Patricia P. Chang, MD, MHS

• Assistant Professor of Medicine
• Adjunct Assistant Professor of Epidemiology
• Director, Heart Failure and Transplantation Program
• Division of Cardiology
• University of North Carolina School of Medicine
• Chapel Hill, North Carolina

Chad Riedy erectile dysfunction caused by vascular disease buy cialis extra dosage 60mg on line, National Advocacy Co-Chair impotence grounds for divorce in tn buy 100mg cialis extra dosage with amex, Cystic Fibrosis Foundation Being diagnosed with cystic fibrosis in 1984 at the age of three years old erectile dysfunction pills supplements cialis extra dosage 100 mg cheap, I was not expected live to see my twelfth birthday and for a good portion of my life we did not have therapies like hypertonic saline most effective erectile dysfunction pills order cialis extra dosage uk, inhaled antibiotics erectile dysfunction specialists buy on line cialis extra dosage, or the vest erectile dysfunction exercise video order 100mg cialis extra dosage fast delivery. I have seen how they have changed the way cf is treated and the difference they have made, but they are the not the answer. They simply help us manage our disease but do not treat the root cause of our disease. Since being on Symdeko for the past five months, I can carry my kids up the stairs to bed. While taking it has not lessened the amount of time I still have to spend on treatments and other cf related responsibilities, it has provided a better quality of life right now and real hope for the days to come. Hope that with decreased exacerbations and lung function deterioration I will be able to grow old and gray with my wife, Julie, see Liam and Tate grow up and have many more days enjoying life. Juliana Keeping, Parent of a Child with Cystic Fibrosis; Communications Director, Patients for Affordable Drugs My name is Juliana Keeping, and my 5-year-old son, Elijah, has cystic fibrosis. Lora Moser family and friends raised $750,000 for the development of Orkambi, Kalydeco and Symdeko. The federal government and the Cystic Fibrosis Foundation took on all the risk in creating these medicines, but Vertex priced the drugs as if it alone took on the risk. Instead of buying its shares to enrich investors and paying executives like Leiden tens of millions, Vertex should use its corporate tax breaks to lower the prices of its medicines. Joseph Mercy Health System * * No relevant conflicts of interest to disclose, defined as more than $10,000 in healthcare company stock or more than $5,000 in honoraria or consultancies during the previous year from health care manufacturers or insurers. Medicine, Northwestern University Jeremy Olimb Pastor and father of No conflicts of interest to report. Ollendorf, PhD Chief Scientific Officer Institute for Clinical and Economic Review Steven D. Dan Ollendorf and Steven Pearson provided methodologic guidance on the clinical and economic evaluations. No funding for this work comes from health insurers, pharmacy benefit managers, or life science companies. The findings contained within this report are current as of the date of publication. Readers should be aware that new evidence may emerge following the publication of this report that could potentially influence the results. For a complete list of stakeholders from whom we requested input, please visit: icer review. Jain has received payments in excess of $5000 from Vertex Pharmaceuticals and Gilead Sciences. Initially, infections are associated with bacteria expected in bronchiectasis of other causes. While lung function is normal at birth, lung infections tend to occur early in life. Acute pulmonary infections requiring antibiotic treatment (pulmonary exacerbations) occur and can rapidly deteriorate pulmonary function. Recently introduced agents that modulate the pathophysiology of the disease, namely, ivacaftor (Kalydeco), lumacaftor, and tezacaftor, represent a new class of treatments, and are the focus of this review. Two types of modulator drugs have been developed, with complementary modes of action. Added to best supportive care, these drugs have been shown to improve respiratory function and weight, and they may slow the rate of decline of respiratory function over time. Evidence was collected from available randomized controlled trials and observational studies. Analytic Framework the analytic framework for this assessment is depicted in Figure 1. We included studies of individuals with mutations that have either gating or other (residual) functional implications. In this population we reviewed evidence on tezacaftor/ivacaftor combination and ivacaftor monotherapy. Within these populations, subgroups of interest were defined according to presence of advanced nonreversible lung disease. For individuals who are candidates for ivacaftor monotherapy, we compared adding ivacaftor to best supportive care versus best supportive care alone and placebo. For individuals who are homozygous for the F508del mutation, we compared adding lumacaftor/ivacaftor or tezacaftor/ivacaftor to best supportive care versus best supportive care alone. Outcomes Outcomes of interest included patient-centered outcomes, other clinical outcomes, important physiologic measurements, adverse events, and costs. We excluded measures of cellular (as opposed to organ) function and other blood, serum, or urine laboratory measures (other than glucose), such as sweat chloride, fecal elastase, sputum inflammatory measures, and nasal potential difference. Timing Randomized controlled and non-randomized comparative studies of all follow-up durations were eligible. Pulmonary abnormality or chest tightness: An adverse effect that has been associated with modulator therapy (primarily lumacaftor/ivacaftor). Additionally, patients routinely take many pills and inhalation treatments as part of standard care and are concerned by the prospect of even more interventions. A third theme was related to financial insecurity induced by the management of the disease. Rather, we are looking for information on low-value services used in the management of cystic fibrosis beyond the potential offsets that arise from a new treatment. All the plans surveyed provided prior authorization criteria for the coverage of lumacaftor/ivacaftor or ivacaftor. It recommends that airway clearance therapy techniques be increased during exacerbations. Our review focused on assessing the intermediate and long-term outcomes and harms assessed in available studies. In vitro and non-human studies were excluded, as were single-dose and pharmacokinetic studies. Data were extracted from the full articles by a single reviewer and validated by a second reviewer. For harms outcomes, we combined data from single-arm studies and individual arms of comparative studies. Pulmonary abnormalities (chest tightness) were too infrequently reported to allow meaningful meta-analysis. Where data were reported for the same study participants at multiple time points. An additional ten non-randomized controlled studies were reported in four publications and six conference abstracts, and four single-arm studies were reported by four publications and three abstracts. Lumacaftor/ivacaftor: We included ten articles on lumacaftor/ivacaftor treatment in individuals who are homozygous for the F508del mutation (seven peer-reviewed publications and two abstracts). All randomized controlled trials were considered good quality, although parallel arm design is more impactful than short-term, crossover design. In a small sample of children aged 6 to 11 years with R117H residual function mutations, those on ivacaftor experienced significant decreases in lung function and trended towards decreased respiratory symptom-related quality of life scores compared to placebo. Children were required to weigh at least 8 kg and to have at least one gating mutation at screening to qualify for enrollment. Gains were similar for patients originally randomized to ivacaftor and placebo in both studies and averaged 9-10 percentage points over 96 weeks. Age-stratified analysis (fi20 and >20 years old) showed a similar trend of weight gain for those on ivacaftor compared to placebo (Appendix F). Individual-level response analysis in this study suggested weight gain and increased lung function were not correlated, though both outcomes improved with ivacaftor treatment. Non-G551D gating mutation individuals on ivacaftor experienced a statistically-significant 0. Participants aged 12 and older reported significant improvements in quality of life regarding respiratory symptoms. Pulmonary Exacerbations Pulmonary exacerbations reported in randomized clinical trials are shown in Table 3. Pulmonary exacerbations were generally reported as either an outcome or adverse event, and in some cases as both, complicating in-depth understanding and analysis. Our meta-analysis and summary results for pulmonary exacerbations use the "outcome" data, not the adverse event data. We noted two discrepancies in pulmonary exacerbations reported as adverse events and outcomes. The two studies, though, had very different estimates of hazard ratios and the meta-analysis is statistically heterogeneous. Two non-randomized, comparative, long-term studies also reported significantly lower risks of pulmonary exacerbations associated with ivacaftor. Both lumacaftor/ivacaftor and tezacaftor/ivacaftor provide improved respiratory-related quality of life compared with placebo. Lumacaftor/ivacaftor and tezacaftor/ivacaftor reduced pulmonary exacerbation events, including those requiring intravenous antibiotics and hospitalizations, compared with placebo. Two treatment regimens were reviewed for individuals homozygous for the F508del mutation: lumacaftor/ivacaftor and tezacaftor/ivacaftor. The long-term safety of lumacaftor/ivacaftor was assessed in two open-label continuation studies. In both trials of lumacaftor/ivacaftor in the six-11 year old population, lumacaftor/ivacaftor provided a statistically significant improvement from baseline with a change of -0. After 96 weeks, those who continued on lumacaftor/ivacaftor 400 mg twice daily maintained a stable reduction (Table 3. Pulmonary exacerbation events were not reported as an outcome in studies of children six-11 years old. Indirect comparison (network meta-analysis) between tezacaftor/ivacaftor and lumacaftor/ivacaftor (400 mg) found no statistically significant difference in pulmonary exacerbations between the two drugs, with an estimated rate ratio of 0. Meta-analysis of Pulmonary Exacerbations in Patients Homozygous for the F508del Mutation Tezacaftor / Lumacaftor/Ivacaftor Tezacaftor/Ivacaftor Ivacaftor vs. Respiratory symptom-related quality of life was improved by both tezacaftor/ivacaftor and ivacaftor monotherapy compared with placebo. Most of the subgroups showed similar relatively consistent treatment effects for tezacaftor/ivacaftor versus placebo; however, age < 18 vs. With one exception, described below, across studies, duration of intervention did not correlate with drug discontinuation rates by metaregression. Summary rates of discontinuation due to adverse events were: ivacaftor monotherapy 1. The three tezacaftor/ivacaftor studies were heterogeneous, with a small study having a higher discontinuation rate (2/17, 11. For lumacaftor/ivacaftor, no correlation with treatment duration was evident (by meta-regression) from four to 72 weeks (P=0. Summary rates of grade 3 or 4 severe adverse events were: ivacaftor monotherapy 5. Nevertheless, within and across studies, all interventions had similar rates of grade 3 or 4 severe adverse events. The open-label extension study allowed the use of hypertonic saline; however, no data was available for our review. One parent, for example, shared that their child experienced beneficial weight gains on lumacaftor/ivacaftor but simultaneously experienced lung function deterioration. We therefore present the results from a societal perspective as a scenario analysis rather than as part of the base case. This population is eligible for treatment with lumacaftor/ivacaftor or tezacaftor/ivacaftor, and we assumed that the age of treatment initiation was six years and older for both treatments given that recommended age for tezacaftor/ivacaftor will likely be lowered with additional trials, as was the case for lumacaftor/ivacaftor. This population is eligible for treatment with tezacaftor/ivacaftor combination or ivacaftor monotherapy, and the age of treatment initiation is 12 years and older. Disease management costs will vary as individuals who live longer will have higher management costs, although individuals on modulator therapy will also have higher lung function, resulting in reductions in these costs. We made this assumption because average lung function generally declines with age. The weight-for-age z-score is constant over the There is limited evidence for how weight-for-age z lifetime of a patient. There is no further drug assumed the same percentage of patients are taking discontinuation after the end of the trial time the drug in the model as in the trials, irrespective of horizon. We assumed that ivacaftor also had an independent effect on the reduction in acute pulmonary exacerbations by reducing the chance that an individual will experience an exacerbation and reducing the number of multiple acute pulmonary exacerbations among those patients experiencing at least one exacerbation. The following equation was used to model the annual mortality rate for age a (fi) for non-transplanted patients84: fi = = 0. Generic drugs are generally expected to have discounted pricing relative to branded competitors, but the size of that future discount is difficult to estimate.

International Normalized Ratio self-management after mechanical heart valve replacement: is an early start advantageousfi A structured teaching and self-management program for patients receiving oral anticoagulation erectile dysfunction medicine in dubai order cialis extra dosage 40 mg with mastercard. A Prospective Controlled Trial Comparing Weekly Self-Testing and Self-dosing with the Standard Management of Patients on Stable Oral Anticoagulation erectile dysfunction treatment viagra buy cialis extra dosage 40mg lowest price. Back to Top Date Sent: 4/24/2020 531 these criteria do not imply or guarantee approval medicare approved erectile dysfunction pump 40mg cialis extra dosage with mastercard. Self-management of oral anticoagulants with a whole blood prothrombin-time monitor in elderly patients with atrial fibrillation erectile dysfunction pump hcpcs generic cialis extra dosage 200 mg visa. Clinical endpoints for studies on self-management of anticoagulation therapy would be bleeding and thromboembolic complications impotence mayo buy cialis extra dosage discount. Six hundred patients (50% of the randomized sample) were included in the analysis erectile dysfunction drugs not working purchase cialis extra dosage 40 mg visa, dropouts and deaths were not included, and analysis was not based on intention to treat. It also showed that significantly more measurements were in the therapeutic range among patients in the self-management group. It is an ongoing trial and the published articles only present the interim analysis with data on 55% of the total sample size. There was no difference between them the in thromboembolic rates, and the difference in the bleeding rates did not reach statistical difference. Articles: the search yielded 20 newer articles many of which were reviews and editorials. The purpose of this review is to assess the home use of the monitors for patients with mechanical heart valves or atrial fibrillation, and not for evaluating the portable systems that have been in use since 1987 (known as point of service). Low-dose International normalized ratio self-management: A promising tool to achieve low complication rates after mechanical heart valve replacement. All studies were conducted among selected groups of patients and the results might not be generalized to all patients with mechanical heart replacement. Back to Top Date Sent: 4/24/2020 532 these criteria do not imply or guarantee approval. Criteria | Codes | Revision History anticoagulation compared with standard monitoring. The meta-analysis had valid methodology, was well conducted, and 10 out of the 14 studies it included were judged to be of good quality. The authors also performed a sensitivity analysis by excluding the studies with the lowest quality. However, the control groups in the trials received their routine care in different settings. The results of a recent meta-analysis (van Walraven, 2006) showed that the study setting has a major influence on anticoagulation control. The education and training were given after randomization, and those who could not complete the training sessions or were incapable of self testing and/or self-management either left the study or were transferred to the routine care group. This resulted in a high dropout rate (20% to > 30%) in the intervention groups, and intention to treat analysis was not conducted in all the trials, which could overestimate the observed results. Ideally, training would be performed prior to randomization to eliminate those who are unable to complete it, and/or are incapable of self testing or self-management, from participating in the trial. The results of this meta-analysis indicate that the thromboembolic events, major bleeds, and death rates were significantly lower in the self-monitoring groups versus the controls who were managed by their personal physicians, anticoagulation management clinics, or managed service. Those who both self-tested and self adjusted their therapy dose had significantly lower thromboembolic events and mortality rates but a non significant reduction the rate of hemorrhage. The difference in thromboembolic event rates was not significant between the intervention and control groups in the pooled results of the 3 trials conducted among patients with mechanical heart valves. The authors did not report on the difference in major hemorrhage or death rate among these patients, and no subgroup analysis was provided for patients with atrial fibrillation. Less than 25% of the eligible patient agreed to participate in the trial and were actually randomized to the study groups. Training on self-testing was given after randomization and only to the intervention group not to the entire population, which resulted in a higher dropout rate (43%) in the self-management group compared to 11% of those in the routine care group. Those who were considered incapable of self managing withdrew from the trial or were returned to the routine care group. The study population who self-selected to enroll was younger and included more men than the eligible population. Patients in the routine care group were managed in a variety of models including anticoagulation clinics, hospital outpatient clinics, and primary care clinics which may have an influence on their anticoagulation control, and outcomes. The study participants were highly motivated, mainly younger, willing to take and complete a structured training course on self-management, and capable of performing self-testing correctly and reliably. The purpose of this review is to assess the home use of the monitors for patients receiving long-term anticoagulation treatment, and not for evaluating the portable systems that have been in use since 1987 (known as point of service). It will have a minimum of 2 years of follow-up, and the primary outcome is event rates (stroke, bleeding or death). Back to Top Date Sent: 4/24/2020 533 these criteria do not imply or guarantee approval. The only published study on home thromboprophylaxis with warfarin anticoagulation therapy after hip and knee replacement surgery was a case series that studied the efficacy of a program designed to maintain the prophylactic anticoagulant oral therapy within the target range. There was only one published empirical study on the home prophylaxis with warfarin after hip and knee arthroplasty. Home prophylactic warfarin anticoagulation program after hip and knee arthroplasty. Back to Top Date Sent: 4/24/2020 534 these criteria do not imply or guarantee approval. Background the pulse oximeter is a completely noninvasive device that provides a means of continuous and quick real-time estimates of arterial oxygen saturation (SaO2). It has been validated relative to transcutaneous oxygen tension, and arterial blood gas measurement. The device estimates arterial hemoglobin saturation by measuring the light absorbance of pulsating vascular tissue at two wavelengths. It is easy to use and interpret and does not need any special training or new skills on the part of the user. Pulse oximetry is becoming a standard of practice during general anesthesia in the United States (Eichhorn, 1986). It is also used as an independent monitor in emergency rooms and intensive care units. Other clinical applications of the device include monitoring patients during transport, respiratory monitoring during narcotic administration, and the evaluation of home-oxygen therapy. The pulse oximeter, however, has some limitations; it does not provide an early warning of decreasing arterial oxygen tension (PaO2) and may fail to detect an inadvertent endobronchial intubation in the operating room. It also cannot distinguish more than two hemoglobin species in the blood; thus methemoglobin and carboxyhemoglobin will cause errors in the pulse oximeter saturation (SpO2) if present in large amounts. Artifactual signals created by patient motion or external light may also create a technical problem and interfere with the device in estimating the oxygen saturation. It was also reported that circumstances that reduce the amplitude of finger pulsation. Back to Top Date Sent: 4/24/2020 535 these criteria do not imply or guarantee approval. A large number was not related to home monitoring of oxygen saturation, and a few addressed the home use of pulse oximetry for the diagnosis of sleep apnea. The search did not reveal any empirical study conducted among adults with chronic obstructive lung disease using a home pulse oximeter to monitor their oxygen saturation. The search revealed three small case series conducted among either healthy infants to assess their oxygen saturation during the first six months or among infants with bronchopulmonary dysplasia receiving home oxygen therapy. The use of home pulse oximetry in the management of oxygen levels for adults or children with respiratory failure or chronic pulmonary disease does not meet the Kaiser Permanente Medical Technology Assessment Criteria. Back to Top Date Sent: 4/24/2020 536 these criteria do not imply or guarantee approval. Background In 1986, Kaiser Foundation Health Plan of Washington experienced an increased use of home oxygen and could find no clinical evidence in patient charts that would support the use of oxygen. In addition, once a patient was placed on home oxygen, they were never re-tested to verify continued need of the treatment. In 1989, a task force was initiated to review use and develop clinical indications for use at Kaiser Permanente. The task force reviewed the current literature and adopted the Medicare home oxygen criteria. In addition, they defined several situations where exceptions would be appropriate. The program was initiated for review of all home oxygen requests, and to set up testing and re-testing programs. Medicare not only approved it, but also adopted several of its most critical features such as the re-testing program. Back to Top Date Sent: 4/24/2020 537 these criteria do not imply or guarantee approval. Back to Top Date Sent: 4/24/2020 538 these criteria do not imply or guarantee approval. Must have complete evaluation and treatment for any underlying peripheral vascular or neuropathic disease. To assess vascular status there must be a documented exam of femoral, popliteal, dorsalis pedis and posterior tibial pulses. Need documentation regarding what specific products have been used, duration, and effectiveness. Back to Top Date Sent: 4/24/2020 539 these criteria do not imply or guarantee approval. Documented evidence of improvement after 24 visits and need for continuing improvement after that point c. Clostridial and non-clostridial myonecrosis: Plan of care indicates use will be in conjunction with other medical/surgical therapies and will not interfere with or delay surgical debridement. Mandibular/maxillary osteoradionecrosis (diagnosis is typically made by a clinical exam with exposed bone, and/or by imaging). History of previous radiation therapy to the mandible or maxilla of at least 5,000-7,000 rads b. Osteoradionecrosis presents some months/years after radiation (sternum, long bones) c. Open or closed crush injury, compartment syndrome, or acute traumatic ischemias (see. Soft tissue radionecrosis as an adjunct to conventional treatment: Typically, bowel, bladder, larynx or wounds in area of prior radiation therapy. Requires visualization of the damaged area with serial exams to monitor progress. Back to Top Date Sent: 4/24/2020 540 these criteria do not imply or guarantee approval. Clinical plan on file from the dentist/oral surgeon detailing planned extractions timeline b. History of at least 5,000-7,000 rads received to the teeth planned for the extraction c. If the initial treatment of 20/10 was delivered within prior 5 years, then only 10 more treatments post extractions are required for any additional extractions done within 5 yrs but not pre extraction) 16. Chronic refractory osteomyelitis, unresponsive to both conventional medical and surgical treatment. Must have a prior infectious disease consultation and surgical consultation regarding debridement. Pelvic bone steomyelitis from decubiti requires debridement and flap surgery and does not respond well to hyperbaric. Background Hyperbaric oxygen therapy consists of placing a patient inside a pressurized chamber in which the patient breathes 100% oxygen under a pressure of greater than one atmosphere.

Estimates of approximately 50 million cases of such infestation is estimated to occur worldwide with 50 erectile dysfunction treatment medscape buy cheap cialis extra dosage 40mg on-line,000 people dying from taeniosis (Wanzala et al impotence 27 years old cheap 60 mg cialis extra dosage free shipping. Cysticerci are found anywhere in the body of the pig impotence young male discount 50mg cialis extra dosage fast delivery, most commonly in the muscle and subcutaneous fat and in the brain (Garcia et al erectile dysfunction muse purchase cialis extra dosage 100 mg. In cattle impotence caused by medication order cialis extra dosage pills in toronto, cysticerci are commonly found in the heart and skeletal muscles herbal erectile dysfunction pills canada order cialis extra dosage 100mg overnight delivery, and are sometimes found in other sites such as the liver, lung, kidneys and lymph nodes (Scandrett 2007). Live cattle having cysticercosis show no symptoms, however, heavy infestations cause myocarditis or heart failure (Wanzala et al. Both bovine and porcine cysticercosis cause economic losses due to condemned, downgraded carcasses and treatment of carcasses before human consumption (Wanzala et al. Although cattle and pigs act as intermediate hosts, humans can also act as intermediate hosts for T. They develop the cystic form either through faecal-oral transmission from contaminated materials (Abuseir et al. Taenia infections are common in environments with poor sanitation, extensive livestock husbandry practices, and inadequate meat inspection, management and control policies 1 | P a g e (Garedaghi et al. Porcine cysticercosis is emerging as a public health and agricultural problem of concern in lesser developed areas (Rajshekhar et al. Development of improved sanitation and hygiene practices have a major impact on the occurrence of cysticercosis in developed countries, and also among urban dwellers in developing countries, because of their effect on the transmission of taeniid eggs (Murrel et al. Public education on the use of latrines and improved standards of human hygiene and avoiding consumption of raw meat are practical measures that can also be practised to prevent transmission of taeniid eggs from infected humans to livestock (Wondimagegnei & Belete 2015; Kumar & Tadesse 2011). Water is regarded as an important factor in the transmission of bovine cysticercosis to a herd and the prevalence and the geographic distribution indicated that a variety of potential risk factors or practices present maintain the cycle of T. Farmers are advised to restrict the access of their cattle to surface drinking water and supply them with fresh water instead. Risk factor studies carried out in a well-defined cattle population, in a well-defined type of farm, in a more limited area and including a more sensitive and specific diagnosis of bovine cysticercosis, using serology. Proper digestion and sanitisation of sludge is a guarantee of a negligible risk for cattle and human health (Cabaret et al. The use of vaccines is an alternative approach for the control of taeniosis and cysticercosis (Flisser & Lightowlers 2001). The vaccine has the potential to be used on a commercial scale for the control of bovine cysticercosis (Lightowlers et al. Paramyosin, also known as B antigen, was identified as a candidate antigen for helminth vaccines and expressed specifically in the metacestode stage of T. The S3P vaccine is expressed recombinantly in M13 filamentous phage (S3Pvac-Phage) and provides high levels of protection against pig cysticercosis under experimental conditions. S3Pvac-Phage significantly reduced the prevalence of cysticercosis among the vaccinated pigs by 54. The efficacy of the S3Pvac-Phage vaccine reported similarly high to that obtained using the synthetic first version of the anti-cysticercosis vaccine (S3Pvac) (Morales et al. In humans, diagnosis of taeniosis is routinely performed by microscopic observation of the morphology of the tapeworm. The sensitivity of this method is low and also lacks specificity due to close similarities in both T. Clear identification is done by examining the morphological features in the scolex and the proglottids of the two parasites. Taenia saginata shows more 4 | P a g e uterine branches in the proglottids than T. Meat inspection alone cannot eradicate the infection because of its low sensitivity which often leads to under-diagnosis, especially in the lightly infected carcasses. Furthermore, the skills and motivation of the meat inspector are important to the success or failure of an inspection. Even though the sensitivity of this method is high in detecting cysticercosis in the heavily infected carcasses, it is not reliable in detecting lightly infected positive carcasses are missed during meat inspection and passed on for human consumption (Minozzo et al. Consequently, meat inspection records tend to underestimate the disease prevalence. Furthermore, during meat inspection there is a possibility 5 | P a g e of mistaken identification of specific taeniid species involved due to cysts having died or degenerated or morphological similarities in lesions caused by taeniid larvae and other tissue parasites such as hydatid cysts and Sarcocystis spp. The majority of cysts (80%) were found on the omentum and the rest on the liver (20 %), all on the visceral surface of the carcasses. In a total of 392 goats and 27 sheep examined by post-mortem, the prevalence of T. The adult parasite has been reported in the small intestines of hosts including dogs, cats, mice and wild carnivores, like the wolf and the fox. The most frequent unusual locations are in the lungs, the kidneys and the brain (Nourani et al. Tongue inspection is also used to detect palpable cysts in pigs at the village level which may indicate porcine cysticercosis, however its low sensitivity reduces its utility as a diagnostic tool (Eshitera et al. The cysticerci presenting white discolouration without distinct proto scolex are considered immature and the ones with proto scolex are matured (Minozzo et al. At week 4, the part of the cysticercus from which the scolex develops begins to evaginate, however there is still no evidence of suckers. At week 12 the larvae have the head retracted into a bladderlike structure and a developing neck (Figure 1. They have gained acceptance as a tool for sero-epidemiological surveys (Onyango-Abuje et al. Although these assays have been reported to be less sensitive in animals infected with fewer cysts, they have been shown to be three times more sensitive than meat inspection (Dorny et al. The other advantage with the serological tests is that they are important tools for epidemiological studies since they can be used on live animals on large scale and the tests are inexpensive and easy to perform (Dorny et al. However, there are disadvantages related to serological tests that include measuring of the antigen exposure rather than actual infection, the interpretation of seropositive results in young pigs may be complicated by the transfer of the maternal antibodies from the sow to piglets (Gonzalez et al. The combined results of the three peptides showed the best balance between sensitivity of (85%) and specificity of (83. The peptide showed the highest sensitivity and specificity of 100 and 95% respectively in meat juices samples. Since the assay can detect twice as many animals as the meat inspection procedure, it was suggested that the assay can be used in the feedlot with herds where an 9 | P a g e exposure to the parasite is expected. However, the test was successful in the naturally heavily infected pigs due to high infection rate compared to the experimentally infected pigs. The assay detected the antigen in serum from 4-5 weeks post-infection onwards and was associated with a current infection. Both antigens and antibodies were detected early and at higher levels in heavily infected pigs than in lightly infected pigs. The two MoAb antibodies of the IgG1 isotype were produced against the secretion and excretion products of T. Similar reactions were obtained in animals harbouring only dead cysticerci and non infected control animals. The test was able to detect circulating antigen also in sheep and pigs, respectively infected with T. The sero-prevalence found in this study was more than 10 11 | P a g e times higher than the annual prevalence (0. The study further indicated that the classical meat inspection techniques detect only a minor fraction of the carcasses infected with cysticerci. A number of molecular assays targeting the mitochondrial cytochrome c oxidase subunit I (cox1) gene were also developed. The assay target cytochrome c oxidase subunit 1 gene with the forward primers specific for T. Coupling of the method with restriction fragment length polymorphism also appeared to be useful for differentiation of geographical isolates of T. The assay was also considered being useful for molecular epidemiological survey of these cestode infections and control of cysticercosis (Yamasaki et al. The use of the cysticerci represented a spectrum of viability and the assay detected 100% of viable and caseated cysts, but failed to detect 1/16 calcified and 2/3 highly degenerated samples. The detection of the tapeworm carriers with the assay was seen as a key factor in controlling the parasite in endemic areas (Praet et al. The limitations of the current meat inspection procedure pose significant challenges for regulators and diagnostic tasked with preventing zoonotic transmission of the parasite. The diagnosis of infected animals is currently carried out in the slaughterhouse by meat inspection. The method is effective in detecting heavily infected carcasses, but not reliable at detecting lightly infected carcasses. During meat inspection, there is also a possibility for mistaken identifications due to cysts having died and degenerated or due to macroscopic morphological similarities in lesions caused by taeniid larvae and other tissue parasites, such as Sarcocystis species. Currently diagnosis of bovine and porcine cysticercosis is mainly by meat inspection which although being useful in detecting cysticercosis in heavily infected carcasses, lightly infected carcasses may be easily missed and passed on for human consumption. As a result, the use of meat inspection records tends to underestimate the disease prevalence. On the other hand, during meat inspection, there is also a possibility for mistaken identifications due to cysts having died and degenerated or due to macroscopic morphological similarities in lesions caused by taeniid larvae and other tissue such as Sarcocystis species (Gonzalez et al. Serological tests have been developed for the detection of specific antibodies or antigens specific to T. Although these assays have been reported to be less sensitive in animals infected with fewer cysts, they have shown to be three to 10 times more sensitive than meat inspection and have been successfully used in the epidemiological surveys (Dorny et al. However, these assays are not species specific which makes it difficult to obtain clear diagnosis of taeniid infections. It is therefore very important to accurately and specifically diagnose the species involved. Accurate diagnosis of infectious diseases is a very important part leading to proper treatment, control and even elimination of the disease. The limitations of the current diagnostic tools create significant challenges for regulators and technicians in preventing zoonotic transmission of the parasites from human to animals and from animals to humans (Gonzalez et al. The pellet was washed with 70% Ethanol twice and mixed and centrifuged at 15 000 rpm for 5 minutes after each wash. The liquid samples were pipetted in the collection tube assemble and spun down at 8 000 x g for 1 minute. Primers for the cox1 gene the Tsag-cox1 F3 and Tsag-cox1 F3 primers were used to amplify the cox1 (238 bp) gene in T. Abattoirs were identified through the assistance of the Free State provincial veterinary services. Geographical coordinates of each determined site were recorded and later used for mapping of specific sites where samples were collected. The supernatant serum from the 5ml venous blood vacutainer was transferred into 1. The Tsag cox1 (F3+B3) and Tsol-cox1 (F3+B3) primers previously designed by (Nkouawa et al. V trans-illuminator of gel documentation system (Bio-Rad Gel Doc) and photographed as described in Appendix 3. Amplification and detection were performed in three step amplifications under the thermal-cycling conditions stated in Table 3. Program Name Cycles Analysis Mode Pre-incubation 1 None 3 step Amplification 45 Quantification Cooling 1 None Table 3. Linear regression was calculated by the LightCycler 96 system Data Analysis software and reactions were performed under conditions explained previously in Tables 3. The increase in fluorescent signal was monitored by the sequence detector as the reaction progressed. Positive samples were defined as those that demonstrated the fluorescent signal above the threshold line and positive reactions were given a cycle threshold Ct value equal to the cycle number where the fluorescence crossed the threshold line. The tongue, diaphragm, heart, masseter muscles of the head and triceps of the foreleg muscles were examined for the presence of the cysts as illustrated in Chapter 1. The samples were collected in the 5ml venous blood vacutainer after slaughtering of the animals and blood was allowed to clot for serum separation. The 50 fil volume of undiluted sera was then added to each well, with each sample running in duplicate.

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Combined deficiency of vitamin B Laboratory Findings 12 12 and folate may occur from severe deficiency of vitamin B12 the investigations of a suspected case of megaloblastic because of the biochemical interrelationship with folate anaemia are aimed at 2 aspects: metabolism. In addition to deficiency of vitamin blood picture, red cell indices, bone marrow findings, and B and folate, megaloblastic anaemias may occasionally be biochemical tests. Based on these principles, the following scheme of investigations is followed: Clinical Features A. General Laboratory Findings Deficiency of vitamin B12 and folate may cause following clinical manifestations which may be present singly or in 1. Esti combination and in varying severity: mation of haemoglobin, examination of a blood film and evaluation of absolute values are essential preliminary 1. Typically, the patient has a smooth, beefy, red concentration may be of a variable degree. Vitamin B12 deficiency, parti cularly in patients of pernicious anaemia, is associated with macrocytosis can also be seen in several other disorders significant neurological manifestations in the form of such as: haemolysis, liver disease, chronic alcoholism, subacute combined, degeneration of the spinal cord and hypothyroidism, aplastic anaemia, myeloproliferative peripheral neuropathy (Chapter 30), while folate deficiency disorders and reticulocytosis. The underlying demonstrates marked anisocytosis, poikilocytosis and pathologic process consists of demyelination of the peripheral presence of macroovalocytes. The reticulocyte count is generally ataxia, poor finger coordination and diminished reflexes. The total white blood cell count may be be decreased and show abnormal morphology such as reduced. Presence of characteristic hypersegmented hypersegmented nuclei and agranular cytoplasm. Prussian blue staining for iron in the blood film should raise the suspicion of megaloblastic marrow shows an increase in the number and size of iron anaemia. Significant findings of marrow blood and marrow investigations and specific tests to examination are as under (Fig. The marrow is hypercellular with following biochemical abnormalities are observed in cases a decreased myeloid-erythroid ratio. Megaloblasts a result of ineffective erythropoiesis causing marrow cell are abnormal, large, nucleated erythroid precursors, breakdown. Special Tests for Cause of Specific Deficiency stains lightly, while the haemoglobinisation of the cytoplasm proceeds normally or at a faster rate i. Megaloblasts with abnormal mitoses laboratories, currently automated multiparametric, may be seen. Features of ineffective erythropoiesis such random access analysers are employed based on separa as presence of degenerated erythroid precursors may be tion techniques by chemiluminescence and enzyme-linked present. The normal Patients with pernicious anaemia have abnormal test range of vitamin B12 in serum is 280-1000 pg/ml. In this test, the serum sample to causing malabsorption, the test is repeated after a course be assayed is added to a medium containing all other of treatment with antibiotics or anti-inflammatory drugs. The medium along with another way of distinguishing whether megaloblastic microorganism is incubated and the amount of vitamin anaemia is due to cobalamine or folate is by serum B12 is determined turbimetrically which is then compared determination of methylmalonic acid and homocysteine with the growth produced by a known amount of vitamin by sophisticated enzymatic assays. Several organisms have been used for this test such cobalamine deficiency, while in folate deficiency there is as Euglena gracilis, Lactobacillus leichmannii, Escherichia coli only elevation of homocysteine and not of methylmalonic and Ochromonas malhamensis. Values of 4 ng/ml or less are generally considered to be diagnostic of folate ii) Radioassay. These tests are more sensitive and have the formerly for assessing folate status but it is less specific advantage over microbiologic assays in that they are and less sensitive than the serum assays. Other pathologic changes are Most cases of megaloblastic anaemia need therapy with secondary to vitamin B deficiency and include 12 appropriate vitamin. This includes: hydroxycobalamin as megaloblastoid alterations in the gastric and intestinal intramuscular injection 1000 fig for 3 weeks and oral folic epithelium and neurologic abnormalities such as acid 5 mg tablets daily for 4 months. Blood transfusion should be avoided the disease has insidious onset and progresses slowly. Packed cells may, clinical manifestations are mainly due to vitamin B12 however, be infused slowly. These include: anaemia, glossitis, neurological Treatment of megaloblastic anaemia is quite gratifying. Reticulo hepatosplenomegaly, congestive heart failure and cytosis appears within 4-5 days after therapy is started and haemorrhagic manifestations. Haemoglobin should rise by 2-3 g/dl each such as autoimmune thyroiditis may be associated. The peripheral neuropathy may show some improvement but subacute combined degeneration of the Diagnostic Criteria spinal cord is irreversible. The condition ii) Megaloblastic anaemia in bone marrow examination, is, therefore, also termed Addisonian megaloblastic anaemia. Minor clinical criteria: by an autoimmune reaction against gastric parietal cells. Reference standard criteria: thyroiditis, vitiligo, diabetes and idiopathic adrenocortical i) Schilling test showing malabsorption of oral cyano insufficiency. Most of the abnormalities due to vitamin B12 deficiency Extravascular haemolysis is more common than the can be corrected except the irreversible damage to the spinal former. Corticosteroid therapy can improve the gastric lesion pathogenesis of various haemolytic anaemias. Acquired haemolytic anaemias caused by a variety of extrinsic environmental factors (extracorpuscular). Hereditary haemolytic anaemias are usually the result of intrinsic red cell defects (intracorpuscular). Haemolytic anaemias are defined as anaemias resulting from an increase in the rate of red cell destruction. These are briefly haemoglobin is not liberated into the plasma in appreciable described below: amounts. However, clinical features common to most congenital and acquired shortening of red cell lifespan does not necessarily result in haemolytic anaemias are as under: anaemia. Positive family history with life-long anaemia in patients causing anaemia to the patient, so-called compensated with congenital haemolytic anaemia. Mild fluctuating jaundice due to unconjugated anaemia may occur by 2 mechanisms: hyperbilirubinaemia. Urine turns dark on standing due to excess of Firstly, the red cells undergo lysis in the circulation and urobilinogen in urine. Splenomegaly is found in most chronic haemolytic In these cases the plasma haemoglobin rises substantially anaemias, both congenital and acquired. In extravascular haemolysis, plasma Pathways by which haemoglobin derived from effete red cells haemoglobin level is, therefore, barely raised. Reticulocyte count reveals reticulocytosis which is generally early and is hence most useful initial test of marrow B. Disorders of red cell interior morphological appearances of red cells described on page 366 and illustrated in Fig. Target cells (Leptocytes) Increased ratio of surface area: volume Thalassaemias Liver disease HbS disease HbC disease 3. Isoimmune haemolytic anaemia in which the antibodies are whenever present, corticosteroid therapy, and in severe cases acquired by blood transfusions, pregnancies and haemolytic blood transfusions. Warm antibodies reactive at body may indicate presence of large quantities of warm temperature and coating the red cells are generally IgG class antibodies in the serum. In more severe cases, haemoglobinaemia and lost resulting in spherical transformation of the red cells haemoglobinuria may be present. It is, thus, the major site of red cell agglutinin disease and paroxysmal cold haemoglobinuria. These cold antibodies are usually directed against the I any apparent cause (idiopathic) but about a quarter of antigen on the red cell surface. Most cold agglutinins affect usual clinical features are as follows: juvenile red blood cells. It is seen In each type of drug-induced immunohaemolytic 313 in the course of certain infections. Mycoplasma anaemia, discontinuation of the drug results in gradual pneumonia, infectious mononucleosis) and in lymphomas. Cyanosis affecting the cold exposed regions such as tips characterised by red cell fragmentation (schistocytosis). Direct external trauma to red Treatment consists of keeping the patient warm and blood cells when they pass through microcirculation, espe treating the underlying cause. Low reticulocyte count since young red cells are affected grafts develop haemolysis. IgM class cold antibody small vessels may occur in the following conditions: has specificity for I antigen, while the rare IgG class i) Abnormalities of the vessel wall. Drugs may cause immunohaemolytic anaemia by 3 different iii) Haemolytic-uraemic syndrome. A small All these conditions are described in relevant sections proportion of patients receiving fi-methyl dopa develop separately. Bartonellosis by direct infection of red cells by the proteins to which an antibody forms. Septicaemia with Clostridium welchii by damaging the red red blood cells or platelets. Normally, the spleen acts as a filter peripheral blood showing numerous ring stages and a crescent of and traps the damaged red blood cells, destroys them and gametocyte. Other microorganisms such as pneumococci, staphylococci splenomegaly exaggerates the damaging effect to which the and Escherichia coli. Lead poisoning shows basophilic stippling of red blood therapy relieves the anaemia as well as improves the cells. There are 3 important types of disease of the cell membrane while normal clone also inherited red cell membrane defects: hereditary continues to proliferate. The defect is a mutation in the stem spherocytosis, hereditary elliptocytosis (hereditary cells affecting myeloid progenitor cells that is normally ovalocytosis) and hereditary stomatocytosis. Thus, as a result of mutation, Hereditary spherocytosis is a common type of hereditary there is partial or complete deficiency of anchor protein. Out haemolytic anaemia of autosomal dominant inheritance in of about 20 such proteins described so far, the lack of two of which the red cell membrane is abnormal. C, this results in spherical contour and small size so as to contain the given volume of haemoglobin in the deformed red cell. D, During passage through the spleen, these rigid spherical cells lose their cell membrane further. This produces a circulating subpopulation of hyperspheroidal spherocytes while splenic macrophages in large numbers phagocytose defective red cells causing splenomegaly. The usual haematological Mutation in spectrin by recessive inheritance called fifispectrin and biochemical findings are as under: causes more severe form of anaemia, while mutation by 1. About half the cases of hereditary erythrocytes in the form of microspherocytes (Fig. Osmotic fragility test is helpful in testing the spheroidal with more common dominant inheritance pattern have nature of red cells which lyse more readily in solutions of milder anaemia. Autohaemolysis test is similar to osmotic fragility test after such unstable membrane but with normal volume, when incubation and shows increased spontaneous released in circulation, lose their membrane further, till they autohaemolysis (10-15% red cells) as compared to normal can accommodate the given volume. Autohaemolysis is correctable by of spheroidal contour and smaller size of red blood cells, addition of glucose. This produces a Spherocytes may also be seen in blood film in acquired subpopulation of hyperspheroidal red cells in the peripheral immune haemolytic anaemia and following red cell blood which are subsequently destroyed in the spleen. The disorder may be clinically apparent at any age from infancy to old age and has equal Hereditary Elliptocytosis (Hereditary Ovalocytosis) sex incidence. The major Hereditary elliptocytosis or hereditary ovalocytosis is another clinical features are as under: autosomal dominant disorder involving red cell membrane 1. The disorder is similar in all unconjugated (indirect) bilirubin in the plasma (also termed respects to hereditary spherocytosis except that the blood congenital haemolytic jaundice). Pigment gallstones are frequent due to increased bile disorder than hereditary spherocytosis. Splenectomy offers the only reliable Acquired causes of elliptocytosis include iron deficiency mode of treatment.

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