Innopran XL

Thomas Norton Denny

• Professor in Medicine
• Research Professor of Global Health
• Member of the Duke Human Vaccine Institute

https://medicine.duke.edu/faculty/thomas-norton-denny

The clinical description established a strong temporal relationship between administra tion of the vaccine and the anaphylactic reaction heart attack vs angina generic 80mg innopran xl fast delivery. The committee assesses the mechanistic evidence regarding an asso ciation between meningococcal vaccine and anaphylaxis as strong based on one case presenting temporality and clinical symptoms consistent with anaphylaxis heart attack 5 stents buy online innopran xl. Weight of Epidemiologic Evidence the epidemiologic evidence is insuffcient or absent to assess an association between meningococcal vaccine and chronic headache pulse pressure vs heart rate purchase innopran xl uk. Mechanistic Evidence the committee did not identify literature reporting clinical blood pressure 14090 buy discount innopran xl on line, diagnostic blood pressure quick fix discount 40 mg innopran xl fast delivery, or experimental evidence of chronic headache after administration of me ningococcal vaccine pulse blood pressure monitor innopran xl 40 mg low cost. Weight of Mechanistic Evidence the committee assesses the mechanistic evidence regarding an as sociation between meningococcal vaccine and chronic headaches as lacking. Adverse Effects of Vaccines: Evidence and Causality 611 Copyright National Academy of Sciences. Immunization of 2-month-old infants with protein-coupled oligosaccharides derived from the capsule of hemophilus-infuenzae type-B. Safety data on meningococcal polysac charide vaccine from the Vaccine Adverse Event Reporting System. Monitoring of adverse events during the 2003 mass vac cination campaign with a trivalent meningococcal A/C/W135 polysaccharide vaccine in Burkina Faso. Preparation and immunochemical properties of the group A, group B, and group C meningococcal polysaccharides. Quantitative determination of human immune-response to immunization with meningococcal vaccines. The effect of variation in molecular weight on the antigenicity of dextran in man. The control of meningo coccic meningitis epidemics by active immunization with meningococcus soluble toxin further studies. Surveillance of adverse effects during a vaccination campaign against meningitis C. Prevention of systemic infections, especially meningitis, caused by Haemophilus infuenzae type B: Impact on public health and implications for other polysaccharide-based vaccines. The changing epidemiology of meningococcal disease in the United States 1992-1996. Correlation be tween antipolysaccharide and the antibody which protects mice against infection with type-I meningococci. Risk of serious neurologic disease after immunization of young children in Britain and Ireland. Adverse Effects of Vaccines: Evidence and Causality 12 Injection-Related Adverse Events the adverse events in this chapter were considered by the committee as potential consequences associated with direct trauma from the adminis tration of various injected vaccines and not necessarily attributable to the contents of the vaccine. Eight publications de scribed cases that did not provide evidence beyond temporality (Bensasson et al. Described below are publications reporting clinical, diagnostic, or ex perimental evidence that contributed to the weight of mechanistic evidence. Case 2 de scribed a 12-year-old girl presenting with swelling, decreased temperature, discoloration, and loss of function of the left arm lasting for 1 week. Symp tom onset developed 30 minutes after receiving the frst dose of a hepatitis B vaccine in the left deltoid muscle. The same symptoms developed within minutes and lasted for 1 week after administration of the second dose of a hepatitis B vaccine in the right arm. The patient was afficted by two ad ditional episodes developing spontaneously; one involved the development of an urticarial rash and pain in the left foot, the second involved swell ing, pallor, coolness, and pain in the left arm and hand. Case 4 describes a 12-year-old girl presenting with discoloration, swelling, and the inability to clench the fngers of the right hand 15 minutes after receiving the frst dose of a hepatitis B vaccine in the right deltoid muscle. Subsequent pertussis vaccines were withheld and the patient tolerated other vaccinations without incident. Each participant received saline, and three concentrations of norepinephrine were administered via intradermal injection twice each. One series of injections was administered on the unaffected extremity in the mirror image region to the area on the affected extremity. Subsequently, the same series of injections were administered on the affected extremity, and the participants rated pain to each of the injections. None of the concentrations of norepinephrine elicited pain in the normal participants. In contrast, the two highest concentrations of nor epinephrine elicited signifcant pain in comparison to saline when injected in the affected extremity. Mailis-Gagnon and Bennett (2004) conducted a study using normal Copyright National Academy of Sciences. Intradermal injection of a placebo or 1 percent solution of phen ylephrine were administered to the forearm, shin of the lower leg, or the suprapatellar area of the upper leg. This is supported by controlled studies, not using vaccines, conducted by Ali and colleagues (2000) and Mailis-Ganon and Bennett (2004) in which pain was elicited after injection of norepinephrine and phenylephrine. The study investigated the occurrence of bursitis/synovitis/tenosynovitis (reported as outpatient clinic visits, emer gency room visits, and hospitalizations) after receipt of hepatitis A vaccine from April 1997 through December 1998. The risk period for outpatient clinic visits and emergency room visits was defned as 30 days after vaccination, whereas the risk period for hospitalizations was defned as 60 days after vaccina tion. The two age groups (children and adults) and events following a frst dose and second dose of hepatitis A vaccine were evaluated separately. The authors only reported statistically signifcant associations in the article, and only one analysis was listed. The relative risk of an emergency room visit for bursitis/synovitis/tenosynovitis within 30 days of administration of a sec ond dose of hepatitis A vaccine among patients aged 18 years was 0. The authors did not observe a consistent protective effect between the administration of hepatitis A vaccine (frst or second dose) and bursitis/synovitis/tenosynovitis for either age group in the three defned settings. Weight of Epidemiologic Evidence the committee has limited confdence in the epidemiologic evi dence, based on one study that lacked validity and precision, to assess an association between the injection of a vaccine and deltoid bursitis. Black and col leagues (2004) identifed cases of bursitis/synovitis/tenosynovitis developing Copyright National Academy of Sciences. Therefore, this publication did not contribute to the weight of mechanistic evidence. Out of the women, eight received an infuenza vaccine, two received a tetanus reduced diphtheria vaccine, and one received a human papillomavirus vac cine. The two men received tetanus, reduced diphtheria, and reduced per tussis vaccine. The onset of pain in the shoulder developed immediately or within 24 hours after vaccination in 54 percent and 93 percent of the cases respectively. Limited and painful range of motion was the most common fnding, whereas weakness, tingling, and numbness were uncommon. In addition, 15 percent of the cases were found to have complete rotator cuff tears. The patient reported similar symptoms accompanied by an inability to raise the arm laterally for more than 1 year after administration of an infuenza vaccine 5 years earlier. Weight of Mechanistic Evidence the publications, described above, presented clinical evidence suff cient for the committee to conclude that the injection of a vaccine was a contributing cause of deltoid bursitis. The committee assesses the mechanistic evidence regarding an as sociation between the injection of a vaccine and deltoid bursitis as strong based on 16 cases presenting defnitive clinical evidence. Weight of Epidemiologic Evidence the epidemiologic evidence is insuffcient or absent to assess an association between the injection of a vaccine and syncope. Mechanistic Evidence the committee identifed 29 publications reporting syncope or syncopal seizure after receipt of an injection. Described below are 12 publications reporting clinical, diagnostic, or experimental evidence that contributed to the weight of mechanistic evidence. The authors identifed cases of syn cope developing within 2 hours after vaccination. The authors identifed 29 cases of syncope or syncopal seizure developing after vaccination. Two participants experienced a vasovagal episode within 30 minutes after receiving a meningococcal vaccine. The authors identifed 10 cases of seizures or tonic-clonic movements during syncope. An 11-year-old boy presented with loss of consciousness, hypotension, bradypnea, and bradycardia 3 minutes after vaccination. The patient had a similar episode 4 months later after receiving a measles, mumps, and rubella vaccine. The authors identifed 697 reports of syncope developing within 12 hours after vaccination. Of the 697 reports 323 oc curred within 5 minutes, 454 occurred within 15 minutes, 500 occurred within 30 minutes, and 511 occurred within 1 hour after vaccination. Case 1 describes a 17-year-old boy who developed syncope 10 min utes after receiving tetanus-diphtheria and measles, mumps, and rubella vaccines. The patient suffered a linear skull fracture and bilateral fronto temporal contusions. Case 2 describes a 12-year-old boy who developed syncope 10 to 15 minutes after receiving a measles, mumps, and rubella vaccine. Case 3 describes a 26-year-old man who developed syncope less than 3 minutes after receiving tetanus-diphtheria and measles, mumps, and rubella vaccines. The patient suffered a linear nondepressed skull fracture and contusions of the frontal and temporal regions. Depression and cognitive defcits continued through a follow-up 2 years after injury. Case 4 describes a 28-year-old man who developed syncope within 1 minute after receiving a measles vaccine. The patient suffered from a subdural and epidural hematoma compressing the right lateral ventricle. The patient experienced months of cognitive, behav ioral, speech, and language problems after the injury. Case 5 describes a 15-year-old boy who developed syncope less than 10 minutes after receiv ing a tetanus-diphtheria vaccine. The patient suffered a massive cerebral hemorrhage from a lacerated middle meningeal artery. Case 6 describes an 18-year-old girl who developed syncope 5 minutes after receiving a tetanus-diphtheria vaccine. The patient suffered a skull fracture, cerebral contusions, and a right frontal hematoma. Miller and Woo (2006) describe a teenage boy who experienced vaso vagal syncope a few minutes after receiving the third dose of a hepatitis B vaccine. Upon regaining consciousness the patient developed seizures and cardiopulmonary arrest after complaining of pain in the chest and arms. Frontal lobe contusions, edema, and cerebral hemorrhage were ob served during autopsy. Syncope developed on the same day of vaccination in 90 percent of the cases reporting a time interval be tween the onset of symptoms and vaccination. Fifty percent of the cases occurring on the day of vaccination developed within 15 minutes after vac cination. Of the 1, 896 reports of syncope, 293 resulted in a fall of which 200 resulted in a head injury. The patient developed syncope, which resolved without complications, immediately after receiving a dose of the quadriva lent human papillomavirus vaccine. Weight of Mechanistic Evidence the publications described above presented clinical evidence suffcient for the committee to conclude that the injection of a vaccine was a con tributing cause of syncope. The clinical descriptions provided in many publications establish a strong temporal relationship between injection of a vaccine and development of syncope. Furthermore, the prodromal symptoms, including dizziness and pallor, described in some publications, are consistent with those developing before vasovagal syncope. Also, one patient experienced a decreased heart rate seconds after venipuncture and before fainting suggesting vasovagal syncope. This patient developed two additional episodes of syncope after injection of two different vaccines, sug gesting that the injection, and not the contents of the vaccine, contributed to the development of syncope. The committee assesses the mechanistic evidence regarding an as sociation between the injection of a vaccine and syncope as strong based on 35 cases1 presenting defnitive clinical evidence. Adverse Effects of Vaccines: Evidence and Causality 625 Copyright National Academy of Sciences. Intradermal injection of norepinephrine evokes pain in patients with sympathetically maintained pain. Clinical trial and post-licensure safety profle of a prophylactic human papillomavirus (types 6, 11, 16, and 18) L1 virus-like particle vaccine. Adverse events following immunisation associated with the 1998 Aus tralian measles control campaign. Impact of unfounded vaccine safety concerns on the nationwide measles-rubella immunization campaign, Georgia, 2008. Safety, tolerability, and immunogenicity of Gardasil given concomitantly with Menactra and Adacel.

Value of debridement and irrigation for the treatment of peri-prosthetic infections arrhythmia in 7 year old purchase innopran xl without a prescription. Use of rifampicin and ciprofloxacin combination therapy after surgical debridement in the treatment of early manifestation prosthetic joint infections heart attack jogging buy generic innopran xl on-line. Infected total hip arthroplasty treated by an irrigation-debridement/component retention protocol blood pressure of 12080 cheap 80mg innopran xl with visa. Suction drainage culture as a guide to effectively treat musculoskeletal infection heart attack enzyme order innopran xl 40 mg with mastercard. A large multicenter study of methicillin susceptible and methicillin-resistant Staphylococcus aureus prosthetic joint infections managed with implant retention blood pressure jnc purchase innopran xl canada. Outcome of acute prosthetic joint infections due to gram-negative bacilli treated with open debridement and retention of the prosthesis hypertension classification jnc 7 buy generic innopran xl 80 mg on line. Efficacy of debridement in hematogenous and early post-surgical prosthetic joint infections. Role of rifampin for treatment of orthopedic implant-related staphylococcal infections: a randomized controlled trial. Comparison of a low-pressure and a high pressure pulsatile lavage during debridement for orthopaedic implant infection. Aggressive early debridement for treatment of acutely infected cemented total hip arthroplasty. Multiple irrigation, debridement, and retention of components in infected total knee arthroplasty. Perioperative antibiotics should not be withheld in proven cases of periprosthetic infection. Prosthesis retention, serial debridement, and antibiotic bead use for the treatment of infection following total joint arthroplasty. Implantation of resorbable gentamicin sponges in addition to irrigation and debridement in 34 patients with infection complicating total hip arthroplasty. The treatment of experimental osteomyelitis by surgical debridement and the implantation of calcium sulfate tobramycin pellets. Switching to oral regimens, if possible, lowers the financial burden on patients and payers, reduces the risks of vascular access, and increases the 287 possibility of home-based therapy. Question 3: What is the ideal length of antibiotic treatment following removal of the infected implant Decreasing the time of antibiotic regimens reduces cost and development of resistance 8-16 and complications inherent to a single or combined therapy. Unfortunately, improved clinical signs during antibiotic therapy alone do not reliably predict eradication of infection or determine the length of antibiotic therapy. Consensus: There is no conclusive evidence supporting a holiday period following discontinuation of antibiotic treatment and prior to reimplantation surgery as a means of ensuring eradication of infection. Delegate Vote: Agree: 74%, Disagree: 22%, Abstain: 4% (Strong Consensus) 30 Justification: Although Bejon et al. In practice, improvement of clinical signs is frequently used as a proxy for infection control and effective antibiotic therapy. However, these improved clinical signs may persist only while such antibiotic therapy is in place and it is desirable to identify persistence of infection before reimplantation. For these reasons, some practitioners feel that, a holiday period of antibiotics prior to reimplantation opens the opportunity for ongoing observation, where stability or clinical improvement could indicate eradication of the infection while deterioration might indicate recurrence. No evidence conclusively supports the need for an ideal length of such a holiday period. Rifampin is not to be used as monotherapy due to its low barrier for development of 36 resistance. It is a significant hepatic enzyme inducer, and as such, increases the metabolism of many important and common drug classes, such as other antibiotics and antifungals, anticoagulants (including warfarin and the 38 oral direct thrombin inhibitors), and immunosuppressants. Consensus: There is no conclusive evidence regarding the best time to start rifampin treatment. Given the potential for development of resistance, it appears prudent to withhold rifampin until 290 bacteremia has cleared and/or primary antibiotic therapy has reached adequate tissue concentrations. Rifampin activity against any isolated pathogen should also be verified around the time of therapy initiation. No evidence is available regarding the ideal length of antibiotic 12, 41-43 17 therapy. Though many practitioners employ it, there is no unanimous recommendation regarding chronic suppressive oral antibiotic therapy in this setting. Question 9: Is there a role for intra-articular local antibiotic treatment after reimplantation Delegate Vote: Agree: 95%, Disagree: 4%, Abstain: 1% (Strong Consensus) 44, 45 Justification: Studies by Whiteside et al. In patients with suspected fungal infection, coverage against common fungi should be considered. Joint aspiration prior to reimplantation may provide useful information regarding the infection status of the joint. If synovial fluid parameters are abnormal (threshold to be determined) then the treating surgeon may decide to delay the reimplantation or subject the patient to further treatment after 19, 49-51 reimplantation. There is also the potential of obtaining peri-articular fluid instead of true articular fluid. There is no evidence that infiltration of saline or sterile fluid into the joint and reaspiration increases the yield of pathogens in culture and no evidence that lavage of the joint has any role in isolation of the infecting organism. Pharmacokinetic considerations in the treatment of methicillin-resistant Staphylococcus aureus osteomyelitis. Perioperative testing for persistent sepsis following resection arthroplasty of the hip for periprosthetic infection. Italian guidelines for the diagnosis and infectious disease management of osteomyelitis and prosthetic joint infections in adults. Emergence of rifampicin resistance during rifampicin-containing treatment in elderly patients with persistent methicillin resistant Staphylococcus aureus bacteremia. Periprosthetic joint infection with negative culture results: clinical characteristics and treatment outcome. Current management of prosthetic joint infections in adults: results of an Emerging Infections Network survey. Question 1: What are the indications and contraindications for one-stage exchange arthroplasty If soft tissue coverage cannot be performed at the time of one-stage exchange arthroplasty, two-stage 7, 17, 18 surgery should be considered. Specific conditions where two-stage exchange may be indicated over one-stage exchange include: 1) patients with systemic manifestations of infection (sepsis); 2) the scenario where infection appears ovious but no organism has been identified; 3) preoperative cultures identifying difficult to treat and antibiotic-resistant organisms; 4) presence of a sinus tract, 5) inadequate and non-viable soft tissue coverage. Although there is variability in the reported rates of success in eradicating infection, a possible increased morbidity and mortality, and variable time periods prior to reimplantation, direct comparisons with one-stage exchange arthroplasty are difficult due to a patient selection bias in 7, 9, 17, 34 the current literature. Delegate Vote: Agree: 87%, Disagree: 9%, Abstain: 4% (Strong Consensus) Justification: There should be ample time to complete antibiotic administration, eradicate infection, repeat the debridement if necessary, and allow for adequate soft tissue preparation in the event of compromised soft tissue coverage. Positive results have been experienced in situations where implantation is conducted within 2-6 weeks of resection, the infecting pathogen is not resistant, and systemic antibiotic administration 7, 18 is ongoing. Patients who underwent two-stage exchange with greater than 6 months between resection and reimplantation experienced no improvement 41 in function when compared to those who were reimplanted within 6 months of resection. Question 4: Is there a difference in cost between one-stage and two-stage exchange arthroplasty If, however, infection is effectively treated without the need for reoperation, one-stage exchange arthroplasty is less expensive than two stage exchange. However, if the results of one-stage and two-stage exchange arthroplasty are comparable, one stage may be preferred due to the advantages of decreased patient morbidity, lower cost, 30, 53 improved mechanical stability of the affected limb, and shorter period of disability. Reinfection rates may be higher when employing a one-stage exchange arthroplasty as compared to a two-stage, However, the cost of additional diagnostic tests and clinical evaluation, coupled with possible reoperation, an analysis that takes into consideration quality 54 adjusted life years highlights the efficacy of a single-stage revision. Reimplantation is appropriate if the infection is adequately controlled following repeat resection, the patient is able to tolerate additional surgery, and such surgery will allow for a functioning joint with adequate soft tissue coverage. Delegate Vote: Agree: 98%, Disagree: 2%, Abstain: 0% (Strong Consensus) Justification: Key factors for the consideration of two-stage exchange are the causative organism, duration and extent of infection, patient willingness and medical fitness to undergo such surgery, and adequate bone stock and viable soft tissues capable of facilitating adequate reconstruction. Involvement of the tibial tuberosity may be an indicator of possible functional failure of two-stage exchange in the knee. The choice between arthrodesis and amputation needs to take into account the clinical situation of the individual and patient preference. Contraindications might apply to non-ambulatory patients or those with extensive medical 2, 7, 17, 18 comorbidity that precludes multiple surgeries. Question 7: If knee arthrodesis is planned for a chronically infected joint, should this be performed in a single stage or two stages Consensus: Knee arthrodesis may be performed as one stage or two stage, but the decision depends on the individual circumstances and the host factors. Thus, inability to perform adequate debridement in one operation should prompt the surgeon to consider two stage arthrodesis of the knee. However, infections due to polymicrobial or resistant organisms have a higher propensity for recurrence of infection and failure when treated 2, 4, 7, 11-18, 40, 71-74 with a one-stage exchange arthroplasty protocol. Delegate Vote: Agree: 98%, Disagree: 1%, Abstain: 1% (Strong Consensus) Justification: Salvage of a failed total joint arthroplasty in the setting of infection with recalcitrant necrotizing fasciitis, resistant organisms, failed arthrodesis, and bone loss is difficult 2, 7, 17, 18, 25, 56, 59, 83, 84 and may not respond to further attempts at reconstruction. Patient outcome with reinfection following reimplantation for the infected total knee arthroplasty. Primary exchange revision arthroplasty for infected total knee replacement: a long-term study. Low relapse with oral antibiotics and two-stage exchange for late arthroplasty infections in 40 patients after 2-9 years. Two-stage exchange knee arthroplasty: does resistance of the infecting organism influence the outcome Two-stage exchange arthroplasty for infected total knee arthroplasty: predictors of failure. The impact of infection after total hip arthroplasty on hospital and surgeon resource utilization. Periprosthetic joint infection: the economic impact of methicillin-resistant infections. Cost analysis of debridement and retention for management of prosthetic joint infection. Infectiological, functional, and radiographic outcome after revision for prosthetic hip infection according to a strict algorithm. Comparison of one and two-stage revision of total hip arthroplasty complicated by infection: a Markov expected-utility decision analysis. Reinfection after prior staged reimplantation for septic total knee arthroplasty: is salvage still possible Failed total knee arthroplasty treated by arthrodesis of the knee using the Ace-Fischer apparatus. Intramedullary fixation for arthrodesis of the knee after infected total knee arthroplasty. Arthrodesis following failed total knee arthroplasty: comprehensive review and meta-analysis of recent literature. Arthrodesis with a short Huckstep nail as a salvage procedure for failed total knee arthroplasty. Above-the-knee amputation after a total knee replacement: prevalence, etiology, and functional outcome. In specific casesone should expand diagnostic testing to include tissue samples for histological examination, especially in cases where there is a high index of clinical 313 suspicion. Resistance of Candida species to fluconazole has been reported in the literature and so susceptibility testing may be requested when resistance to fluconazole is suspected based on isolated species. In none of the studies was the growth medium or the time of incubation further specified. Fungal selective media must be included and should have prolonged incubation according to national laboratory standards. Moulds, especially dimorphic fungi, often grow poorly in typical instrumented blood culture systems. Alternative culture techniques include the lysis centrifugation method, in which the lysed and pelleted blood specimen can be used. Identification of the isolate to species level is mandatory because treatment may differ based on species. Samples from tissues and body fluids can be also investigated using alternative procedures. These techniques have been positively evaluated in some studies, but they are not generally available, and third-party evaluation of their accuracy has not been 14 carried out so far. Extensive and radical intraoperative debridement of all infected and necrotic tissue as well as removal of all cement was emphasized as highly important regarding the outcome. To prevent bacterial superinfection the spacers were impregnated with combined antimicrobial medication (gentamicin and vancomycin, tobramycin and vancomycin, teicoplanin and amphotericin B, vancomycin and amphotericin B, vancomycin, vancomycin and piperacillin, and cefamandole). A systemic antifungal agent was administered in all but one reported patient and the most frequent agents for a systemic treatment were fluconazole and amphotericin B given either orally or intravenously. A combination of antifungal medication or a sequential antifungal therapy with exchange of 1, 3, 8, 13, 15-17, 21, 22, 27-33 medication was present in about 25% of the reported cases. Similar to bacteria in biofilm there is higher resistance of fungi in biofilms, the surgical procedure that decreases the biofilm, and fungal load is probably the most important aspect of the treatment. When voriconazole is chosen, loss of mechanical 3, 18, 27, 29, 34-45 strength should be kept in mind when fabricating spacers. There is no clear evidence for the timing of reimplantation based on laboratory tests. Fungal prosthetic arthritis: presentation of two cases and review of the literature. Successful salvage of a primary total knee arthroplasty infected with Candida parapsilosis. Mucoraceae infections of antibiotic-loaded cement spacers in the treatment of bacterial infections caused by knee arthroplasty. Successful treatment of prosthetic knee Candida glabrata infection with caspofungin combined with flucytosine.

Articles written in languages other than English were translated using Google Translate or a professional translation service heart attack 101 buy innopran xl without a prescription. Decisions from the Vaccine Injury Compensation Program were not reviewed blood pressure medication list a-z generic innopran xl 40mg free shipping, because they are not published in the peer-reviewed medical literature pulse pressure queen generic innopran xl 80 mg. Adverse Effects of Vaccines: Evidence and Causality 41 Copyright National Academy of Sciences blood pressure chart in urdu buy cheap innopran xl 40mg online. Section I contained those articles on which the committee focused its initial review blood pressure water pill discount innopran xl 40mg amex. The frst assessment applies to the weight of evidence from the epide miologic literature; the second applies to the weight of evidence from the biological and clinical (mechanistic) literature blood pressure testing purchase innopran xl 80mg with visa. In assessing the weights of evidence, each individual article (or fndings within an article if more than one outcome or vaccine was studied) was evaluated for its strengths and weaknesses. These weights of evidence are meant to summarize the assessment of the quality and quantity of evidence. The committee then reviewed the two weight-of-evidence assessments in order to make a conclusion about the causal relationship. Epidemiologic Evidence Experimental studies (trials) are generally considered more rigorous than observational studies; controlled studies are generally considered more rigorous than uncontrolled studies. A brief description of major study designs and methodological considerations can be found in Appendix A. Surveillance studies were reviewed, but the absence of a control group lim ited their contribution to the weight of epidemiologic evidence; studies that included individual case descriptions were reviewed for their contribution to the evaluation of mechanistic evidence (discussed in subsequent sections). Small clinical studies that were not controlled for vaccine administration were generally reviewed for contributions to the mechanistic weight of evidence. Studies that were deemed to be very seriously fawed did not contribute to the weight of evidence; they are identifed in the text for completeness but are not discussed in depth. A specifc study could have fewer limitations for some vaccines or some outcomes than for others. Small clinical studies can be well conducted but the number of subjects may be too small to detect most adverse events. Although most effcacy studies include a safety com ponent, the results are often nonspecifc. Studies in which no cases of a specifc adverse event were identifed are uninformative for this review, because if the vaccinated cohort does not include enough cases to approximate background rates, the study is under powered to inform an assessment. The upper limit of the 95% confdence interval will always overlap with the background rate unless the vaccine is protective. Some might use that information as means to approximate an upper limit on risk, but the committee did not see that as its charge (see Chapter 13). The committee was rigorous in assessing the strengths and weaknesses of each epidemiologic study. For many of the conditions and adverse events considered by the committee, the expected incidence and prevalence rates in the general unvaccinated population as well as in unvaccinated but po tentially susceptible subgroups may be very low. Although randomized clinical trials aiming to study vaccine effcacy may provide the most valid, controlled circumstances in which to also study vaccine safety, such trials inevitably enroll too few study par Copyright National Academy of Sciences. Some studies, as will be documented in chapters that follow, reviewed are likely the most meth odologically sound that can be done given the nature of the exposure and the outcomes, even if the studies have some residual limitation due to the challenges that often attend such research. Cochrane reviews, for example, focus on randomized controlled trials, which is an uncommon design in vaccine safety studies. Other efforts focused on evidence for or against a clinical practice or intervention (Guyatt et al. Consequently, the committee adopted key components of these other approaches to develop a summary classifcation scheme that incorporates both the quality and quantity of the individual studies and the consistency of the group of studies in terms of direction of effect. A key concept to these classifcations is confdence, which refers to the confdence the committee has that the true effect lies close to that of the estimate of the average overall effect for the body of evidence. Validity refers to the absence of confounding, selection bias and information or measurement bias. The wider the 95% confdence inter vals, the less statistical power to detect a difference as signifcant. However, the Agency for Healthcare Research and Quality advises the Evidence-based Practice Centers that it has funded to produce evidence reports on important issues in health care to view an evidence base of a single study with caution (Owens et al. Mechanistic Evidence the committee assessed the mechanisms of vaccine adverse events by identifying and evaluating clinical and biological evidence. First, the com mittee looked for evidence in the peer-reviewed literature that a vaccine was or may be a cause of an adverse event in one or more persons (from case reports or clinical studies) in a reasonable time period after the vaccination. Then the committee looked for other information from the clinical and biological (human, animal, or in vitro studies) literature that would provide evidence of a pathophysiological process or mechanism that is reasonably likely to cause the adverse event or to occur in response to specifc im munization. Chapter 3 contains a discussion of the major mechanisms the Copyright National Academy of Sciences. The committee identifed many case reports in the literature describ ing adverse events following vaccination. At a minimum, for a case to factor into the weight-of-evidence assessment, it had to include specifc mention of the vaccine administered, evidence of clinician-diagnosed health outcome, 3 and a specifed and reasonable time interval. As discussed in the next section, however, these three criteria were only necessary but not suffcient to affect the weight of mechanistic evidence. After identifying cases with the three basic elements, the committee looked for evidence in the case descriptions and in other clinical or biological litera ture of a possible operative mechanism(s) that would support a judgment that the vaccination was related to the adverse event. Rechallenge cases, in which an adverse event occurred after more than one administration of a particular vaccine in the same individual, could infuence the weight of evidence. Each rechallenge, however, must meet the same attributes of reasonable latency, documentation of vaccination receipt, and clinician diagnosis of the health outcome. The value for the committee of rechallenge cases is much greater for monophasic conditions (events that typically happen only once, 3On occasion, the case report author describes clinical test results or observations but does not proffer a diagnosis. In these cases, the committee assigned the case report to the health outcome it felt appropriate. For example, most adverse reactions from live virus vaccines would not be expected to occur within hours of vaccination; rather, time must elapse for viral replication. Another factor that affected the weight of evidence was information in the clinical workup that eliminated well-accepted alternative explanations for the condition, thus increasing the possibility that the vaccine could be associated with the adverse event. Another particularly strong piece of evidence in the case description that affected the weight of evidence is isolation of vaccine strain virus from the patient. Evidence from animal studies is also informative if the model of the disease is well established as applicable to humans or if the basic immunol ogy of the vaccine reaction is well understood. In vitro studies can also be informative, but such data must be eyed with skepticism regarding their relationship to the human experience. Specifc examples of relevant clinical or biological information are discussed in Chapter 3 generally and in the vaccine-specifc Chapters 4 through 11. The committee also searched for other appropriate frameworks for evaluating biological evidence as support for causation analyses. Each category includes consideration of the clinical information from case reports and consideration of clinical and experimental evidence from other sources. Evidence consisting only of parallels with the natural infections is never suffcient to merit a conclusion other than the evidence is inadequate to accept or reject a causal relationship. On occasion, the committee determined that at least two cases, taken together, while suggestive, are nonetheless insuffcient for the com mittee to conclude the vaccine may be a contributing cause of the adverse event, based on an overall assessment of attribution in the available cases and clinical, diagnostic, or experimental evidence consistent with relevant biological response to vaccine. The committee then 6The committee considered the clinical manifestations of the natural infection against which the vaccine is directed to be suffcient for a weight of evidence of weak, rather than lacking. As will be discussed in a subsequent section, a mechanism weight of evidence of weak alone is never suffcient to support a causality conclusion other than the evidence is inadequate to accept or reject a causal relationship. Even in the presence of a convincing protective effect of vaccine in epidemiology, studies may not rule out the possibility that the re action is caused by vaccine in a subset of individuals. The committee then established a general framework by which the two streams of evidence (epidemiologic and mechanistic) infuence the fnal causality conclusion. This framework needed to ac commodate the reality that for any given causality conclusion one or both of the types of evidence could be lacking, the two types of evidence could confict, or neither type of evidence might defnitively infuence the causal ity conclusion. The framework also had to accommodate known limitations of both types of evidence. Epidemiologic analyses are usually unable to detect an increased or decreased risk that is small, unless the study population is very large or the difference between the groups. Epidemiologic analyses also cannot identify with cer tainty which individual in a population at risk will develop a given condi tion. These studies also can fail to detect risks that affect a small subset of the population. Mechanistic evidence, particularly that emerging from case reports, occasionally can provide compelling evidence of an association between exposure to a vaccine and an adverse reaction in the individual being studied, but it provides no meaningful information about the degree of risk to the population or even to other individuals who have the same predisposing characteristics. The occurrence rate of the adverse event or condition in the general population cannot be estimated from case reports, 9 nor can one be certain that the risk is homogeneous across potentially vul nerable subgroups within the general population. The framework does not accommodate any information regarding the beneft of the vaccine to either population or individual health. The focus of this particular committee is only on the question of what particular vac cines can cause particular adverse effects. In general, the framework shown in Figure 2-2 illustrates how causality conclusions can be based primarily on epidemiologic evidence, primarily on mechanistic evidence, or on a combination of the two, and that on occa sion expert judgment, such as that provided by the complement of expertise represented on the committee, is needed to weigh uncertain or competing evidence. Adverse Effects of Vaccines: Evidence and Causality 51 Copyright National Academy of Sciences. The framework also allows strong mechanistic evidence, which requires at least one case report in which compelling evidence exists that the vac cine indeed did cause the adverse event, to carry suffcient weight for the committee to conclude the evidence convincingly supports a causal relation ship. The committee considered laboratory-confrmed, vaccine-strain virus isolation compelling evidence to attribute the disease to the vaccine-strain virus and not other etiologies. The committee recognizes that vaccine-strain virus can transiently appear in otherwise sterile spaces after vaccination; however, the committee determined that the accurate detection of vaccine strain virus in symptomatic individuals to be strong evidence that the vaccine caused the symptoms. For most of the specifc causality conclusions in this category, more than one compelling case report existed. The isolated report of one convincing case provides no information about the risk of the adverse effect in the total population of vaccinated individuals compared with unvaccinated individuals. If the one convincing case has an underlying condition that may increase susceptibility to the adverse effect, it might have no relevance to the otherwise not-susceptible population. In all but one of these relationships, the conclusion was based on strong mechanistic evidence with the epidemiologic evidence rated as either limited confdence or insuffcient. A weight of mechanistic evidence of low-intermediate was not suffcient, without concurring epidemiologic evi dence, to support a conclusion favoring acceptance of a causal relationship.

Syndromes

• MRI of the head
• Joint pain
• Primary liver disease
• If you breastfeed, you might reduce colic by allowing the baby to finish the first breast before offering the second. The concentration of breast milk changes during a feeding. At first, the milk is low in calories and fat. But the milk at the end of emptying each breast, called the hindmilk, is far richer and sometimes more soothing. If the baby still seems uncomfortable or is eating too much, then offering only one breast (as often as desired) over a 2 - 3 hour period. This might give the baby more hindmilk.
• Dehydration
• Screening for depression
• Chest x-ray
• You fall and hit your abdomen.

Poliomyelitis may be on the verge of worldwide eradication: only 7 countries remained endemic at end 2002 (Afghanistan pulse pressure 32 purchase innopran xl now, Egypt hypertension benign 4011 buy cheap innopran xl 80mg on line, India hypertension and pregnancy purchase innopran xl 40mg with amex, Niger blood pressure uk purchase 80 mg innopran xl otc, Nigeria hypertension labs discount innopran xl 80 mg otc, Pakistan blood pressure chart during stress test discount innopran xl amex, Somalia). The greatest risks of polio are now on the Indian subcontinent (89% of cases in 2002) and in West Africa (10% of cases in 2002). Although wild poliovirus transmission has ceased in the majority of countries, importation remains a threat. The virus was also found among members of a related religious group in Canada, although no cases occurred. Imported wild poliovirus has recently caused paralytic cases in countries as diverse as Algeria, Bulgaria, Burkina Faso, Georgia, Ghana, the Islamic Republic of Iran, Lebanon, Togo and Zambia. With the exception of rare imported cases, the few cases of poliomyelitis recognized in industrialized countries, until recent changes in immunization policy, were caused by vaccine virus strains. In tropical countries, a less pro nounced seasonal peak occurred in the hot and rainy season. Clusters of susceptible persons, including groups that refuse immunization, minority populations, migrants and other unregistered children, nomads, refugees and urban poor are at high risk. Where sanitation levels are high, pharyngeal spread may be relatively more important. In rare instances, milk, foodstuffs and other materials contaminated with feces have been incriminated as vehicles. No reliable evidence of spread by insects exists; water and sewage are rarely implicated. Poliovirus is demonstrable in throat secretions as early as 36 hours and in feces 72 hours after exposure to infection in both clinical and inapparent cases. The rate of paralysis among infected nonimmune adults is higher than that among nonimmunized infants and young children. Type-specic immunity, apparently of lifelong duration, follows both clinically recognizable and inapparent infections. Second attacks are rare and result from infection with a poliovirus of a different type. Intramuscular injections, trauma or surgery during the incubation period or prodromal illness may provoke paralysis in the affected extrem ity. The signicance of these cases with regard to the possibility of eventually stopping poliomyelitis immunization is under review and studies are in place to look for instances in developing countries. No secondary cases were associated with long-term excretors of vaccine-derived polioviruses. More troublesome have been epidemics of poliomyelitis caused by vaccine-derived polio viruses, which are often recombinants with other neurovirulent enteric viruses capa ble of spreading through populations. These viruses become manifest in non-vaccinated or incompletely vaccinated indi viduals. These campaigns should be conducted during the cool, dry season to achieve maximum effect. On the attainment of a high level of control in a country, targeted house-to-house mop-up immunization campaigns in high-risk areas are recommended to interrupt the nal chains of transmission. With progress towards the international goal of eradica tion, the risk prole of paralytic poliomyelitis is changing, particularly in industrialized and high/middle income coun tries. Results of virus culture of stools, demo graphic information, immunization history, clinical examina tion and examination for residual paralysis after 60 days will be covered in supplemental reports. Nonparalytic cases are also reported to the local health authority, Class 2 (see Reporting). In communities with modern and adequate sewage disposal systems, feces and urine can be discharged directly into sewers without preliminary disinfection. Epidemic measures: In any country, a single case of poliomy elitis must now be considered a public health emergency, requiring an extensive supplementary immunization response over a large geographic area. Disaster implications: Overcrowding of nonimmune groups and collapse of the sanitary infrastructure pose an epidemic threat. Planning a large-scale immunization response must begin immediately and, if epidemiologically appropriate, in coordi nation with bordering countries. Primary isolation of the virus is often best accomplished in a laboratory designated to be part of the Global Polio Eradication Laboratory Network. Once a wild poliovirus is isolated, molecular epidemiology can often help trace the source. An independent international commission has certied that no locally acquired cases of polio have occurred in the Americas since August 1991. Respiratory symptoms are often mild when compared with the extensive pneumonia demonstrable by X-ray examination. Cough is initially absent or nonproductive; when present, sputum is mucopurulent and scant. Pleuritic chest pain and splenomegaly occur infrequently; pulse may be slow in relation to temperature. Encephalitis, myocarditis and thrombophlebitis are occa sional complications; relapses may occur. Although usually mild or moderate, human disease can be severe, especially in untreated elderly persons. Isolation of the infectious agent from sputum, blood or postmortem tissues in mice, eggs or cell culture, under safe laboratory conditions only, conrms the diagnosis. Recovery of the agent may be difficult, especially if the patient has received broad-spectrum antibiotics. Outbreaks occasionally occur in households, pet shops, aviaries, avian exhibits and pigeon lofts. Apparently healthy birds can be carriers and shed the infectious agent, particularly when subjected to stress through crowding and shipping. Imported psittacine birds are the most frequent source of exposure, followed by turkey and duck farms; processing and rendering plants have also been sources of occupational disease. Rarely, person-to-person transmission may occur during acute illness with parox ysmal coughing; these cases may have been caused by the recently described C. Preventive measures: 1) Educate the public to the danger of exposure to infected pet birds. Medical personnel responsible for occupational health in processing plants should be aware that febrile respiratory illness with headache or myalgia among the employees may be psittacosis. Prevent or eliminate avian infections through quarantine and appropriate antibiotics. Tetracyclines can be effective in control ling disease in psittacines and other companion birds if properly administered to ensure adequate intake for at least 30 and preferably 45 days. Infected birds must be treated or destroyed and the area where they were housed thoroughly cleaned and disinfected with a phenolic compound. Control of patient, contacts and the immediate environment: 1) Report to local health authority: Obligatory case report in many countries, Class 2 (see Reporting). If they cannot be killed, ship swab-cultures of their cloacae or droppings to the laboratory in appropriate transport media and shipping containers, in compliance with postal regulations; after the cultures are taken, the birds should be treated with a tetracycline drug. Place in plastic bags, close securely and ship frozen (on dry ice) to nearest laboratory capable of isolating Chlamydia. Erythromycin is an alternative when tetracycline is contrain dicated (pregnancy, children under 9). Epidemic measures: Cases are usually sporadic or conned to family outbreaks, but epidemics related to infected aviaries or bird suppliers may be extensive. In poultry ocks, large doses of tetracycline can suppress, but not elimi nate, infection and thus may complicate investigations. International measures: Compliance with national regula tions to control importation of psittacine birds. There is considerable variation in severity and duration; infections may be inapparent or present as a nonspecic fever of unknown origin. A pneumonitis may be found on X-ray examination, but cough, expectora tion, chest pain and physical ndings in the lungs are not prominent. Acute and chronic granuloma tous hepatitis, which can be confused with tuberculous hepatitis, has been reported. Chronic Q fever manifests primarily as endocarditis and this form of the disease can occur in up to half the people with antecedent valvular disease. Q fever endocarditis can occur on prosthetic or abnormal native cardiac valves; these infections may have an indolent course, extending over years, and can present up to 2 years after initial infection. Other rare clinical syndromes, including neurological syndromes, have been described. The case-fatality rate in untreated acute cases is usually less than 1% but has been reported as high as 2. Recovery of the infectious agent from blood is diagnostic but poses a hazard to laboratory workers. The organism has unusual stability, can reach high concentrations in animal tissues, particularly placenta, and is highly resistant to many disinfectants. It is endemic in areas where reservoir animals are present, and affects veterinarians, meat workers, sheep (and occasionally dairy) workers and farmers. Epidemics have occurred among workers in stockyards, meatpacking and rendering plants, laboratories and in medical and veterinary centers that use sheep (especially pregnant ewes) in research. Transovarial and transstadial transmission are common in ticks that participate in wildlife cycles in rodents, larger animals and birds. Infected animals, including sheep and cats, are usually asymptomatic, but shed massive numbers of organisms in placental tissues at parturition. Airborne particles containing organisms may be carried downwind for a distance of one kilometer or more; contamination also occurs through direct contact with infected animals and other contaminated materials, such as wool, straw, fertilizer and laundry. Raw milk from infected cows contains organisms and may be responsible for some cases. Immunity following recov ery from clinical illness is probably lifelong, with cell-mediated immunity lasting longer than humoral. Preventive measures: 1) Educate persons in high risk occupations (sheep and dairy farmers, veterinary researchers, abbatoir workers) on sources of infection and the necessity for adequate disinfec tion and disposal of animal products of conception; restrict access to cow and sheep sheds, barns and laboratories with potentially infected animals, and stress the value of inactiva tion procedures such as pasteurization of milk. It should also be considered for abattoir workers and others in hazardous occupations, including those carrying out medical research with pregnant sheep. To avoid severe local reactions, vaccine administra tion should be preceded by a skin sensitivity test with a small dose of diluted vaccine; vaccine should not be given to individuals with a positive skin or antibody test or a docu mented history of Q fever. This should include a baseline serum evaluation, followed by periodic evaluations. Animals used in research should also be assessed for Q fever infection through serol ogy. Laboratory clothes must be appropriately bagged and washed to prevent infection of laundry personnel. Sheep holding facilities should be away from populated areas and measures should be implemented in order to prevent air ow to other occupied areas; no casual visitors should be permit ted. Use precautions at postmortem examination of suspected cases in humans or animals. Chronic disease (endocarditis): Doxycycline in combination with hydroxy chloroquine for 18 to 36 months. Surgical replacement of the infected valve may be necessary in some patients for hemo dynamic reasons.

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