascular collapse Liver Methadone is metabolized by the liver. Ten patients deceased two to six days after the start of a methadone maintenance programme with an average daily dose of 60 mg of methadone (Drummer et al. Probably the methadone piled in these patients to very toxic levels, because all patients suffered from chronic hepatitis and liver disease Urogenital Reduced urinary excretion, and urinary tract spasms of the ureter Endocrine Hypoadrenalism in chronic methadone users (Dackis et al. Gastrointestinal Nausea, vomiting, constipation, anorexia, stomach cramps, diseases of the bile duct Neuromuscular Rhabdomyolysis, weakness overall Pulmonary Apnea, respiratory depression, dyspnoea Miscellaneous Miosis, histamine secretion, skin rash, hives, itching 20. In male heroin addicts receiving methadone maintenance programme, sexual performance was significantly reduced (Cicero et al. Clients in a methadone maintenance programme or patients for the treatment of pain regularly administered methadone, primarily suffer from constipation, but also actually have a few other medical problems due to methadone, as long as they continue taking the methadone (Novick et al. Other complaints are contraction of the pupils (and therefore bad night vision), blurred vision, sweating, decreased libido, menstrual disorders, urinary retention, insomnia, respiratory disorders and occasionally pain in the joints and bones. Dirty syringes from one to the other user are passed and the impurities in street heroin can be purchased for serious health problems. Gradually, the user develops tolerance for side effects and the desired effects are more appreciated. Tolerance, however, usually occurs quickly for the desired effects such as euphoria, analgesia and rest. As compensation for the development of tolerance to increase, users usually take their daily dose, and/or change to another mode of administration, so that more of the substance reaches the brains and the effect occurs more rapidly. Effects of short-term heroin use in low dose Respiratory Slowing of the respiratory rate, which becomes more pronounced at higher doses.

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The aim of the trial was to investigate whether the lateral glide mobilisation was effective in the management of cervicobrachial pain. Assessment Physiotherapists identified a total of 286 patients with cervicobrachial pain who were suitable for physiotherapy. Of these, 174 were ineligible to participate due to co-existing upper limb pathology (n=57), being older than 65 years of age (n=22) and other reasons (n=66) such as involvement in litigation, the presence of bilateral symptoms or presence of red flags (Figure 6-1). Eligible participants (n=112) were invited to attend the first appointment with a Trial Physiotherapist (Section 5. Thirteen patients decided not to participate in the trial; 99 gave informed consent and were randomised to receive lateral glide mobilisation and self-management (n=49; Mobilisation group) or self-management alone (n=50; Comparator group). The randomisation procedure resulted in a balance of numbers across groups (Figure 6-1). One participant in the Mobilisation group 164 withdrew after starting treatment due to dissatisfaction with the intervention because he did not believe that he was actually receiving treatment. Ninety two percent (n=46) of participants in the Comparator group and 86% (n=42) in the Mobilisation group completed assessments at the primary end point (52 weeks) (Figure 6-1). Completion numbers exceeded the minimum number required for the primary analysis i. Loss to follow-up was below the reported acceptable level of 20% at each time point (Sackett et al. Overall, there was a balanced level of attrition across groups for the primary outcome measure at 6 (n=8 Comparator group; n= 6 Mobilisation group) and 52 week follow-up (n=4 Comparator group; n=7 Mobilisation group), thus, imputation tests for missing data were not conducted later in the analysis (Section 5. Initially, four centres were included as part of the trial: two community primary care centres in Birmingham, one acute general hospital in the West Midlands and one orthopaedic centre in Bristol. However, neither community centre recruited any participants during the first year of the trial. Whilst a combination of events contributed to this, the major reason was changes to the musculoskeletal service at each centre that resulted in a noticeable negative effect on staff morale and resignation of several staff, including those who had been trained to participate in the research trial. Additional staffing and service pressures prohibited commitment from the local collaborator at one of the centres and the research co-ordinator at the other went on maternity leave. Consequently, it became unfeasible to run the trial at these sites and participation of the two community centres was discontinued one year into the trial. There were also difficulties at the orthopaedic centre, with only three participants being recruited over one year. The local collaborator attributed the low recruitment (two participants in the first four months) to a period of annual leave affecting many of the staff involved with the trial. When recruitment did not improve (over the next two months), the Principal Investigator arranged a meeting with the local collaborator and research co-ordinator. The key issue was that potential participants were not being seen by Assessment Physiotherapists, so, were not being identified for the trial. Although a number of strategies were put in place to address this, further issues prevailed, including maternity leave of clinical staff, sickness absence and role change of clinical staff involved in the trial. Given these difficulties, the local collaborator felt unable to continue overseeing the project and, therefore, 167 participation of the orthopaedic centre was discontinued. Data from the three participants recruited from this site were excluded from the data analysis, since it has been reported that recruitment imbalance across sites may lead to loss of study power (Senn, 1998; Lin, 1999). Although statistical models have been developed to address imbalance in multi-centre studies (Ruvuna, 1994; Vierron & Giraudeau, 2009), when extreme imbalance exists (as in this trial) excluding participants has been advocated as a more practical option (Pickering & Weatherall, 2007). Ninety nine participants were recruited over a period of 25 months from the acute general hospital in the West Midlands. The majority of Trial Physiotherapists did not have a preference at the start of the trial, but developed a preference in favour of the lateral glide by the end (Table 6-1). Such reasons were expected in a pragmatic clinical trial (Gueorguieva & Krystal, 2004; Kwok et al. Most participants (n= 78; 88%) completed the standard questionnaire at final outcome time point. Eleven participants (12%), who did not attend the 52 week review appointment, completed a shortened version of the 170 questionnaire via the postal system. The postal questionnaire was used by 9(10%) and 2(2%) of the Comparator and Mobilisation groups, respectively. However, an appreciation of between-group characteristics was included to provide information to support arguments when interpreting the results. Baseline demographic data (Table 6-3) indicated that participants in the two groups had similar characteristics. There were slightly fewer female participants in the Comparator group (n=24; 47%), compared with the Mobilisation group (n=27; 53%). More participants in the Mobilisation group (n=10) had an extended time off work (>16 days) compared to the Comparator group (n=3). Thirty per cent (n=15) in the Mobilisation group smoked compared with 40% (n=20) in the Comparator group. The majority of participants were right arm dominant; however, there was no apparent relationship between arm dominance and side affected by cervicobrachial pain. More participants in the Mobilisation group had received physiotherapy for their cervicobrachial pain in the past. Benefit from previous physiotherapy was less in the Mobilisation group (47%) compared to the Comparator group (92%); however past physiotherapy experience did not affect preference for intervention-type. More male participants responded in the Comparator group compared to the Mobilisation group, but, the same trend was not seen for females. Increased levels of chronicity led to an increase in response rate in the Comparator group, however this did not seem to affect response rate in the Mobilisation group. There was one protocol violation during the intervention period (defined as the period up to the six week follow-up). A participant in the Mobilisation group received additional treatment (acupuncture). Although this was a seemingly high level of additional treatment, there was no statistically significant inter-group difference (for responders at one year) on the use of additional treatment between the end of the intervention period and one year follow-up (p= 0. Table 6-6: Treatment received beyond the intervention period (6 weeks to one year) Intervention Comparator Mobilisation Total p value Additional Treatment n (%) n (%) None 15 (30) 13 (27) 28 Some 23 (46) 24 (49) 47 Unknown 12 (24) 12 (24) 24 Total 50 49 99 p=0. Two participants went on to receive surgery to the cervical spine; both were in the Mobilisation group. Mean scores ranged from 65 (baseline) to 37 (52 week follow-up) in the Comparator group and 63 (baseline) to 40 (26 weeks) in the Mobilisation group. This indicated that there was a clinically meaningful improvement, on average, for participants in both groups. This indicated that there was no clinically meaningful improvement, for participants in either group. Mean scores ranged from 48 (baseline) to 28 (52 week follow-up) in the Comparator group and 48 (baseline) to 30 (26 weeks) in the Mobilisation group. There was a mean decrease of 20mm for the Comparator group and 15 for the Mobilisation group at 52 week follow-up compared to baseline (Table 6-10). This indicated that there was a clinically meaningful improvement for the Comparator group only. The mean between-group difference from baseline to 52 week follow-up was 5mm, which was not a clinically meaningful difference. Mean scores were 2 across groups indicating that, on average, both groups had achieved a clinically meaningful improvement (Table 6-10). Twenty-seven of the participants were clinically improved on both outcome measures (box A), 13 of which were in the Mobilisation group. There was no statistically significant between-group difference on medication use at 6 week follow-up (Mann-Whitney Z score = -0. Mean scores ranged from 30 (baseline) to 19 (26 and 52 week follow-ups) in the Comparator group and 36 (baseline) to 26 (26 and 52 weeks) in the Mobilisation group. Mean scores ranged from 65 (baseline) to 72 (26 week follow-up) in the Comparator group and 59 (baseline) to 64 (26 and 52 weeks) in the Mobilisation group (Table 6-11, Figure 6-6). After accounting for time and statistically significant baseline covariates (gender p=0. Mean scores varied from 35 (baseline right side bend) to 72 (left rotation at 52 weeks) in the Comparator group and 34 (baseline right side bend) to 69 (left rotation at 26 weeks) in the Mobilisation group (Table 6-13).

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Data suggests that smoking may interfere with the beneficial effects of some antihypertensive agents, such as blockers or may prevent the benefits of more intensive blood pressure lowering (European Society of Hypertension, 2003). There is a rapid decline in cardiovascular risk, by as much as 50% after 1 year, for those who stop smoking. Up to 10 years may be needed to reach the risk level of those who never smoked (Williams et al. Individuals need to recognize their increased risk due to smoking and the benefits of cessation. Despite significant declines in smoking in the past three decades, trends to stop smoking have slowed, and recently, smoking has increased among young minorities. This emphasizes that tobacco use should be assessed at every visit (Keevil, Stein & McBride, 2002). Physician advice and encouragement given repeatedly over time has shown to reduce smoking by 21% (Williams et al. Although there is less support for advice given by non-physician clinicians, the overall recommendation suggests that all clinicians provide interventions (Rice & Stead, 2005). This review notes the potential benefits of smoking cessation advice and/or counseling given by nurses to clients, with reasonable evidence that intervention can be effective. Nurses are the largest healthcare workforce, and are involved in virtually all levels of healthcare. Similar advice and encouragement given by nurses at health checks or prevention activities may be less effective, but may still have some impact. It recognizes that nurses have advocacy opportunities both in their individual practices and as a strong united voice. Nurses are encouraged to integrate tobacco use assessment, counseling and interventions into their practices and to lead in conducting research. Public Health Service-sponsored Clinical Practice Guideline: Treating Tobacco Use and Dependence (Fiore, 2000) recommends that medical offices include tobacco use as a vital sign. Highest screening and counseling rates are found when tobacco use is included with the vital signs for each client (Keevil et al. The probability of successful smoking cessation increases with each attempt and there is a 10-fold increase in success rates among those counseled during a clinical visit. Follow up and the number of contacts between the client and provider are also significant predictors of clinical success (Keevil et al, 2002). Nurses are involved in the majority of these visits and could therefore have a profound effect on the reduction of tobacco use (Whyte, 2003 as cited in Rice & Stead, 2005). Individuals who use tobacco can benefit from several types of interventions (Fiore et al, 2000). Public Health Service, is an integrated stage-based brief smoking cessation intervention. Practicing nurses should be encouraged to inquire about the availability of additional training on smoking cessation in their community. The lower amounts of nicotine contained in smoking cessation aids does not usually raise blood pressure, therefore, these aids may be used with appropriate counseling and behaviour interventions (Khoury et al. Nicotine replacement therapy is not an independent risk factor for acute myocardial events. The evidence on the impact of a smoke-free policy on smoking cessation rates is not yet available. However, some insight can be gleaned from the review of the literature on the effects of smoke-free workplaces, which reveals that these policies not only protect non-smokers from the dangers of passive smoking, but also encourage those who smoke to quit or to smoke 3. Outside pressures or demands, especially those in which we perceive a loss of control, can make us feel tense. Stress related to depression, social isolation, and lack of quality support increases the risk of coronary artery disease similar to conventional risk factors such as smoking, dyslipidemia and hypertension, but it remains unclear what the role of effective stress management is when optimizing blood pressure control (Bunker et al. Stressful situations range from major life altering events to multiple small situations that build up over time. Awareness of what causes stress, acceptance that life is not perfect and coping by learning strategies to effectively handle stress can reduce the risk of stress related conditions and enhance overall general health. It will take patience to understand, acknowledge and accept those problems that have been a part of their lives for a long time. Facilitate client to think critically and adopt strategies to accept the situation. Remember that we are all different, and that coping strategies should be individualized. However, nurses are in the best position to provide education about antihypertensive medications and monitor their therapeutic effectiveness (Bengtson & Drevenhorn, 2003). Studies have found that nursing interventions, including blood pressure checks, lifestyle and medication advice and monitoring, either on home visits or at the community clinics, were effective in reducing blood pressure in hypertensive clients (Garcia-Pena et al. Hence, nurses must be knowledgeable about the classes of medications that may be prescribed for clients diagnosed with hypertension. Nurses should educate clients that combination therapy may be necessary to manage their hypertension. Refer to Appendix O for a summary of medications commonly prescribed for hypertension. Refer to Appendix O for suggested resources regarding global vascular protection risk and treatment recommendations for clients with high risk health conditions. Some clients who take over-the-counter medications, vitamin/nutritional supplements or elect to augment their pharmacological treatment of blood pressure with herbal remedies (Miller & Kazal, 1998) may be unaware that any of these preparations may have potential interactions with the antihypertensive medications or may cause elevated blood pressure. To date, the effectiveness and safety of herbal preparations has not been studied in the same rigorous manner as conventional treatment, hence, evidence-based guidelines for the use of alternative treatments are not currently available. Some herbal remedies have been known to potentiate the antihypertensive effects of the drugs. It is important that nurses, in collaboration with pharmacists and physicians, educate clients about antihypertensive medications, including potential interactions with herbals/supplements/ over-the-counter preparations and to either avoid these remedies or take them with caution. Substance abuse and hypertension are an important health concern, especially in adolescent and young adults presenting with elevated blood pressure and associated cardiovascular conditions (Ferdinand, 2000).

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No well-designed prospective epidemiological studies exist that have assessed the incidence and prevalence of renal disease in heroin users (Jaffe and Kimmel, 2006b). Malnutrition, poor housing, untreated illness and frequent use of and physical dependence on other psychoactive drugs, together with heroin dependence, are likely to result in a generally poor condition and lowered resistance to disease. Heroin users have a death rate 13-17 times that of their age matched peers, and a 14-fold risk of suicide (Darke et al. Overall mortality rate for any liver disease in an heroin-dependent Australian ageing cohort was 1. Liver mortality increased over time and became the most common cause of death in this ageing heroin-dependent cohort (Gibson et al. This percentage is probably an underestimate of the disease burden attributable to illicit opioids, because they omit differences across subregions in the quality of data on causes of mortality and estimates of mortality and morbidity attributable to hepatitis and violence (Degenhardt et al. Acute cocaine administration increases heart rate, vasoconstriction and hypertension, and hyperthermia. At low doses, these physiological changes are usually not harmful, but they can be toxic or even fatal at high dose. Adverse consequences of heavy cocaine use are seizures, heart failure, stroke, or intracranial haemorrhage (Brands et al. Cocaine is vasoconstrictive and has local anaesthetic effects and type I antidysrhythmic properties (Bauman et al. The initial effect of cocaine on the cardiovascular system is a transient bradycardia, secondary to stimulation of the vagal nuclei. The combined use of cocaine and alcohol generates the metabolite cocaethylene, which has a direct myocardial depressant effect (Henning et al. The combination of cocaine and tobacco smoking gives coronary vasoconstriction in a synergistic manner (Moliterno et al. The severe effects depicted in Table 9 are mostly seen with high-dose use, particularly in individuals with long-standing patterns of chronic intake. Behavioural and subjective effects of cocaine in humans (Meyer and Quenzer, 2005) Mild to moderate effects Severe effects Mood amplification; both euphoria Irritability, hostility, anxiety, fear, and dysphoria withdrawal Heightened energy Extreme energy or exhaustion Sleep disturbance, insomnia Total insomnia Motor excitement, restlessness Compulsive motor stereotypies Talkativeness, pressure of speech Rambling, incoherent speech Hyperactive ideation Disjointed flight of ideas Increased sexual interest Decreased sexual interest Anger, verbal aggression Possible extreme violence Mild to moderate anorexia Total anorexia Inflated self-esteem Delusions of grandiosity 22. Reactive hyperaemia of nasal mucosa causes a persistent rhinitis in patients who regularly insufflate cocaine. Premature atherosclerosis and left ventricular hypertrophy develop in chronic cocaine users. Risks of cocaine use in the short-term are heart attack, respiratory failure, cerebral haemorrhage, renal infarction, seizure, acute state of agitation and overdoses. Cocaine is a vasoconstrictor, which decreases blood flow to the heart and brains temporarily: the risk of heart infarct and stroke increases. In high dose, cocaine use can lead to panic attacks or a temporary paranoid psychosis with delusions and hallucinations, i. Repetitive scratching (Meyer and Quenzer, 2005) may lead to infection of the wounds. Cocaine is commonly used nasal, but this does not apply to crack cocaine (cocaine base formed from cocaine hydrochloride) which can be smoked. Mean physiological and subjective effects of cocaine administered via different routes (Jones, 1990) Effect Route (Dose in mg/kg) i. Common disorders among heavy crack users are sleep disorders (insomnia followed by exhaustion), eating disorders (appetite suppression alternating with intense hunger) and sexual dysfunction (often impotence). Cocaine (and crack) impairs the immune defence against infections by inhibiting neutrophils and macrophages (Baldwin et al. In particular, the smoking of crack and the intravenous use of cocaine are associated with high-risk sexual practices. Chronic base cocaine use can lead to over-fatigue and weight loss, leading to complete exhaustion. However, lifetime-risk increase has been reported in recent prospective studies to be much lower, with an average risk increase (over non-users) of about 6% (Amin et al. Regarding a non-fatal myocardial infarction, the population attributable fraction of cocaine use was 0. According to Jellinek Clinic one out of four non-fatal heart attacks in men aged <45 years is related to cocaine use. The acute respiratory complaints include cough with sputum production, chest pain with or without shortness of breath, haemoptysis and exacerbation of asthma. It has been suggested that there is a connection between binge use and transmission risk. The reason may be the high prevalence of unprotected sex, having multiple partners, and exchange sex for drugs or money. In several studies, prevalence rates of 20-30% have been reported in Europe and 16-65% in the United States (Ruiz and Strain, 2011). In a prospective study among drug injectors in Amsterdam, the incidence of abscess was 33 per 100 person-years. Skin and soft tissue infections may progress to systemic infections including endocarditis. Most fatalities associated with cocaine use are caused by cardiovascular or cerebrovascular accidents. Therefore, chronic cocaine use may be overlooked as the cause of death and reported death rates likely underestimate the real death rate by cocaine. Approximately 5% to 10% of emergency department visits in the United States is believed to be secondary to cocaine usage, leading to the evaluation of approximately 64,000 patients annually for possible myocardial infarction, of which approximately 57% are admitted to the hospital, resulting in an annual cost exceeding 60 million (Maraj et al. Overindulgence will produce early symptoms of alcohol intoxication, like nausea and vomiting, which urges most people to temporarily stop drinking alcohol. Headache (hang-over), impaired sexual capability and temporary loss of memory are typical symptoms of high alcohol consumption and intoxication. Moreover, due to the diminished reaction time and impaired locomotor activity, alcohol intoxicated subjects are more liable to sometimes fatal traffic accidents and injuries. In alcoholics, the risk of death by suicide, homicide, fire, and drowning is roughly doubled. In Europe, alcohol is involved in 40% of murders and manslaughters, and in 16% of suicides (Anderson and Baumberg, 2006). World-wide, approximately 125 million people are affected by alcohol-use disorders and many more people suffer from alcohol use disorders than from illicit drug use disorders. Annually, alcohol kills 35 people per every 100,000, whereas for illicit drugs this is nine times less. Proportions attributable to alcohol use for major alcohol related diseases and injuries (Room et al. This explains why the population level social harm scores for legal drugs are generally higher than individual level social harm scores (and thus the total harm score), whereas the opposite is generally true for illicit drugs (cf. In 2006, the epidemiological studies on long term effects of alcohol consumption have been reviewed by the Dutch Health Council (Health Council of the Netherlands, 2006) and parts are used in the present review. The few cohort studies conducted among women all confirm the protective effects of alcohol at consumption levels below a rather high (see below) cut-off level of 48 g/day (Fuchs et al. However, it has been suggested that the cardiac protection caused by alcohol is overestimated in prospective epidemiological mortality studies, because of contamination of the abstainer category with occasional or former drinkers (Filmore et al. Indeed, the harm of alcohol consumption is many times higher than its protective effects, considering that consumption of alcohol is related to over 60 medical conditions. This is confirmed by the data depicted in Table 12, which reflect the proportions attributable to excessive alcohol use for major alcohol related diseases and injuries. Non-drinkers have higher all-cause mortality than light and moderate drinkers, and heavy drinkers have even higher all-cause mortality than either group. A meta-analysis, published in 1996, of 16 cohort studies on alcohol consumption and all-cause mortality confirms the J-shape curve (Holman et al. An important prospective cohort study not yet included in the latter review nor in the meta-analysis, was the study by Thun et al.

References:

  • https://www.canjurol.com/html/free-articles/V21I3S1_09F_DrMiner.pdf
  • http://www.unepfi.org/fileadmin/biodiversity/TEEBforBusiness_summary.pdf
  • https://mmcp.health.maryland.gov/epsdt/healthykids/Documents/Communicable_Diseases_Fact_Sheet.pdf

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